Patterns of inheritance

Patterns of Inheritance

Concept Outline
Mendel solved the mystery of heredity.
Early Ideas about Heredity: The Road to Mendel. Before
Mendel, biologists believed in the direct transmission of traits.
Mendel and the Garden Pea. Mendel, a monk, experimented
with heredity in edible peas, as had many others, but he
counted his results.
What Mendel Found. Mendel found that contrasting traits
segregated among second-generation progeny in the ratio 3:1.
Mendel's Model of Heredity. Mendel proposed that
information rather than the trait itself is inherited, with each
parent contributing one copy.
How Mendel Interpreted His Results. Mendel found that
one alternative of a trait could mask the other in
heterozygotes, but both could subsequently be expressed in
homozygotes of future generations.
Mendelian Inheritance Is Not Always Easy to Analyze.
A variety of factors can disguise the Mendelian segregation
of alleles.
„
Genes are on chromosomes.
Chromosomes: The Vehicles of Mendelian Inheritance. FIGURE 13.1
Mendelian segregation reflects the random assortment of Human beings are extremely diverse in appearance. The
chromosomes in meiosis. differences between us are partly inherited and partly the result
of environmental factors we encounter in our lives.
Genetic Recombination. Crossover frequency indicates the
physical distance between genes and is used to construct
genetic maps.

13.3 Human genetics follows Mendelian principles. E very living creature is a product of the long evolution-
ary history of life on earth. While all organisms share
this history, only humans wonder about the processes that
Multiple Alleles: The ABO Blood Groups. The human ABO
blood groups are determined by three / gene alleles.
led to their origin. We are still far from understanding
Human Chromosomes. Humans possess 2 3 pairs of
everything about our origins, but we have learned a great
chromosomes, one of them determining the sex. deal. Like a partially completed jigsaw puzzle, the bound-
Human Abnormalities Due to Alterations in Chromosome aries have fallen into place, and much of the internal struc-
Number. Loss or addition of chromosomes has serious ture is becoming apparent. In this chapter, we will discuss
consequences. one piece of the puzzle—the enigma of heredity. Why do
Human Genetic Disorders. Many heritable human disorders groups of people from different parts of the world often
are the result of recessive mutations in genes. differ in appearance (figure 13.1)? Why do the members of
Genetic Counseling. Some gene defects can be detected early a family tend to resemble one another more than they re-
in pregnancy. semble members of other families?

241

heredity.
Early Ideas about Heredity:
The Road to Mendel
As far back as written records go, patterns of resemblance
among the members of particular families have been noted
and commented on (figure 13.2). Some familial features are
unusual, such as the protruding lower lip of the European
royal family Hapsburg, evident in pictures and descriptions
of family members from the thirteenth century onward.
Other characteristics, like the occurrence of redheaded
children within families of redheaded parents, are more
common (figure 13.3). Inherited features, the building
blocks of evolution, will be our concern in this chapter.
Like many great puzzles, the riddle of heredity seems
simple now that it has been solved. The solution was not an
easy one to find, however. Our present understanding is
the culmination of a long history of thought, surmise, and
investigation. At every stage we have learned more, and as
we have done so, the models we use to describe the mecha-
nisms of heredity have changed to encompass new facts.
FIGURE 13.2
Heredity is responsible for family resemblance. Family
Classical Assumption 1: Constancy of Species resemblances are often strong—a .visual manifestation of the
Two concepts provided the basis for most of the thinking mechanism of heredity. This is the Johnson family, the wife and
daughters of one of the authors. While each daughter is different,
about heredity before the twentieth century. The first is
all clearly resemble their mother.
that heredity occurs within species. For a very long time peo-
ple believed that it was possible to obtain bizarre compos-
ite animals by breeding (crossing) widely different species.
The minotaur of Cretan mythology, a creature with the
body of a bull and the torso and head of a man, is one ex-
ample. The giraffe was thought to be another; its scientific
name, Giraffa camelopardalis, suggests the belief that it was
the result of a cross between a camel and a leopard. From
the Middle Ages onward, however, people discovered that
such extreme crosses were not possible and that variation
and heredity occur mainly within the boundaries of a par-
ticular species. Species were thought to have been main-
tained without significant change from the time of their
creation.

Classical Assumption 2: Direct Transmission
of Traits
The second early concept related to heredity is that traits
are transmitted directly. When variation is inherited by off-
spring from their parents, what is transmitted? The ancient
Greeks suggested that the parents' body parts were trans- FIGURE 13.3
mitted directly to their offspring. Hippocrates called this Red hair is inherited. Many different traits are inherited in
type of reproductive material gonos, meaning "seed." human families. This redhead is exhibiting one of these traits.
Hence, a characteristic such as a misshapen limb was the
result of material that came from the misshapen limb of a from the other parts, and the child was formed after the
parent. Information from each part of the body was sup- hereditary material from all parts of the parents' bodies had
posedly passed along independently of the information come together.

242 Part IV Reproduction and Heredity

This idea was predominant until fairly It is worth repeating that the offspring
recently. For example, in 1868, Charles of Koelreuter's crosses were not identical
Darwin proposed that all cells and tissues to one another. Some resembled the hy-
excrete microscopic granules, or "gem- brid generation, while others did not. The
mules," that are passed to offspring, guid- alternative forms of the traits Koelreuter
ing the growth of the corresponding part in was studying were distributed among the
the developing embryo. Most similar theo- offspring. A modern geneticist would say
ries of the direct transmission of hereditary the alternative forms of each trait were
material assumed that the male and female segregating among the progeny of a mat-
contributions blend in the offspring. Thus, ing, meaning that some offspring exhibited
parents with red and brown hair would one alternative form of a trait (for example,
produce children with reddish brown hair, hairy leaves), while other offspring from
and tall and short parents would produce the same mating exhibited a different alter-
children of intermediate height. native (smooth leaves). This segregation of
alternative forms of a trait provided the
clue that led Gregor Mendel to his under-
Koelreuter Demonstrates standing of the nature of heredity.
Hybridization between Species
Taken together, however, these two con-
Knight Studies Heredity in Peas
cepts lead to a paradox. If no variation en-
ters a species from outside, and if the varia- Over the next hundred years, other investi-
tion within each species blends in every gators elaborated on Koelreuter's work.
generation, then all members of a species FIGURE 13.4 Prominent among them were English gen-
should soon resemble one another exactly. The garden pea, Pimm tleman farmers trying to improve varieties
Obviously, this does not happen. Individu- sativum. Easy to cultivate and of agricultural plants. In one such series of
als within most species differ widely from able to produce many distinctive experiments, carried out in the 1790s,
each other, and they differ in characteristics varieties, the garden pea was a T. A. Knight crossed two true-breeding
that are transmitted from generation to popular experimental subject in varieties (varieties that remain uniform
generation. investigations of heredity as long from one generation to the next) of the
How could this paradox be resolved? Ac- as a century before Gregor garden pea, Pisum sativum (figure 13.4).
Mendel's experiments.
tually, the resolution had been provided One of these varieties had purple flowers,
long before Darwin, in the work of the and the other had white flowers. All of the
German botanist Josef Koelreuter. In 1760, progeny of the cross had purple flowers.
Koelreuter carried out the first successful hybridizations Among the offspring of these hybrids, however, were some
of plant species, crossing different strains of tobacco and plants with purple flowers and others, less common, with
obtaining fertile offspring. The hybrids differed in appear- white flowers. Just as in Koelreuter's earlier studies, a trait
ance from both parent strains. When individuals within the from one of the parents disappeared in one generation
hybrid generation were crossed, the offspring were highly only to reappear in the next.
variable. Some of these offspring resembled plants of the In these deceptively simple results were the makings of a
hybrid generation (their parents), but a few resembled the scientific revolution. Nevertheless, another century passed
original strains (their grandparents). before the process of gene segregation was fully appreci-
ated. Why did it take so long? One reason was that early
The Classical Assumptions Fail workers did not quantify their results. A numerical record
of results proved to be crucial to understanding the process.
Koelreuter's work represents the beginning of modern Knight and later experimenters who carried out other
genetics, the first clues pointing to the modern theory of crosses with pea plants noted that some traits had a
heredity. Koelreuter's experiments provided an impor- "stronger tendency1'" to appear than others, but they did not
tant clue about how heredity works: the traits he was record the numbers of the different classes of progeny. Sci-
studying could be masked in one generation, only to ence was young then, and it was not obvious that the num-
reappear in the next. This pattern contradicts the theory bers were important.
of direct transmission. How could a trait that is transmit-
ted directly be latent and then reappear? Nor were the Early geneticists demonstrated that some forms of
traits of Koelreuter's plants blended. A contemporary ac- an inherited trait (1) can disappear in one generation
count stated that the traits reappeared in the third gener- only to reappear unchanged in future generations;
ation "fully restored to all their original powers and (2) segregate among the offspring of a cross; and (3) are
more likely to be represented than their alternatives.
properties."

Chapter 13 Patterns of Inheritance 243

Mendel and the Garden Pea
The first quantitative studies of inheritance were carried
out by Gregor Mendel, an Austrian monk (figure 13.5).
Born in 1822 to peasant parents, Mendel was educated in a
monastery and went on to study science and mathematics
at the University of Vienna, where he failed his examina-
tions for a teaching certificate. He returned to the
monastery and spent the rest of his life there, eventually
becoming abbot. In the garden of the monastery, Mendel
initiated a series of experiments on plant hybridization (fig-
ure 13.6). The results of these experiments would ulti-
mately change our views of heredity irrevocably.

Why Mendel Chose the Garden Pea
For his experiments, Mendel chose the garden pea, the
same plant Knight and many others had studied earlier.
The choice was a good one for several reasons. First, many
earlier investigators had produced hybrid peas by crossing
different varieties. Mendel knew that he could expect to
observe segregation of traits among the offspring. Second,
a large number of true-breeding varieties of peas were
available. Mendel initially examined 32. Then, for further
study, he selected lines that differed with respect to seven
easily distinguishable traits, such as round versus wrinkled
seeds and purple versus white flowers, a characteristic
Knight had studied. Third, pea plants are small and easy to
grow, and they have a short generation time. Thus, one can
conduct experiments involving numerous plants, grow sev-
eral generations in a single year, and obtain results rela-
tively quickly. FIGURE 13.5
A fourth advantage of studying peas is that the sexual or- Gregor Johann Mendel. Cultivating his plants in the garden of a
gans of the pea are enclosed within the flower (figure 13.7). monastery in Brunn, Austria (now Brno, Czech Republic),
The flowers of peas, like those of most flowering plants, con- Mendel studied how differences among varieties of peas were
tain both male and female sex organs. Furthermore, the ga- inherited when the varieties were crossed. Similar experiments
metes produced by the male and female parts of the same had been done before, but Mendel was the first to appreciate the
significance of the results.
flower, unlike those of many flowering plants, can fuse to
form viable offspring. Fertilization takes
place automatically within an individual
flower if it is not disturbed, resulting in
offspring that are the progeny from a
single individual. Therefore, one can ei-
ther let individual flowers engage in
self-fertilization, or remove the flow-
er's male parts before fertilization and
introduce pollen from a strain with al-
ternative characteristics, thus perform-
ing cross-pollination which results in
cross-fertilization.

FIGURE 13.6
The garden where Mendel carried out
his plant-breeding experiments. Gregor
Mendel did his most important scientific
experiments in this small garden in a
monastery.


Mendel's Experimental Design
Mendel was careful to focus on only a few specific differ- Petals
ences between the plants he was using and to ignore the
countless other differences he must have seen. He also had
the insight to realize that the differences he selected to ana-
lyze must be comparable. For example, he appreciated that Anther S
trying to study the inheritance of round seeds versus tall
height would be useless; the traits, like apples and oranges,
are not comparable.
Mendel usually conducted his experiments in three stages: Carpel 9

1. First, he allowed pea plants of a given variety to pro-
duce progeny by self-fertilization for several genera-
tions. Mendel was thus able to assure himself that the
forms of traits he was studying were indeed constant,
transmitted unchanged from generation to genera- FIGURE 13.7
Structure of the pea flower (longitudinal section). In a pea
tion. Pea plants with white flowers, for example,
plant flower, the petals enclose the male anther (containing pollen
when crossed with each other, produced only off- grains, which give rise to haploid sperm) and the female carpel
spring with white flowers, regardless of the number (containing ovules, which give rise to haploid eggs). This ensures
of generations. that self-fertilization will take place unless the flower is disturbed.
2. Mendel then performed crosses between varieties
exhibiting alternative forms of traits. For example,
he removed the male parts from
the flower of a plant that pro-
duced white flowers and fertilized
it with pollen from a purple-
flowered plant. He also carried
out the reciprocal cross, using
pollen from a white-flowered in-
dividual to fertilize a flower on a
pea plant that produced purple
Pollen transferred from white
flowers (figure 13.8). flower to stigma of purple flower
Anthers
3. Finally, Mendel permitted the removed
hybrid offspring produced by
these crosses to self-pollinate for
several generations. By doing so,
he allowed the alternative forms
of a trait to segregate among the
progeny. This was the same ex-
perimental design that Knight
and others had used much earlier.
But Mendel went an important
step farther: he counted the num-
bers of offspring of each type in
each succeeding generation. No
one had ever done that before.
The quantitative results Mendel
obtained proved to be of supreme
importance in revealing the
process of heredity. FIGURE 13.8
How Mendel conducted his experiments. Mendel pushed aside the petals of a white
Mendel's experiments with the flower and cut off the anthers, the source of the pollen. He then placed that pollen onto the
garden pea involved crosses stigma (part of the carpel) of a similarly castrated purple flower, causing cross-fertilization
between true-breeding varieties, to take place. All the seeds in the pod that resulted from this pollination were hybrids of the
followed by a generation or more white-flowered male parent and the purple-flowered female parent. After planting these
of inbreeding. seeds, Mendel observed what kinds of plants they produced. All of the progeny of this cross
had purple flowers.


What Mendel Found intermediate color, as the theory of blending inheritance
would predict. Instead, in every case the flower color of
The seven traits Mendel studied in his experiments pos- the offspring resembled one of their parents. It is custom-
sessed several variants that differed from one another in ary to refer to these offspring as the first filial (filius is
ways that were easy to recognize and score (figure 13.9). Latin for "son"), or FI, generation. Thus, in a cross of
We will examine in detail Mendel's crosses with flower white-flowered with purple-flowered plants, the FI off-
color. His experiments with other traits were similar, and spring all had purple flowers, just as Knight and others
they produced similar results. had reported earlier.
Mendel referred to the trait expressed in the FI plants
as dominant and to the alternative form that was not ex-
The FI Generation
pressed in the FI plants as recessive. For each of the
When Mendel crossed two contrasting varieties of peas, seven pairs of contrasting forms of traits that Mendel ex-
such as white-flowered and purple-flowered plants, the amined, one of the pair proved to be dominant and the
hybrid offspring he obtained did not have flowers of other recessive.

Trait Dominant vs. recessive F2 generation Ratio
Dominant form Recessive form

Flower
color 705 224 3.15:1
Purple White
"
Seed
color
O 6022 2001 3.01:1
Yellow Green

Seed
shape
x -<•' 5474 1850 2.96:1
Round Wrinkled

Pod X 152 2.82:1
428
color ,„=**•'
Green Yellow

Pod
shape </
882 299 2.95:1
Round ' "Constricted

Flower
position
651 207 3.14:1

Axial

Plant
height 787 277 2.84:1

Tall Dwarf

FIGURE 13.9
Mendel's experimental results. This table illustrates the seven pairs of contrasting traits Mendel studied in his crosses of the garden pea
and presents the data he obtained for these crosses. Each pair of traits appeared in the p2 generation in very close to a 3:1 ratio.


The ¥2 Generation
After allowing individual FI plants to mature and self-
pollinate, Mendel collected and planted the seeds from
each plant to see what the offspring in the second filial, or
p2, generation would look like. He found, just as Knight
had earlier, that some p2 plants exhibited white flowers, the
recessive form of the trait. Latent in the FI generation, the
recessive form reappeared among some ¥2 individuals.
Believing the proportions of the F2 types would provide
some clue about the mechanism of heredity, Mendel
counted the numbers of each type among the F2 progeny.
In the cross between the purple-flowered FI plants, he
counted a total of 929 F2 individuals (see figure 13.9). Of
these, 705 (75.9%) had purple flowers and 224 (24.1%) had
white flowers. Approximately /4 of the p2 individuals exhib-
ited the recessive form of the trait. Mendel obtained the
same numerical result with the other six traits he examined:
!
/ of the p2 individuals exhibited the dominant form of the
trait, and 14 displayed the recessive form. In other words,
the dominant: recessive ratio among the p2 plants was al-
ways close to 3:1. Mendel carried out similar experiments
with other traits, such as wrinkled versus round seeds (fig- у 97 y
ure 13.10), and obtained the same result.

FIGURE13.il
A page from Mendel's notebook. In these notes, Mendel is
trying various ratios in an unsuccessful attempt to explain a
segregation ratio disguised by phenotypes that are so similar he
cannot distinguish them from one another.

A Disguised 1:2:1 Ratio
Mendel went on to examine how the F2 plants passed traits
on to subsequent generations. He found that the recessive
К were always true-breeding. In the cross of white-flowered
with purple-flowered plants, for example, the white-
flowered p2 individuals reliably produced white-flowered
offspring when they were allowed to self-fertilize. By con-
trast, only И of the dominant purple-flowered F2 individuals
(i4 of all p2 offspring) proved true-breeding, while 2A were
not. This last class of plants produced dominant and reces-
sive individuals in the third filial (Рз) generation in a 3:1
ratio. This result suggested that, for the entire sample, the
3:1 ratio that Mendel observed in the p2 generation was
really a disguised 1:2:1 ratio: !4 pure-breeding dominant
individuals, 1A not-pure-breeding dominant individuals, and
14 pure-breeding recessive individuals (figure 13.11).

When Mendel crossed two contrasting varieties and
counted the offspring in the subsequent generations, he
found all of the offspring in the first generation
FIGURE 13.10
exhibited one (dominant) trait, and none exhibited the
Seed shape: a Mendelian trait. One of the differences Mendel
other (recessive) trait. In the following generation, 25%
studied affected the shape of pea plant seeds. In some varieties,
were pure-breeding for the dominant trait, 50% were
the seeds were round, while in others, they were wrinkled. As you
hybrid for the two traits and appeared dominant, and
can see, the wrinkled seeds look like dried-out versions of the
25% were pure-breeding for the recessive trait.
round ones.


Mendel's Model of Heredity
From his experiments, Mendel was able to understand four
things about the nature of heredity. First, the plants he
crossed did not produce progeny of intermediate appear-
ance, as a theory of blending inheritance would have pre-
dicted. Instead, different plants inherited each alternative
intact, as a discrete characteristic that either was or was not
visible in a particular generation. Second, Mendel learned
that for each pair of alternative forms of a trait, one alter-
native was not expressed in the FI hybrids, although it
reappeared in some ¥2 individuals. The "invisible" trait
must therefore be latent (present but not expressed) in the
FI individuals. Third, the pairs of alternative forms of the
traits examined segregated among the progeny of a particu-
lar cross, some individuals exhibiting one form of a trait,
some the other. Fourth, pairs of alternatives were expressed
in the ¥2 generation in the ratio of % dominant to К reces-
sive. This characteristic 3:1 segregation is often referred to
as the Mendelian ratio. FIGURE 13.12
To explain these results, Mendel proposed a simple A recessive trait. Blue eyes are considered a recessive trait in
model. It has become one of the most famous models in the humans, although many genes influence eye color.
history of science, containing simple assumptions and mak-
ing clear predictions. The model has five elements:
4. The two alleles, one contributed by the male gamete
1. Parents do not transmit physiological traits directly to and one by the female, do not influence each other in
their offspring. Rather, they transmit discrete infor- any way. In the cells that develop within the new in-
mation about the traits, what Mendel called "factors." dividual, these alleles remain discrete. They neither
These factors later act in the offspring to produce the blend with nor alter each other. (Mendel referred to
trait. In modern terms, we would say that information them as "uncontaminated.") Thus, when the individ-
about the alternative forms of traits that an individual ual matures and produces its own gametes, the alleles
expresses is encoded by the factors that it receives from for each gene segregate randomly into these gametes,
its parents. as described in point 2.
2. Each individual receives two factors that may code for 5. The presence of a particular allele does not ensure mat
the same form or for two alternative forms of the trait. the form of the trait encoded by it will be expressed in
We now know that there are two factors for each trait an individual carrying that allele. In heterozygous indi-
present in each individual because these factors are car- viduals, only one allele (the dominant one) is ex-
ried on chromosomes, and each adult individual is pressed, while the other (recessive) allele is present but
diploid. When the individual forms gametes (eggs or unexpressed. To distinguish between the presence of
sperm), they contain only one of each kind of chromo- an allele and its expression, modern geneticists refer to
some; the gametes are haploid. Therefore, only one fac- the totality of alleles that an individual contains as the
tor for each trait of the adult organism is contained in individual's genotype and to the physical appearance
the gamete. Which of the two factors for each trait of that individual as its phenotype. The phenotype of
ends up in a particular gamete is randomly determined. an individual is the observable outward manifestation
3. Not all copies of a factor are identical. In modern of its genotype, the result of the functioning of the en-
terms, the alternative forms of a factor, leading to alter- zymes and proteins encoded by the genes it carries. In
native forms of a trait, are called alleles. When two other words, the genotype is the blueprint, and the
haploid gametes containing exactly the same allele of a phenotype is the visible outcome.
factor fuse during fertilization to form a zygote, the off-
spring that develops from that zygote is said to be ho- These five elements, taken together, constitute Mendel's
mozygous; when the two haploid gametes contain dif- model of the hereditary process. Many traits in humans
ferent alleles, the individual offspring is heterozygous. also exhibit dominant or recessive inheritance, similar to
In modern terminology, Mendel's factors are called the traits Mendel studied in peas (figure 13.12, table 13.1).
genes. We now know that each gene is composed of a
particular DNA nucleotide sequence (chapter 3). The The genes that an individual has are referred to as its
genotype; the outward appearance of the individual is
particular location of a gene on a chromosome is re-
referred to as its phenotype.
ferred to as the gene's locus (plural, loci).


How Mendel Interpreted His Results flower color. The dominant allele is written in upper case,
as P; the recessive allele (white flower color) is assigned the
Does Mendel's model predict the results he actually ob- same symbol in lower case, p.
tained? To test his model, Mendel first expressed it in In this system, the genotype of an individual that is
terms of a simple set of symbols, and then used the symbols true-breeding for the recessive white-flowered trait
to interpret his results. It is very instructive to do the same. would be designated pp. In such an individual, both
Consider again Mendel's cross of purple-flowered with copies of the allele specify the white-flowered phenotype.
white-flowered plants. We will assign the symbol P to the Similarly, the genotype of a true-breeding purple-flowered
dominant allele, associated with the production of purple individual would be designated PP, and a heterozygote
flowers, and the symbol p to the recessive allele, associated would be designated Pp (dominant allele first). Using
with the production of white flowers. By convention, ge- these conventions, and denoting a cross between two
netic traits are usually assigned a letter symbol referring to strains with x, we can symbolize Mendel's original cross
their more common forms, in this case "P" for purple as pp x PP (figure 13.13).

White Purple
(PP)
, (Pp)

Pp Pp PP Pp

Purple Purple Pp PP
(PP) generation (PP) F2 generation

FIGURE 13.13
Mendel's cross of pea plants differing in flower color. All of the offspring of the first cross (the FI generation) are Pp heterozygotes
with purple flowers. When two heterozygous FI individuals are crossed, three kinds of ¥2 offspring are possible: PP homozygotes (purple
flowers); Pp heterozygotes (also purple flowers); andpp homozygotes (white flowers). Therefore, in the p2 generation, the ratio of
dominant to recessive type is 3:1.

Table Ш
Recessive Traits Phenotypes Dominant Traits Phenotypes

Common baldness M-shaped hairline receding with Middigital hair Presence of hair on middle
age segment of fingers
Albinism Lack of melanin pigmentation Brachydactyly Short fingers
Alkaptonuria Inability to metabolize Huntington's disease Degeneration of nervous
homogenistic acid system, starting in middle age
Red-green color Inability to distinguish red or Phenylthiocarbamide (PTC) Ability to taste PTC as bitter
blindness green wavelengths of light sensitivity
Cystic fibrosis Abnormal gland secretion, Camptodactyly Inability to straighten the
leading to liver degeneration and little finger
lung failure Hypercholesterolemia (the most Elevated levels of blood
Duchenne muscular Wasting away of muscles during common human Mendelian cholesterol and risk of heart
dystrophy childhood disorder—1:500) attack
Hemophilia Inability to form blood clots Polydactyly Extra fingers and toes
Sickle cell anemia Defective hemoglobin that
causes red blood cells to curve
and stick together


The FI Generation
Using these simple symbols, we can now go back and reex-
amine the crosses Mendel carried out. Since a white-flowered
parent (fp) can produce only p gametes, and a pure purple-
flowered (homozygous dominant) parent (PP) can produce
only P gametes, the union of an egg and a sperm from
these parents can produce only heterozygous Pp offspring
in the FI generation (see figure 13.13). Because the P allele
is dominant, all of these FI individuals are expected to
have purple flowers. The p allele is present in these het-
erozygous individuals, but it is not phenotypically ex-
pressed. This is the basis for the latency Mendel saw in re-
cessive traits.

The РЗ Generation
When FI individuals are allowed to self-fertilize, the P and
p alleles segregate randomly during gamete formation.
Their subsequent union at fertilization to form ¥2 individu- (a)
als is also random, not being influenced by which alterna-
tive alleles the individual gametes carry. What will the p2
individuals look like? The possibilities may be visualized in
a simple diagram called a Punnett square, named after its
originator, the English geneticist Reginald Crundall Pun-
nett (figure 13.14). Mendel's model, analyzed in terms of a
Punnett square, clearly predicts that the F2 generation
should consist of % purple-flowered plants and 14 white-
flowered plants, a phenotypic ratio of 3:1.

The Laws of Probability Can
Predict Mendel's Results (b)

A different way to express Mendel's result is to say that FIGURE 13.14
there are three chances in four (%) that any particular ¥2 in- A Punnett square, (a) To make a Punnett square, place the
dividual will exhibit the dominant trait, and one chance in different possible types of female gametes along one side of a
four (14) that an F2 individual will express the recessive trait. square and the different possible types of male gametes along the
Stating the results in terms of probabilities allows simple other, (b) Each potential zygote can then be represented as the
predictions to be made about the outcomes of crosses. If intersection of a vertical line and a horizontal line.
both FI parents are Pp (heterozygotes), the probability that
a particular F2 individual will be pp (homozygous recessive)
is the probability of receiving a p gamete from the male (A)
Mendel's First Law of Heredity: Segregation
times the probability of receiving a p gamete from the fe-
male (A), or 1A. This is the same operation we perform in Mendel's model thus accounts in a neat and satisfying way for
the Punnett square illustrated in figure 13.14. The ways the segregation ratios he observed. Its central assumption—
probability theory can be used to analyze Mendel's results that alternative alleles of a trait segregate from each other in
is discussed in detail on page 272. heterozygous individuals and remain distinct—has since
been verified in many other organisms. It is commonly re-
ferred to as Mendel's First Law of Heredity, or the Law
Further Generations of Segregation. As you saw in chapter 12, the segregational
As you can see in figure 13.13, there are really three kinds behavior of alternative alleles has a simple physical basis, the
of F2 individuals: 14 are pure-breeding, white-flowered indi- alignment of chromosomes at random on the metaphase
viduals (pp); Уг are heterozygous, purple-flowered individu- plate. It is a tribute to the intellect of Mendel's analysis that
als (Pp); and 14 are pure-breeding, purple-flowered individ- he arrived at the correct scheme with no knowledge of the
uals (PP). The 3:1 phenotypic ratio is really a disguised cellular mechanisms of inheritance; neither chromosomes
1:2:1 genotypic ratio. nor meiosis had yet been described.


The Testcross To perform his testcross, Mendel crossed heterozygous
FI individuals back to the parent homozygous for the reces-
To test his model further, Mendel devised a simple and
sive trait. He predicted that the dominant and recessive
powerful procedure called the testcross. Consider a purple-
traits would appear in a 1:1 ratio, and that is what he ob-
flowered plant. It is impossible to tell whether such a plant
served.
is homozygous or heterozygous simply by looking at its
For each pair of alleles he investigated, Mendel observed
phenotype. To learn its genotype, you must cross it with
phenotypic ¥2 ratios of 3:1 (see figure 13.13) and testcross
some other plant. What kind of cross would provide the
ratios very close to 1:1, just as his model predicted.
answer? If you cross it with a homozygous dominant indi-
Testcrosses can also be used to determine the genotype of
vidual, all of the progeny will show the dominant pheno-
an individual when two genes are involved. Mendel carried out
type whether the test plant is homozygous or heterozygous.
many two-gene crosses, some of which we will soon discuss.
It is also difficult (but not impossible) to distinguish be-
He often used testcrosses to verify the genotypes of particular
tween the two possible test plant genotypes by crossing
dominant-appearing p2 individuals. Thus an ¥2 individual
with a heterozygous individual. However, if you cross the
showing both dominant traits (A_ BJ) might have any of the
test plant with a homozygous recessive individual, the two
following genotypes: AABB, AaBB, AABb or AaBb. By crossing
possible test plant genotypes will give totally different re-
dominant-appearing ¥2 individuals with homozygous recessive
sults (figure 13.15):
individuals (that is, A_ B_ x aabb), Mendel was able to deter-
mine if either or both of the traits bred true among the prog-
Alternative 1: unknown individual homozygous (PP). eny, and so to determine the genotype of the ¥2 parent:
PP x pp: all offspring have purple
AABB trait A breeds true trait В breeds true
flowers (Pp)
AaBB trait В breeds true
Alternative 2: unknown individual heterozygous (Pp).
Pp x pp: Уг of offspring have white flow- AAbb trait A breeds true
ers (pp) and И have purple flowers (Pp) AaBb

т Dominant phenotype
(unknown genotype)

if Pp

00
Pp PP

PP PP
Pp PP

Homozygous Homozygous
recessive recessive
(white) All offspring are purple; (white) Half of offspring are white;
therefore, unknown therefore, unknown flower
flower is homozygous is heterozygous

Alternative 1 Alternative 2
FIGURE 13.15
A testcross. To determine whether an individual exhibiting a dominant phenotype, such as purple flowers, is homozygous or
heterozygous for the dominant allele, Mendel crossed the individual in question with a plant that he knew to be homozygous recessive, in
this case a plant with white flowers.


Mendel's Second Law of Heredity:
Independent Assortment
After Mendel had demonstrated that different alleles of a
given gene segregate independently of each other in Round yellow Wrinkled green
seeds (RRYY) seeds (rryy)
crosses, he asked whether different genes also segregate in-
dependently. Mendel set out to answer this question in a
straightforward way. He first established a series of pure-
breeding lines of peas that differed in just two of the seven All round yellow
pairs of characteristics he had studied. He then crossed seeds (RrYy)
contrasting pairs of the pure-breeding lines to create het-
erozygotes. In a cross involving different seed shape alleles
(round, R, and wrinkled, r) and different seed color alleles
Sperm
(yellow, Y, and green, y), all the Fj individuals were identi-
cal, each one heterozygous for both seed shape (Rr) and (RY к rY ry
seed color (Yy). The FI individuals of such a cross are dihy-
F2 generation
brids, individuals heterozygous for each of two genes.
RRYY J RRYy RrYY RrYy
The third step in Mendel's analysis was to allow the di- 9/16 are round yellow
hybrids to self-fertilize. If the alleles affecting seed shape 3/16 are round green
and seed color were segregating independently, then the RRYy RRyy RrYy ^вг
Rryy 3/16 are wrinkled yellow
probability that a particular pair of seed shape alleles Eggs
1/16 are wrinkled green
would occur together with a particular pair of seed color
alleles would be simply the product of the individual prob- RrYY RrYy rrYY rrYy

abilities that each pair would occur separately. Thus, the
probability that an individual with wrinkled green seeds RrYy Rryy rrYy rryy
(rryy) would appear in the ¥2 generation would be equal to
the probability of observing an individual with wrinkled FIGURE 13.16
seeds (/4) times the probability of observing one with green Analyzing a dihybrid cross. This Punnett square analyzes the
seeds (K), or УК,. results of Mendel's dihybrid cross between plants with round
Since the genes concerned with seed shape and those yellow seeds and plants with wrinkled green seeds. The ratio of
concerned with seed color are each represented by a pair the four possible combinations of phenotypes is predicted to be
of alternative alleles in the dihybrid individuals, four types 9:3:3:1, the ratio that Mendel found.
of gametes are expected: RY, Ry, rY, and ry. Therefore, in
the F2 generation there are 16 possible combinations of
alleles, each of them equally probable (figure 13.16). Of These results are very close to a 9:3:3:1 ratio (which
these, 9 possess at least one dominant allele for each gene would be 313:104:104:35). Consequently, the two genes ap-
(signified R Y , where the dash indicates the presence peared to assort completely independently of each other.
of either allele) and, thus, should have round, yellow Note that this independent assortment of different genes in
seeds. Of the rest, 3 possess at least one dominant R allele no way alters the independent segregation of individual pairs
but are homozygous recessive for color (R_yy); 3 others of alleles. Round versus wrinkled seeds occur in a ratio of ap-
possess at least one dominant Y allele but are homozygous proximately 3:1 (423:133); so do yellow versus green seeds
recessive for shape (rrY ); and 1 combination among the (416:140). Mendel obtained similar results for other pairs.
16 is homozygous recessive for both genes (rryy). The hy- Mendel's discovery is often referred to as Mendel's
pothesis that color and shape genes assort independently Second Law of Heredity, or the Law of Independent
thus predicts that the p2 generation of this dihybrid cross Assortment. Genes that assort independently of one an-
will display a 9:3:3:1 ratio: nine individuals with round, other, like the seven genes Mendel studied, usually do so
yellow seeds, three with round, green seeds, three with because they are located on different chromosomes, which
wrinkled, yellow seeds, and one with wrinkled, green segregate independently during the meiotic process of ga-
seeds (see figure 13.16). mete formation. A modern restatement of Mendel's Second
What did Mendel actually observe? From a total of 556 Law would be that genes that are located on different chromo-
seeds from dihybrid plants he had allowed to self-fertilize, somes assort independently during meiosis.
he observed:
Mendel summed up his discoveries about heredity in
315 round yellow (R_Y_) two laws. Mendel's First Law of Heredity states that
108 round green (R yy) alternative alleles of a trait segregate independently; his
101 wrinkled yellow (rrY, ) Second Law of Heredity states that genes located on
different chromosomes assort independently.
32 wrinkled green (rryy)


Mendelian Inheritance Is Not White
Always Easy to Analyze
Mendel's original paper describing his experiments, pub-
lished in 1866, is charming and interesting to read. His ex-
planations are clear, and the logic of his arguments is pre-
sented lucidly. Although Mendel's results did not receive
much notice during his lifetime, three different investiga-
tors independently rediscovered his pioneering paper in
1900, 16 years after his death. They came across it while
searching the literature in preparation for publishing their AAbb ааВВ
own findings, which closely resembled those Mendel had
presented more than three decades earlier.

Modified Mendelian Ratios
In the decades following the rediscovery of Mendel in
1900, many investigators set out to test Mendel's ideas. Ini- Purple
tial work was carried out primarily in agricultural animals
and plants, since techniques for breeding these organisms
were well established. However, scientists attempting to
confirm Mendel's theory often had trouble obtaining the
same simple ratios he had reported. This was particularly AII/AaBb
true for dihybrid crosses. Recall that when individuals het-
erozygous for two different genes mate (a dihybrid cross), FIGURE 13.17
How epistasis affects grain color. The purple pigment found
four different phenotypes are possible among the progeny:
in some varieties of corn is the product of a two-step
offspring may display the dominant phenotype for both biochemical pathway. Unless both enzymes are active (the plant
genes, either one of the genes, or for neither gene. Some- has a dominant allele for each of the two genes, A and B), no
times, however, it is not possible for an investigator to pigment is expressed.
identify successfully each of the four phenotypic classes, be-
cause two or more of the classes look alike. Such situations
proved confusing to investigators following Mendel.
Why Was Emerson's Ratio Modified? When genes act
sequentially, as in a biochemical pathway, an allele ex-
Epistasis pressed as a defective enzyme early in the pathway blocks
the flow of material through the rest of the pathway. This
One example of such difficulty in identification is seen in makes it impossible to judge whether the later steps of the
the analysis of particular varieties of corn, Zevz mays. Some pathway are functioning properly. Such gene interaction,
commercial varieties exhibit a purple pigment called antho- where one gene can interfere with the expression of an-
cyanin in their seed coats, while others do not. In 1918, other gene, is the basis of the phenomenon called epistasis.
geneticist R. A. Emerson crossed two pure-breeding corn The pigment anthocyanin is the product of a two-step
varieties, neither exhibiting anthocyanin pigment. Surpris- biochemical pathway:
ingly, all of the FI plants produced purple seeds.
When two of these pigment-producing FI plants were Enzyme 1 Enzyme 2
crossed to produce an ¥2 generation, 56% were pigment Starting molecule —> Intermediate —> Anthocyanin
(Colorless) (Colorless) (Purple)
producers and 44% were not. What was happening? Emer-
son correctly deduced that two genes were involved in pro- To produce pigment, a plant must possess at least one
ducing pigment, and that the second cross had thus been a good copy of each enzyme gene (figure 13.17). The domi-
dihybrid cross like those performed by Mendel. Mendel nant alleles encode functional enzymes, but the recessive al-
had predicted 16 equally possible ways gametes could com- leles encode nonfunctional enzymes. Of the 16 genotypes
bine with each other, resulting in genotypes with a pheno- predicted by random assortment, 9 contain at least one
typic ratio of 9:3:3:1 (9 + 3 + 3 + 1 = 16). How many of dominant allele of both genes; they produce purple prog-
these were in each of the two types Emerson obtained? He eny. The remaining 7 genotypes lack dominant alleles at ei-
multiplied the fraction that were pigment producers (0.56) ther or both loci (3 + 3 + 1 = 7) and so are phenotypically
by 16 to obtain 9, and multiplied the fraction that were not the same (nonpigmented), giving the phenotypic ratio of 9:7
(0.44) by 16 to obtain 7. Thus, Emerson had a modified that Emerson observed. The inability to score enzyme
ratio of 9:7 instead of the usual 9:3:3:1 ratio. 2 when enzyme 1 is nonfunctional is an example of epistasis.


Continuous Variation
Few phenotypes are the result of the action
of only one gene. Instead, most traits reflect
the action of polygenes, many genes that
act sequentially or jointly. When multiple
genes act jointly to influence a trait such as
height or weight, the trait often shows a
range of small differences. Because all of the
genes that play a role in determining pheno-
types such as height or weight segregate in-
dependently of one another, one sees a gra-
dation in the degree of difference when
many individuals are examined (figure
13.18). We call this graduation continuous 30-
variation. The greater the number of genes
that influence a trait, the more continuous
the expected distribution of the versions of ш
я
that trait. .1
20
~ 1

How can one describe the variation in a Т!
С /
trait such as the height of the individuals in
Number о

figure 13.18я? Individuals range from quite j
о

short to very tall, with average heights
1

more common than either extreme. What
one often does is to group the variation into
categories—in this case, by measuring the 1 1- '
э

heights of the individuals in inches, round-
5 0" 5 У 6 О1
ing fractions of an inch to the nearest whole
Height
number. Each height, in inches, is a sepa- •

rate phenotypic category. Plotting the (Ь)
numbers in each height category produces a
FIGURE 13.18
histogram, such as that in figure 13.18£. Height is a continuously varying trait, (a) This photograph shows the variation in
The histogram approximates an idealized height among students of the 1914 class of the Connecticut Agricultural College.
bell-shaped curve, and the variation can be Because many genes contribute to height and tend to segregate independently of one
characterized by the mean and spread of another, there are many possible combinations of those genes, (b) The cumulative
that curve. contribution of different combinations of alleles to height forms a continuous spectrum
of possible heights—a random distribution, in which the extremes are much rarer
than the intermediate values.
Pleiotropic Effects
Often, an individual allele will have more
than one effect on the phenotype. Such an
allele is said to be pleiotropic. When the pioneering Pleiotropic effects are characteristic of many inherited
French geneticist Lucien Cuenot studied yellow fur in disorders, such as cystic fibrosis and sickle cell anemia,
mice, a dominant trait, he was unable to obtain a true- both discussed later in this chapter. In these disorders,
breeding yellow strain by crossing individual yellow mice multiple symptoms can be traced back to a single gene
with each other. Individuals homozygous for the yellow al- defect. In cystic fibrosis, patients exhibit clogged blood
lele died, because the yellow allele was pleiotropic: one ef- vessels, overly sticky mucus, salty sweat, liver and pancreas
fect was yellow color, but another was a lethal develop- failure, and a battery of other symptoms. All are pleio-
mental defect. A pleiotropic gene alteration may be tropic effects of a single defect, a mutation in a gene that
dominant with respect to one phenotypic consequence encodes a chloride ion transmembrane channel. In sickle
(yellow fur) and recessive with respect to another (lethal cell anemia, a defect in the oxygen-carrying hemoglobin
developmental defect). In pleiotropy, one gene affects molecule causes anemia, heart failure, increased suscepti-
many traits, in marked contrast to polygeny, where many bility to pneumonia, kidney failure, enlargement of the
genes affect one trait. Pleiotropic effects are difficult to spleen, and many other symptoms. It is usually difficult to
predict, because the genes that affect a trait often perform deduce the nature of the primary defect from the range of
other functions we may know nothing about. its pleiotropic effects.


Lack of Complete Dominance Sperm

Not all alternative alleles are fully
dominant or fully recessive in het-
erozygotes. Some pairs of alleles in-
stead produce a heterozygous pheno-
type that is either intermediate
between those of the parents (incom- CRCR
plete dominance), or representative of
both parental phenotypes (codomi-
nance). For example, in the cross of •Eggs
red and white flowering Japanese four
o'clocks described in figure 13.19, all
the FI offspring had pink flowers—
T generation
indicating that neither red nor white
flower color was dominant. Does this All CRCW CRCV
example of incomplete dominance CWCW
argue that Mendel was wrong? Not at F2 generation
all. When two of the FI pink flowers 1:2:1
were crossed, they produced red-,
CRCR:CRCW:CWCW
pink-, and white-flowered plants in a
1:2:1 ratio. Heterozygotes are simply FIGURE 13.19
intermediate in color. Incomplete dominance. In a cross between a red-flowered Japanese four o'clock,
genotype CRCR, and a white-flowered one (CWCW), neither allele is dominant. The
heterozygous progeny have pink flowers and the genotype CRCW. If two of these
Environmental Effects heterozygotes are crossed, the phenotypes of their progeny occur in a ratio of 1:2:1
(red:pink:white).
The degree to which an allele is
expressed may depend on the envi-
ronment. Some alleles are heat-
sensitive, for example. Traits influ-
enced by such alleles are more sensi-
tive to temperature or light than are
the products of other alleles. The
arctic foxes in figure 13.20, for ex-
ample, make fur pigment only when
the weather is warm. Similarly, the
ch allele in Himalayan rabbits and
Siamese cats encodes a heat-sensitive
version of tyrosinase, one of the en- FIGURE 13.20
zymes mediating the production of Environmental effects on an allele. An arctic fox in winter has a coat that is almost white,
melanin, a dark pigment. The ch so it is difficult to see the fox against a snowy background. In summer, the same fox's fur
version of the enzyme is inactivated darkens to a reddish brown, so that it resembles the color of the surrounding tundra. Heat-
at temperatures above about 33°C. sensitive alleles control this color change.
At the surface of the main body and
head, the temperature is above 33°C
and the tyrosinase enzyme is inactive, while it is more A variety of factors can disguise the Mendelian
active at body extremities such as the tips of the ears and segregation of alleles. Among them are gene
tail, where the temperature is below 33°C. The dark interactions that produce epistasis, the continuous
melanin pigment this enzyme produces causes the ears, variation that results when many genes contribute to a
snout, feet, and tail of Himalayan rabbits and Siamese trait, incomplete dominance that produces
cats to be black. heterozygotes unlike either parent, and environmental
influences on the expression of phenotypes.


13.2 .
are on chromes
. • .-.-. -

Chromosomes: The Vehicles
of Mendelian Inheritance
Chromosomes are not the only kinds of structures that seg-
regate regularly when eukaryotic cells divide. Centrioles
also divide and segregate in a regular fashion, as do the mi-
tochondria and chloroplasts (when present) in the cyto-
plasm. Therefore, in the early twentieth century it was by
no means obvious that chromosomes were the vehicles of
hereditary information.

The Chromosomal Theory of Inheritance
A central role for chromosomes in heredity was first sug-
gested in 1900 by the German geneticist Karl Correns, in
one of the papers announcing the rediscovery of Mendel's
work. Soon after, observations that similar chromosomes FIGURE 13.21
paired with one another during meiosis led directly to the Red-eyed (wild type) and white-eyed (mutant) Drosophila.
chromosomal theory of inheritance, first formulated by The white-eyed defect is hereditary, the result of a mutation in a
the American Walter Sutton in 1902. gene located on the X chromosome. By studying this mutation,
Morgan first demonstrated that genes are on chromosomes.
Several pieces of evidence supported Sutton's theory. One
was that reproduction involves the initial union of only two
cells, egg and sperm. If Mendel's model were correct, then
these two gametes must make equal hereditary contribu-
tions. Sperm, however, contain little cytoplasm, suggesting resolved. A single small fly provided the proof. In 1910
that the hereditary material must reside within the nuclei of Thomas Hunt Morgan, studying the fruit fly Drosophila
the gametes. Furthermore, while diploid individuals have melanogaster, detected a mutant male fly, one that differed
two copies of each pair of homologous chromosomes, ga- strikingly from normal flies of the same species: its eyes
metes have only one. This observation was consistent with were white instead of red (figure 13.21).
Mendel's model, in which diploid individuals have two Morgan immediately set out to determine if this new
copies of each heritable gene and gametes have one. Finally, trait would be inherited in a Mendelian fashion. He first
chromosomes segregate during meiosis, and each pair of ho- crossed the mutant male to a normal female to see if red or
mologues orients on the metaphase plate independently of white eyes were dominant. All of the FI progeny had red
every other pair. Segregation and independent assortment eyes, so Morgan concluded that red eye color was domi-
were two characteristics of the genes in Mendel's model. nant over white. Following the experimental procedure
that Mendel had established long ago, Morgan then
crossed the red-eyed flies from the FI generation with each
A Problem with the Chromosomal Theory other. Of the 4252 F2 progeny Morgan examined, 782
However, investigators soon pointed out one problem with (18%) had white eyes. Although the ratio of red eyes to
this theory. If Mendelian traits are determined by genes lo- white eyes in the ¥2 progeny was greater than 3:1, the re-
cated on the chromosomes, and if the independent assort- sults of the cross nevertheless provided clear evidence that
ment of Mendelian traits reflects the independent assort- eye color segregates. However, there was something about
ment of chromosomes in meiosis, why does the number of the outcome that was strange and totally unpredicted by
traits that assort independently in a given kind of organism Mendel's theory—all of the white-eyed p2 flies тоете males!
often greatly exceed the number of chromosome pairs the How could this result be explained? Perhaps it was im-
organism possesses? This seemed a fatal objection, and it possible for a white-eyed female fly to exist; such individu-
led many early researchers to have serious reservations als might not be viable for some unknown reason. To test
about Sutton's theory. this idea, Morgan testcrossed the female FI progeny with
the original white-eyed male. He obtained both white-eyed
and red-eyed males and females in a 1:1:1:1 ratio, just as
Morgan's White-Eyed Fly Mendelian theory predicted. Hence, a female could have
The essential correctness of the chromosomal theory of white eyes. Why, then, were there no white-eyed females
heredity was demonstrated long before this paradox was among the progeny of the original cross?

256 PartlV Reproduction and Heredity

Y chromosome X chromosome with X chromosome with
white-eye gene red-eye gene

Parents

X
Male Female

F1 generation

X
Male Female

F2 generation

FIGURE 13.22
Morgan's experiment demonstrating
the chromosomal basis of sex linkage
in Drosophila. The white-eyed mutant
male fly was crossed with a normal female.
The FI generation flies all exhibited red
eyes, as expected for flies heterozygous for
a recessive white-eye allele. In the ¥2
generation, all of the white-eyed flies
were male.

Sex Linkage chromosome is said to be sex-linked. Knowing the white-
eye trait is recessive to the red-eye trait, we can now see
The solution to this puzzle involved sex. In Drosophila, the
that Morgan's result was a natural consequence of the
sex of an individual is determined by the number of copies
Mendelian assortment of chromosomes (figure 13.22).
of a particular chromosome, the X chromosome, that an
Morgan's experiment was one of the most important in
individual possesses. A fly with two X chromosomes is a fe-
the history of genetics because it presented the first clear
male, and a fly with only one X chromosome is a male. In
evidence that the genes determining Mendelian traits do
males, the single X chromosome pairs in meiosis with a
indeed reside on the chromosomes, as Sutton had pro-
large, dissimilar partner called the Y chromosome. The
posed. The segregation of the white-eye trait has a one-to-
female thus produces only X gametes, while the male pro-
one correspondence with the segregation of the X chromo-
duces both X and Y gametes. When fertilization involves
some. In other words, Mendelian traits such as eye color in
an X sperm, the result is an XX zygote, which develops into
Drosophila assort independently because chromosomes do.
a female; when fertilization involves a Y sperm, the result is
When Mendel observed the segregation of alternative traits
an XY zygote, which develops into a male.
in pea plants, he was observing a reflection of the meiotic
The solution to Morgan's puzzle is that the gene causing
segregation of chromosomes.
the white-eye trait in Drosophila resides only on the X
chromosome—it is absent from the Y chromosome. (We Mendelian traits assort independently because they are
now know that the Y chromosome in flies carries almost no determined by genes located on chromosomes that
functional genes.) A trait determined by a gene on the sex assort independently in meiosis.


Genetic Recombination The chromosomal exchanges Stern demonstrated pro-
vide the solution to the paradox, because crossing over
Morgan's experiments led to the general acceptance of can occur between homologues anywhere along the
Sutton's chromosomal theory of inheritance. Scientists length of the chromosome, in locations that seem to be
then attempted to resolve the paradox that there are more randomly determined. Thus, if two different genes are
independently assorting Mendelian genes than chromo- located relatively far apart on a chromosome, crossing
somes. In 1903 the Dutch geneticist Hugo de Vries sug- over is more likely to occur somewhere between them
gested that this paradox could be resolved only by assum- than if they are located close together. Two genes can be
ing that homologous chromosomes exchange elements on the same chromosome and still show independent as-
during meiosis. In 1909, French cytologist F. A. Janssens sortment if they are located so far apart on the chromo-
provided evidence to support this suggestion. Investigating some that crossing over occurs regularly between them
chiasmata produced during amphibian meiosis, Janssens (figure 13.24).
noticed that of the four chromatids
involved in each chiasma, two
crossed each other and two did not.
He suggested that this crossing of Abnormality at
F! female
chromatids reflected a switch in one locus of
chromosomal arms between the pa- Abnormality at /F] X chromosome
ternal and maternal homologues, in- another locus of ' U
X chromosome
volving one chromatid in each ho-
mologue. His suggestion was not
accepted widely, primarily because
car •~> "*•
it was difficult to see how two chro- No
в ~ f
-s
•
crossing

ou
matids could break and rejoin at ex-
over
actly the same position.

Crossing Over
Later experiments clearly estab- car 1 4
" 4.
car T +

r
~
8 + <~*
lished that Janssens was indeed cor- J LJ
rect. One of these experiments, •
car Q Q
performed in 1931 by American ge- + i
4~-

~-~
neticist Curt Stern, is described in --X.

figure 13.23. Stern studied two sex- Fertilization X
/
/ .."-^^
linked eye traits in Drosophila strains by sperm
whose X chromosomes were visibly from carnation / 1V
F-| male ч

8
abnormal at both ends. He first ex- r-*.
car
p / ^
^ ^I car ^ ^ car
car
)+
amined many flies and identified ^car car
4- -IB + 4- 4-
^ в
those in which an exchange had oc-
curred with respect to the two eye
traits. He then studied the chromo-
v> ] ^
D
Carnation, Normal Carnation
somes of those flies to see if their bar
Bar
X chromosomes had exchanged
arms. Stern found that all of the in-
dividuals that had exchanged eye Parental combinations of Recombinant combinations
both genetic traits and of both genetic traits and
traits also possessed chromosomes chromosome abnormalities chromosome abnormalities
that had exchanged abnormal ends.
The conclusion was inescapable: FIGURE 13.23
genetic exchanges of traits such as Stern's experiment demonstrating the physical exchange of chromosomal arms during
eye color involve the physical ex- crossing over. Stern monitored crossing over between two genes, the recessive carnation eye
change of chromosome arms, a phe- color (car) and the dominant bar-shaped eye (B), on chromosomes with physical peculiarities
nomenon called crossing over. visible under a microscope. Whenever these genes recombined through crossing over, the
Crossing over creates new combina- chromosomes recombined as well. Therefore, the recombination of genes reflects a physical
tions of genes, and is thus a form of exchange of chromosome arms. The "+" notation on the chromosomes refers to the wild-type
genetic recombination. allele, the most common allele for a particular gene.


Using Recombination to Make Genetic Maps Chromosome Location of genes
number
Because crossing over is more frequent between two genes
that are relatively far apart than between two that are close
together, the frequency of crossing over can be used to map
©
the relative positions of genes on chromosomes. In a cross,
the proportion of progeny exhibiting an exchange between Flower color Seed color
two genes is a measure of the frequency of crossover events
between them, and thus indicates the relative distance sepa-
rating them. The results of such crosses can be used to con-
struct a genetic map that measures distance between genes
in terms of the frequency of recombination. One "map
unit" is defined as the distance within which a crossover
event is expected to occur in an average of 1% of gametes.
A map unit is now called a centimorgan, after Thomas
Hunt Morgan.
In recent times new technologies have allowed geneti-
cists to create gene maps based on the relative positions
of specific gene sequences called restriction sequences be-
cause they are recognized by DNA-cleaving enzymes Flower position Pod shape Plant
called restriction endonucleases. Restriction maps, dis- height
cussed in chapter 18, have largely supplanted genetic re-
combination maps for detailed gene analysis because they ©
are far easier to produce. Recombination maps remain
Pod color
the method of choice for genes widely separated on a
chromosome.

The Three-Point Cross. In constructing a genetic map,
one simultaneously monitors recombination among three
or more genes located on the same chromosome, referred
to as syntenic genes. When genes are close enough to-
gether on a chromosome that they do not assort indepen- ©
dently, they are said to be linked to one another. A cross Seed shape
involving three linked genes is called a three-point cross.
Data obtained by Morgan on traits encoded by genes on
FIGURE 13.24
the X chromosome of Drosophila were used by his student
The chromosomal locations of the seven genes studied by
A. H. Sturtevant, to draw the first genetic map (figure
Mendel in the garden pea. The genes for plant height and pod
13.25). By convention, the most common allele of a gene is shape are very close to each other and rarely recombine. Plant
often denoted on a map with the symbol "+" and is desig- height and pod shape were not among the pairs of traits Mendel
nated as wild type. All other alleles are assigned specific examined in dihybrid crosses. One wonders what he would have
symbols. made of the linkage he surely would have detected had he tested
this pair of traits.

FIGURE 13.25
The first genetic map. This map of
the X chromosome of Drosophila was Genetic
prepared in 1913 by A. H. Sturtevant, a Recombination map
student of Morgan. On it he located the Five frequencies
.58 r~ - r
relative positions of five recessive traits traits
у andw 0.010
that exhibited sex linkage by estimating
у Yellow body color v andm 0.030
their relative recombination frequencies v andr 0.269
w White eye color ол т
in genetic crosses. Sturtevant arbitrarily v and w 0.300 -O't
v Vermilion eye color .31 у
chose the position of the yellow gene т Miniature wing v and/ 0.322
as zero on his map to provide a frame r Rudimentary wing w and т 0.327
of reference. The higher the у andm 0.355 .01 — w
recombination frequency, the farther wandr 0.450 0 Г-. У
apart the two genes. с


Analyzing a Three-Point Cross. The first genetic map Table 13.2 summarizes the results Sturtevant obtained.
was constructed by A. H. Sturtevant, a student of Morgan's The parentals are represented by the highest number of
in 1913. He studied several traits of Drosophila, all of which progeny and the double crossovers by the lowest number.
exhibited sex linkage and thus were encoded by genes re- To analyze his data, Sturtevant considered the traits in
siding on the same chromosome (the X chromosome). pairs and determined which involved a crossover event.
Here we will describe his study of three traits: y, yellow
1. For the body trait (y) and the eye trait (w), the first
body color (the normal body color is grey), w, white eye
two classes, [+ +] and [y w], involve no crossovers
color (the normal eye color is red), and min, miniature
(they are parental combinations). In table 13.2, no
wing (the normal wing is 50% longer).
progeny numbers are tabulated for these two classes
Sturtevant carried out the mapping cross by crossing a
on the "body-eye" column (a dash appears instead).
female fly homozygous for the three recessive alleles with a
2. The next two classes have the same body-eye combi-
normal male fly that carried none of them. All of the prog-
nation as the parents, [+ +] and [y w], so again no
eny were thus heterozygotes. Such a cross is conventionally
numbers are entered as recombinants under body-eye
represented by a diagram like the one that follows, in which
crossover type.
the lines represent gene locations and + indicates the nor-
3. The next two classes, [+ w] and [y +], do not have the
mal, or "wild type" allele. Each female fly participating in a
same body-eye combinations as the parent chromo-
cross possesses two homologous copies of the chromosome
somes), so the observed numbers of progeny are
being mapped, and both chromosomes are represented in
recorded, 16 and 12, respectively.
the diagram. Crossing over occurs between these two
4. The last two classes also differ from parental chromo-
copies in meiosis.
somes in body-eye combination, so again the ob-
у TV mm served numbers of each class are recorded, 1 and 0.
P generation 5. The sum of the numbers of observed progeny that
у w mm (Y chromosome) are recombinant for body (y) and eye (TV) is 16 + 12
+ 1, or 29. Since the total number of progeny is 2205,
this represents 29/2205, or 0.01315. The percentage
у in mm
of recombination between у and w is thus 1.315%, or
FI generation
1.3 centimorgans.
females + + +

These heterozygous females, the FI generation, are the To estimate the percentage of recombination between
key to the mapping procedure. Because they are heterozy- eye (TV) and wing (mm), one proceeds in the same manner,
gous, any crossing over that occurs during meiosis will, if it obtaining a value of 32.608%, or 32.6 centimorgans. Simi-
occurs between where these genes are located, produce ga- larly, body (y) and wing (min) are separated by a recombi-
metes with different combinations of alleles for these nation distance of 33.832%, or 33.8 centimorgans.
genes—in other words, recombinant chromosomes. Thus, From this, then, we can construct our genetic map. The
a crossover between the homologous X chromosomes of biggest distance, 33.8 centimorgans, separates the two out-
such a female in the interval between the у and w genes will side genes, which are evidently у and min. The gene w is
yield recombinant y +] and [+ TV] chromosomes, which are between them, near j/.
different combinations than we started with. (In the
parental chromosomes, w is always linked with у and
+ linked with +.)
1.3 32.6
У +
—>

In order to see all the recombinant types that might The two distances 1.3 and 32.6 do not add up to 33.8
be present among the gametes of these heterozygous but rather to 33.9. The difference, 0.1, represents chromo-
flies, Sturtevant conducted a testcross. He crossed female somes in which two crossovers occurred, one between}' and
heterozygous flies to males recessive for all three traits w and another between w and min. These chromosomes do
and examined the progeny. Since males contribute either not exhibit recombination between у and min.
a Y chromosome with no genes on it or an X chromo- Genetic maps such as this are the key tools in genetic
some with recessive alleles at all three loci, the male con- analysis, permitting an investigator reliably to predict how
tribution does not disguise the potentially recombinant a newly discovered trait, once it has been located on the
female chromosomes. chromosome map, will recombine with many others.


It ?S Si
Table 13.2 Я>turtevant s Results
ннщякявнининвн ИИш " ' • . . '
Phenotypes Crossover Types
Number of
Body Eye Wing Progeny Body-Eye Eye- Wing Body-Wing

Parental + + + 758 — — -—
jy TV min 700 -—
+ + ШВ 401 401 401
Single crossover 317 317 317
+ zy гш'и 16 16 16
12 12 — 12
^ + +
Double crossover + ID + 1 1 1 —
j> + тяги 0 0 0 —
TOTAL 2205 29 719 746
Recombination frequency (%) 1.315 32.608 33.832

The Human Genetic Map I Ichthyosis, X-linked
I Placental steroid sulfatase deficiency
,1 Kallmann syndrome
Genetic maps of human chromosomes (figure 13.26) are of /I Chondrodysplasia punctata,
/ I X-linked recessive
great importance. Knowing where particular genes are lo- /"-•s-Y temia
cated on human chromosomes can often be used to tell 'me
Duchenne muscular dystrophy ' smia, X-iinked
whether a fetus at risk of inheriting a genetic disorder actu- Becker muscular dystrophy I
ally has the disorder. The genetic-engineering techniques Chronic granulomatous disease '
described in chapter 18 have begun to permit investigators Retinitis pigmentosa-3 | ' Adrenal hypoplasia

to isolate specific genes and determine their nucleotide se-
quences. It is hoped that knowledge of differences at the
gene level may suggest successful therapies for particular
Norrie disease 1
Retinitis pigrnentosa-2 |
1 Glycerol kinase deficiency

Ornithine transcarbamylase
deficiency

lncontinentia pigmenti
genetic disorders and that knowledge of a gene's location
on a chromosome will soon permit the substitution of nor-
I Wiskott-Aldrich syndrome
Menkes syndrome

| Androgen insensitivity
mal genes for dysfunctional ones. Because of the great po-
Charcot-lvlarie-Tooth neuropathy
tential of this approach, investigators are working hard to PGK defii
Choroideremia
Cleft palate, X-linked
assemble a detailed map of the entire human genome, the Spastic paraplegia, X-linked,
Anhidrotic ectodermal dysplasia | uncomplicated
so-called human genome project, described in chapter 18. Deafness with stapes fixation
Agammaglobulinemia I
Initially, this map will consist of a "library" of thousands of Kennedy disease I PRPS-related gout
small fragments of DNA whose relative positions are Pelizaeus-Merzbacher disease I : Lowe syndrome
known. Investigators wishing to study a particular gene will Alport syndrome
Lesch-Nyhan syndrome
Fabry disease |
first use techniques described in chapter 18 to screen this HPRT-related gout
Immunodeficiency, X-linked, I
library and determine which fragment carries the gene of with hyper IgM
Hunter syndrome
: Hemophilia В
interest. They will then be able to analyze that fragment in Lymphopi
.ymphoprohferative syndrome |
Hemophilia A
detail. In parallel with this mammoth undertaking, the en- Г
G6PD deficiency: favism
Albinism-deafness syndrome I Drug-sensitive anemia
tire genomes of other, smaller genomes have already been Chronic hemolytic anemia
Manic-depressive illness, X-linked
sequenced, including yeasts and several bacteria. Progress Fragile-X syndrome |
Colorblindness, {several forms)
Dyskeratosis congenita
on the human genome is rapid, and the full map is expected TKCR syndrome
Adrenoleukodystrophy
within the decade. Adrenomyeloneuropathy
Ernery-Dreifuss muscular dystrophy
Diabetes insipidus, renal
Myotubular myopathy, X-linked
Gene maps locate the relative positions of different
genes on the chromosomes of an organism. FIGURE 13.26
Traditionally produced by analyzing the relative The human X chromosome gene map. Over 59 diseases have
amounts of recombination in genetic crosses, gene been traced to specific segments of the X chromosome. Many of
maps are increasingly being made by analyzing the sizes these disorders are also influenced by genes on other
of fragments made by restriction enzymes. chromosomes.


endelian principles.

Multiple Alleles: The ABO
Blood Groups Possible alleles from female
/*") or (f] or
A gene may have more than two alleles in a population, and
most genes possess several different alleles. Often, no single
allele is dominant; instead, each allele has its own effect, /Л/.4 JAJB
_0)
and the alleles are considered codominant. СО

A human gene that exhibits more than one codominant ог
о
allele is the gene that determines ABO blood type. This
ш
gene encodes an enzyme that adds sugar molecules to lipids _ш 1A1B fli
_ш
on the surface of red blood cells. These sugars act as recog- "со
nition markers for cells in the immune system and are called _ф
.О

cell surface antigens. The gene that encodes the enzyme, des- 8
о
ignated 7, has three common alleles: IB, whose product adds CL

the sugar galactose; IA, whose product adds galactosamine;
and /', which codes for a protein that does not add a sugar.
Different combinations of the three / gene alleles occur in
different individuals because each person possesses two copies
Blood types
of the chromosome bearing the / gene and may be homozy-
gous for any allele or heterozygous for any two. An individual
heterozygous for the IA and IB alleles produces both forms of FIGURE 13.27
the enzyme and adds bom galactose and galactosamine to the Multiple alleles control the ABO blood groups. Different
surfaces of red blood cells. Because both alleles are expressed combinations of the three / gene alleles result in four different
simultaneously in heterozygotes, the IA and IB alleles are blood type phenotypes: type A (either 1A1A homozygotes or lAi
codominant. Both IA and IB are dominant over the / allele be- heterozygotes), type В (either PIB homozygotes or IBi
cause both IA or IB alleles lead to sugar addition and the / al- heterozygotes), type AB (IAIB heterozygotes), and type О
(ii homozygotes).
lele does not. The different combinations of the three alleles
produce four different phenotypes (figure 13.27):
1. Type A individuals add only galactosamine. They are
either IAIA homozygotes or IAi heterozygotes. The Rh Blood Group
2. Type В individuals add only galactose. They are ei- Another set of cell surface markers on human red blood
ther IBIB homozygotes or IBi heterozygotes. cells are the Rh blood group antigens, named for the rhe-
3. Type AB individuals add both sugars and are IAfB sus monkey in which they were first described. About 85%
heterozygotes. of adult humans have the Rh cell surface marker on their
4. Type О i n d i v i d u a l s add neither sugar and are red blood cells, and are called Rh-positive. Rh-negative
ii homozygotes. persons lack this cell surface marker because they are ho-
These four different cell surface phenotypes are called mozygous recessive for the gene encoding it.
the ABO blood groups or, less commonly, the Landsteiner If an Rh-negative person is exposed to Rh-positive
blood groups, after the man who first described them. As blood, the Rh surface antigens of that blood are treated like
Landsteiner noted, a person's immune system can distin- foreign invaders by the Rh-negative person's immune sys-
guish between these four phenotypes. If a type A individual tem, which proceeds to make antibodies directed against
receives a transfusion of type В blood, the recipient's im- the Rh antigens. This most commonly happens when an
mune system recognizes that the type В blood cells possess a Rh-negative woman gives birth to an Rh-positive child
"foreign" antigen (galactose) and attacks the donated blood (whose father is Rh-positive). Some fetal red blood cells
cells, causing the cells to clump, or agglutinate. This also cross the placental barrier and enter the mother's blood-
happens if the donated blood is type AB. However, if the stream, where they induce the production of "anti-Rh" an-
donated blood is type O, no immune attack will occur, as tibodies. In subsequent pregnancies, the mother's antibod-
there are no galactose antigens on the surfaces of blood cells ies can cross back to the new fetus and cause its red blood
produced by the type О donor. In general, any individual's cells to clump, leading to a potentially fatal condition called
immune system will tolerate a transfusion of type О blood. erythroblastosis fetalis.
Because neither galactose nor galactosamine is foreign to
Many blood group genes possess multiple alleles,
type AB individuals (whose red blood cells have both sug-
several of which may be common within populations.
ars), those individuals may receive any type of blood.


Human Chromosomes
It wasn't until 1956 that techniques were developed that al-
lowed investigators to determine the exact number of chro-
mosomes in human cells. We now know that each human
somatic cell normally has 46 chromosomes, which in meio-
sis form 23 pairs. By convention, the chromosomes are di-
vided into seven groups (designated A through G), each
characterized by a different size, shape, and appearance.
The differences among the chromosomes are most clearly
visible when the chromosomes are arranged in order in a
karyotype (figure 13.28). Techniques that stain individual
segments of chromosomes with different-colored dyes
make the identification of chromosomes unambiguous.
Like a fingerprint, each chromosome always exhibits the
same pattern of colored bands.

Sex Chromosomes
Of the 23 pairs of human chromosomes, 22 are perfectly
matched in both males and females and are called auto-
somes. The remaining pair, the sex chromosomes, con-
sist of two similar chromosomes in females and two dis-
similar chromosomes in males. In humans, as in Drosophila
(but by no means in all diploid species), females are desig-
nated XX and males XY. One of the pair of sex chromo-
somes in the male (the Y chromosome) is highly con-
densed and bears few functional genes in most organisms.
Because few of the genes on the Y chromosome are ex-
pressed, recessive alleles on a male's single X chromosome
have no active counterpart on the Y chromosome. Some of
the active genes the Y chromosome does possess are re-
sponsible for the features associated with "maleness" in
humans. Consequently, any individual with at least one FIGURE 13.28
Y chromosome is a male, and any individual without a A human karyotype. This karyotype shows the colored banding
Y chromosome is a female. patterns, arranged by class A-G.

Barr Bodies
Although males have only one copy of the X chromosome
and females have two, female cells do not produce twice
as much of the proteins encoded by genes on the X chro-
mosome. Instead, one of the X chromosomes in females is
inactivated early in embryonic development, shortly after
/ Random
inactivation
V
the embryo's sex is determined. Which X chromosome is
Zygote
inactivated varies randomly from cell to cell. If a woman is
heterozygous for a sex-linked trait, some of her cells will
express one allele and some the other. The inactivated
and highly condensed X chromosome is visible as a deeply
staining Barr body attached to the nuclear membrane
Barr body
(figure 13.29).

One of the 23 pairs of human chromosomes carries the FIGURE 13.29
genes that determine sex. The gene determining Barr bodies. In the developing female embryo, one ot the
maleness is located on a version of the sex chromosome X chromosomes (determined randomly) condenses and becomes
called Y, which has few other transcribed genes. inactivated. These condensed X chromosomes, called Barr bodies,
then attach to the nuclear membrane.


Human Abnormalities
Due to Alterations in
Chromosome Number
Occasionally, homologues or sister
chromatids fail to separate properly in
meiosis, leading to the acquisition or 6 7 8 9 10 11 12

loss of a chromosome in a gamete.
This condition, called primary non-
disjunction, can result in individuals 13
it
14
i
15
-VV
J«

16
»* It

18

with severe abnormalities if the af- *** — A'*"
fected gamete forms a zygote. +
19 20 21 22 X Y

Nondisjunction Involving FIGURE 13.30
Autosomes Down syndrome. As shown in this male karyotype, Down syndrome is associated with
trisomy of chromosome 21. A child with Down syndrome sitting on his father's knee.
Almost all humans of the same sex
have the same karyotype, for the same
reason that all automobiles have en-
gines, transmissions, and wheels: other
arrangements don't work well. Humans who have lost even I
100.0
one copy of an autosome (called monosomics) do not sur-
/*
vive development. In all but a few cases, humans who have
gained an extra autosome (called trisomics) also do not ш 30.0
survive. However, five of the smallest autosomes—those о
20.0
/•
-о 2 I
numbered 13, 15, 18, 21, and 22—can be present in hu- с •£
>> t±
w
mans as three copies and still allow the individual to survive !й
11
.
10.0 Т*
for a time. The presence of an extra chromosome 13, 15, or
и
о=
Q о
18 causes severe developmental defects, and infants with ч- О
Ъ о /
such a genetic makeup die within a few months. In con- 3.0
8s
С Ф
trast, individuals who have an extra copy of chromosome 21
or, more rarely, chromosome 22, usually survive to adult-
тз
'о
_с
0) О. 2.0
*/*
1.0
hood. In such individuals, the maturation of the skeletal * • * • *• *
system is delayed, so they generally are short and have poor •• •*•
muscle tone. Their mental development is also affected, 0.3 _ 0
1 1 1 1 1 1 1
and children with trisomy 21 or trisomy 22 are always men-
15 20 25 30 35 40 45 50
tally retarded.
Age of mother

Down Syndrome. The developmental defect produced
by trisomy 21 (figure 13.30) was first described in 1866 by FIGURE 13.31
J. Langdon Down; for this reason, it is called Down syn- Correlation between maternal age and the incidence of
drome (formerly "Down's syndrome"). About 1 in every Down syndrome. As women age, the chances they will bear a
750 children exhibits Down syndrome, and the frequency is child with Down syndrome increase. After a woman reaches 35,
similar in all racial groups. Similar conditions also occur in the frequency of Down syndrome increases rapidly.
chimpanzees and other related primates. In humans, the
defect is associated with a particular small portion of chro-
mosome 21. When this chromosomal segment is present in Not much is known about the developmental role of the
three copies instead of two, Down syndrome results. In genes whose duplication produces Down syndrome, although
97% of the human cases examined, all of chromosome 21 is clues are beginning to emerge from current research. Some
present in three copies. In the other 3%, a small portion of researchers suspect that the gene or genes that produce Down
chromosome 21 containing the critical segment has been syndrome are similar or identical to some of the genes associ-
added to another chromosome by translocation; it exists ated with cancer and with Alzheimer's disease. The reason
along with the normal two copies of chromosome 21. This for this suspicion is that one of the human cancer-causing
condition is known as translocation Down syndrome. genes (to be described in chapter 17) and the gene causing


Alzheimer's disease are located on the segment of chromo- Female
some 21 associated with Down syndrome. Moreover, cancer
is more common in children with Down syndrome. The in-
cidence of leukemia, for example, is 11 times higher in chil-
dren with Down syndrome than in unaffected children of
the same age.
How does Down syndrome arise? In humans, it comes
about almost exclusively as a result of primary nondisjunc-
tion of chromosome 21 during egg formation. The cause of
these primary nondisjunctions is not known, but their inci-
dence, like that of cancer, increases with age (figure 13.31).
In mothers younger than 20 years of age, the risk of giving
birdi to a child with Down syndrome is about 1 in 1700; in
mothers 20 to 30 years old, the risk is only about 1 in 1400.
In mothers 30 to 35 years old, however, the risk rises to
1 in 750, and by age 45, the risk is as high as 1 in 16!
Primary nondisjunctions are far more common in
women than in men because all of the eggs a woman will
ever produce have developed to the point of prophase in
meiosis I by the time she is born. By the time she has chil-
dren, her eggs are as old as she is. In men, by contrast, new
sperm develop daily. Therefore, there is a much greater FIGURE 13.32
chance for problems of various kinds, including those that How nondisjunction can produce abnormalities in the
number of sex chromosomes. When nondisjunction occurs
cause primary nondisjunction, to accumulate over time in
in the production of female gametes, the gamete with two
the gametes of women than in those of men. For this rea-
X chromosomes (XX) produces Klinefelter males (XXY) and
son, the age of the mother is more critical than that of the XXX females. The gamete with no X chromosome (O) produces
father in couples contemplating childbearing. Turner females (XO) and nonviable OY males lacking any
X chromosome.
Nondisjunction Involving the Sex Chromosomes
Individuals that gain or lose a sex chromosome do not
generally experience the severe developmental abnormali- short stature, with a webbed neck and immature sex organs
ties caused by similar changes in autosomes. Such individu- that do not undergo changes during puberty. The mental
als may reach maturity, but they have somewhat abnormal abilities of an XO individual are in the low-normal range.
features. This condition, called Turner syndrome, occurs roughly
once in every 5000 female births.
The X Chromosome. When X chromosomes fail to sep-
arate during meiosis, some of the gametes that are produced The Y Chromosome. The Y chromosome can also fail
possess both X chromosomes and so are XX gametes; the to separate in meiosis, leading to the formation of YY ga-
other gametes that result from such an event have no sex metes. When these gametes combine with X gametes, the
chromosome and are designated "O" (figure 13.32). XYY zygotes develop into fertile males of normal appear-
If an XX gamete combines with an X gamete, the result- ance. The frequency of the XYY genotype is about 1 per
ing XXX zygote develops into a female with one functional 1000 newborn males, but it is approximately 20 times
X chromosome and two Barr bodies. She is sterile but usu- higher among males in penal and mental institutions. This
ally normal in other respects. If an XX gamete instead observation has led to the highly controversial suggestion
combines with a Y gamete, the effects are more serious. that XYY males are inherently antisocial, a suggestion sup-
The resulting XXY zygote develops into a sterile male who ported by some studies but not by others. In any case, most
has many female body characteristics and, in some cases, XYY males do not develop patterns of antisocial behavior.
diminished mental capacity. This condition, called Klinefel-
ter syndrome, occurs in about 1 out of every 500 male births. Gene dosage plays a crucial role in development, so
If an О gamete fuses with a Y gamete, the resulting OY humans do not tolerate the loss or addition of
zygote is nonviable and fails to develop further because chromosomes well. Autosome loss is always lethal, and
humans cannot survive when they lack the genes on the an extra autosonie is with few exceptions lethal too.
X chromosome. If, on the other hand, an О gamete fuses with Additional sex chromosomes have less serious
consequences, although they can lead to sterility.
an X gamete, the XO zygote develops into a sterile female of


Human Genetic Disorders

о
О
Percent of normal enzyme function
In chapter 17 we will discuss the process of mutation, which pro-
duces variant alleles. At this point, we will note only that muta-
tion involves random changes in genes, and that such changes
rarely improve the functioning of the proteins those genes en-

01
-

о
code, just as randomly changing a wire in a computer rarely im-
proves the computer's functioning. Therefore, variant alleles
arising from mutation are rare in populations of organisms.
Nevertheless, some alternative alleles with detrimental
effects are present in populations. Usually, they are reces-

о
sive to other alleles. When two seemingly normal individu- Tay-Sachs Carrier Normal
als who are heterozygous for such an allele produce off- (homozygous (heterozygous) (homozygous
recessive) dominant)
spring homozygous for the allele, the offspring suffer the
detrimental effects of the mutant allele. When a detrimen-
tal allele occurs at a significant frequency in a population, FIGURE 13.33
the harmful effect it produces is called a genetic disorder. Tay-Sachs disease. Homozygous individuals (left bar) typically have
Table 13.3 lists some of the most prevalent genetic disor- less than 10% of die normal level of hexosaminidase k(rightbar), while
ders in humans. We know a great deal about some of them, heterozygous individuals (middle bar) have about 50% of the normal
level—enough to prevent deterioration of the central nervous system.
and much less about many others. Learning how to prevent
them is one of the principal goals of human genetics.
ern and Central Europe. In these populations, it is esti-
Most Gene Defects Are Rare: Tay-Sachs Disease mated that 1 in 28 individuals is a heterozygous carrier of
Tay-Sachs disease is an incurable hereditary disorder in the disease, and approximately 1 in 3500 infants has the
which the brain deteriorates. Affected children appear nor- disease. Because the disease is caused by a recessive allele,
mal at birth and usually do not develop symptoms until most of the people who carry the defective allele do not
about the eighth month, when signs of mental deteriora- themselves develop symptoms of the disease.
tion appear. The children are blind within a year after The Tay-Sachs allele produces the disease by encoding a
birth, and they rarely live past five years of age. nonfunctional form of the enzyme hexosaminidase A. This
Tay-Sachs disease is rare in most human populations, enzyme breaks down gangliosides, a class of lipids occurring
occurring in only 1 of 300,000 births in the United States. within the lysosomes of brain cells (figure 13.33). As a re-
However, the disease has a high incidence among Jews of sult, the lysosomes fill with gangliosides, swell, and eventu-
Eastern and Central Europe (Ashkenazi), and among ally burst, releasing oxidative enzymes that kill the cells.
American Jews, 90% of whom trace their ancestry to East- There is no known cure for this disorder.

ant Genetic Disorders
Dominant/ Frequency among
Disorder Symptom Defect Recessive Human Births

Cystic fibrosis Mucus clogs lungs, liver, Failure of chloride ion Recessive 1/2500
and pancreas transport mechanism (Caucasians)
Sickle cell anemia Poor blood circulation Abnormal hemoglobin Recessive 1/625
molecules (African Americans)
Tay-Sachs disease Deterioration of central Defective enzyme Recessive 1/3500
nervous system in infancy (hexosaminidase A) (Ashkenazi Jews)
Phenylketonuria Brain fails to develop in Defective enzyme Recessive 1/12,000
infancy (phenylalanine hydroxylase)
Hemophilia Blood fails to clot Defective blood clotting factor Sex-linked 1/10,000
VIII recessive (Caucasian males)
Huntington's disease Brain tissue gradually Production of an inhibitor of Dominant 1/24,000
deteriorates in middle age brain cell metabolism
Muscular dystrophy Muscles waste away Degradation of myelin coating Sex-linked 1/3700
(Duchenne) of nerves stimulating muscles recessive (males)
Hypercholesterolemia Excessive cholesterol levels Abnormal form of cholesterol Dominant 1/500
in blood, leading to heart cell surface receptor
disease


Gene Defects Are Inherited in Families:
Hemophilia
When a blood vessel ruptures, the blood in the immediate
area of the rapture forms a solid gel called a clot. The clot
forms as a result of the polymerization of protein fibers cir-
culating in the blood. A dozen proteins are involved in this
process, and all must function properly for a blood clot to
form. A mutation causing any of these proteins to loose
their activity leads to a form of hemophilia, a hereditary
condition in which the blood is slow to clot or does not clot
at all.
Hemophilias are recessive disorders, expressed only
when an individual does not possess any copy of the normal
allele and so cannot produce one of the proteins necessary for
clotting. Most of the genes that encode the blood-clotting
proteins are on autosomes, but two (designated VIII and
FIGURE 13.34
IX) are on the X chromosome. These two genes are sex-
Queen Victoria of England, surrounded by some of her
linked: any male who inherits a mutant allele of either of
descendants in 1894. Of Victoria's four daughters who lived to
the two genes will develop hemophilia because his other bear children, two, Alice and Beatrice, were carriers of Royal
sex chromosome is a Y chromosome that lacks any alleles hemophilia. Two of Alice's daughters are standing behind Victoria
of those genes. (wearing feathered boas): Princess Irene of Prussia (right), and
The most famous instance of hemophilia, often called the Alexandra (left), who would soon become Czarina of Russia. Both
Royal hemophilia, is a sex-linked form that arose in the royal Irene and Alexandra were also carriers of hemophilia.
family of England. This hemophilia was caused by a
mutation in gene IX that oc-
curred in one of the parents of
Queen Victoria of England
(1819-1901; figure 13.34). In Louis II
the five generations since 9
Grand Duke of Hesse
Queen Victoria, 10 of her male
descendants have had hemo-
philia. The present British
royal family has escaped the 1
Edward VII
Frederick Victoria Alice Duke of Alfred i Helena Arthu Prince
disorder because Queen Victo- Hesse Henry
III
ria's son, King Edward VII, did I No hemophilia | ("NO hemophilia ]
not inherit the defective allele, German r-4 King
Royal '-r George V
and all the subsequent rulers of House Princess Maurice Leopold Queen Alfonso
England are his descendants. Eugenie King of
Spain
Three of Victoria's nine chil-
dren did receive the defective
©
Alfonso Jamie Juan
Gonzalo
allele, however, and they car-
ried it by marriage into many
of the other royal families of О
King Juan
Europe (figure 13.35). It is still Carlos
being transmitted to future No evidence No evidence
generations through these fam- of hemophilia of hemophilia

ily lines—except in Russia, Spanish Royal House

where all of the five children of British Royal House
VII
Alexandra, Victoria's grand- William Henry
daughter, were killed soon
after the Russian revolution in
FIGURE 13.35
1917. (Speculation that one The Royal hemophilia pedigree. Queen Victoria's daughter Alice introduced hemophilia into the
daughter, Anastasia, might Russian and Austrian royal houses, and Victoria's daughter Beatrice introduced it into the Spanish
have survived ended in 1996 royal house. Victoria's son Leopold, himself a victim, also transmitted the disorder in a third line of
when DNA analysis confirmed descent. Half-shaded symbols represent carriers with one normal allele and one defective allele; fully
the identity of her remains.) shaded symbols represent affected individuals.


Gene Defects Often Affect
Specific Proteins: Sickle Cell
Anemia
Sickle cell anemia is a heritable disor-
der first noted in Chicago in 1904. Af-
flicted individuals have defective mole-
cules of hemoglobin, the protein within
red blood cells that carries oxygen.
Consequently, these individuals are un-
able to properly transport oxygen to
their tissues. The defective hemoglobin
molecules stick to one another, form-
ing stiff, rod-like structures and result-
ing in the formation of sickle-shaped
red blood cells (figure 13.36). As a re-
sult of their stiffness and irregular
shape, these cells have difficulty mov-
ing through the smallest blood vessels;
they tend to accumulate in those vessels
and form clots. People who have large FIGURE 13.36
proportions of sickle-shaped red blood Sickle cell anemia. In individuals homozygous for the sickle cell trait, many of the red
cells tend to have intermittent illness blood cells have sickle or irregular shapes, such as the cell on the far right.
and a shortened life span.
The hemoglobin in the defective
red blood cells differs from that in
normal red blood cells in only one of
hemoglobin's 574 ammo acid subunits.
In the defective hemoglobin, the
amino acid valine replaces a glutamic
acid at a single position in the protein.
Interestingly, the position of the
change is far from the active site of he-
moglobin where the iron-bearing
heme group binds oxygen. Instead, the
change occurs on the outer edge of the
protein. Why then is the result so cat-
astrophic? The sickle cell mutation
puts a very nonpolar amino acid on the Sickle cell / Falciparum
allele in Africa malaria in Africa
surface of the hemoglobin protein,
creating a "sticky patch" that sticks to I -5%
other such patches—nonpolar amino
acids tend to associate with one an- Hi 0-20%
other in polar environments like water.
As one hemoglobin adheres to an- FIGURE 13.37
other, ever-longer chains of hemoglo- The sickle cell allele confers resistance to malaria. The distribution of sickle cell
anemia closely matches the occurrence of malaria in central Africa. This is not a
bin molecules form.
coincidence. The sickle cell allele, when heterozygous, confers resistance to malaria, a
Individuals heterozygous for the very serious disease.
sickle cell allele are generally indistin-
guishable from normal persons. How-
ever, some of their red blood cells show the sickling charac- heterozygous for this allele, and fully 6% are homozygous
teristic when they are exposed to low levels of oxygen. The and express the disorder. What factors determine the high
allele responsible for sickle cell anemia is particularly com- frequency of sickle cell anemia in Africa? It turns out that
mon among people of African descent; about 9% of African heterozygosity for the sickle cell anemia allele increases re-
Americans are heterozygous for this allele, and about 0.2% sistance to malaria, a common and serious disease in central
are homozygous and therefore have the disorder. In some Africa (figure 13.37). We will discuss this situation in more
groups of people in Africa, up to 45% of all individuals are detail in chapter 19.


Not All Gene Defects Are Recessive: 100
Huntington's Disease
Not all hereditary disorders are recessive. Huntington's 75 -
disease is a hereditary condition caused by a dominant al-
Huntington's
lele that causes the progressive deterioration of brain cells disease
(figure 13.38). Perhaps 1 in 24,000 individuals develops the о 50
disorder. Since the allele is dominant, every individual that
carries the allele expresses the disorder. Nevertheless, the
disorder persists in human populations because its symp- CD
25 -
Q-
toms usually do not develop until the affected individuals
are more than 30 years old, and by that time most of those
individuals have already had children. Consequently, the 10 20 30 40 50 60 70 80
allele is often transmitted before the lethal condition devel- Age in years
ops. A person who is heterozygous for Huntington's dis-
ease has a 50% chance of passing the disease to his or her
children (even though the other parent does not have the FIGURE 13.38
disorder). In contrast, the carrier of a recessive disorder Huntington's disease is a dominant genetic disorder. It is
such as cystic fibrosis has a 50% chance of passing the allele because of the late age of onset of this disease that it persists
to offspring and must mate with another carrier to risk despite the fact that it is dominant and fatal.
bearing a child with the disease.

Some Gene Defects May Soon Be Curable:
Cystic Fibrosis
Some of the most common and serious gene defects result
from single recessive mutations, including many of the de-
fects listed in table 13.3. Recent developments in gene
technology have raised the hope that this class of disorders
may be curable. Perhaps the best example is cystic fibrosis,
the most common fatal genetic disorder among Caucasians
(figure 13.39). As we learned in chapter 6, affected individ-
uals secrete a thick mucus that clogs their lungs, and the
passages of their pancreas and liver. About 1 in 20 Cau-
casians has a copy of the defective gene but shows no symp-
toms; homozygous recessive individuals make up about 1 in
2500 Caucasian children. These individuals inevitably die
from complications that result from their disease.
We know that the cause of cystic fibrosis is a defect in
the way certain cells regulate the transport of chloride
ions across their membranes. Cystic fibrosis occurs when
an individual is homozygous for an allele that encodes a
defective version of the protein that regulates the chlo-
ride transport channel. This allele is recessive to the gene FIGURE 13.39
that codes for the normal version of the regulatory pro- A child with cystic fibrosis. In cystic fibrosis patients, the mucus
tein, so the chloride channels of heterozygous individuals that normally lines the insides of the lungs thickens, making
function normally and the individuals do not develop cys- breathing difficult. Affected children are expected to live into
tic fibrosis. their late twenties.
The gene responsible for cystic fibrosis, dubbed CFTR
for cystic fibrosis transmembrane regulator, was isolated in
1989, and attempts are underway to introduce healthy Many heritable disorders are the result of recessive
copies of the gene into cystic fibrosis patients. This gene mutations in genes encoding critical proteins such as
transfer therapy was carried out successfully with mice in those that clot blood, carry oxygen, or transport
1994, but initial attempts to introduce the gene into hu- chloride ions into and out of cells. All such disorders
mans (using cold viruses to carry the gene) have not yet are potentially curable if ways can be found to
successfully introduce undamaged copies of the genes
succeeded. These procedures are discussed in detail in
into affected individuals.
chapter 18.


Genetic Counseling Amniotic fluid

Although most genetic disorders can-
not yet be cured, we are learning a
great deal about them, and progress
toward successful therapy is being
made in many cases. In the absence of
a cure, however, the only recourse is
to try to avoid producing children
with these conditions. The process of
identifying parents at risk of produc-
ing children with genetic defects and
of assessing the genetic state of early
embryos is called genetic counseling.
If a genetic defect is caused by a re-
cessive allele, how can potential par-
ents determine the likelihood that they
carry the allele? One way is through
pedigree analysis, often employed as an
aid in genetic counseling. By analyzing FIGURE 13.40
a person's pedigree, it is sometimes Amniocentesis. A needle is inserted into the amniotic cavity, and a sample of amniotic
possible to estimate the likelihood that fluid, containing some free cells derived from the fetus, is withdrawn into a syringe. The
the person is a carrier for certain disor- fetal cells are then grown in culture and their karyotype and many of their metabolic
ders. For example, if one of your rela- functions are examined.
tives has been afflicted with a recessive
genetic disorder such as cystic fibrosis,
it is possible that you are a heterozy-
gous carrier of the recessive allele for that disorder. When a
couple is expecting a child, and pedigree analysis indicates
that both of them have a significant probability of being
heterozygous carriers of a recessive allele responsible for a
serious genetic disorder, the pregnancy is said to be a high-
risk pregnancy. In such cases, there is a significant proba-
bility that the child will exhibit the clinical disorder.
Another class of high-risk pregnancies is that in which
the mothers are more than 35 years old. As we have seen,
the frequency of birth of infants with Down syndrome in-
creases dramatically in the pregnancies of older women (see
figure 13. 31).
When a pregnancy is diagnosed as being high-risk, many
women elect to undergo amniocentesis, a procedure that per-
mits the prenatal diagnosis of many genetic disorders (figure
1 3 .40). In the fourth month of pregnancy, a sterile hypoder-
mic needle is inserted into the expanded uterus of the
mother, removing a small sample of the amniotic fluid
bathing the fetus. Within the fluid are free-floating cells de-
rived from the fetus; once removed, these cells can be grown
in cultures in the laboratory. During amniocentesis, the po- FIGURE 13.41
sition of the needle and that of the fetus are usually observed An ultrasound view of a fetus. During the fourth month of
by means of ultrasound (figure 13.41). The sound waves used pregnancy, when amniocentesis is normally performed, the fetus
usually moves about actively. The head of the fetus above is to the left.
in ultrasound are not harmful to mother or fetus, and they
permit the person withdrawing the amniotic fluid to do so
without damaging the fetus. In addition, ultrasound can be
used to examine the fetus for signs of major abnormalities. removes cells from the chorion, a membranous part of the
In recent years, physicians have increasingly turned to a placenta that nourishes the fetus. This procedure can be
new, less invasive procedure for genetic screening called used earlier in pregnancy (by the eighth week) and yields
chorionic villi sampling. In this procedure, the physician results much more rapidly than does amniocentesis.


_GJ(2AJT T С GJfJAATTC
Z^GA^ATT^C
с т ТА A)()G ГЖЬ1АА^ Q^ZIIIZZZZZ С Т ТА A )(}G
t t t
Cut Cut Cut

Short fragment Medium-length fragment

Medium-length fragment
— Short fragment

Long Short
(a) No mutation Gel electrophoresis

GAM A T T 3
FIGURE 13.42
C T T A A }()( ТА'АС
RFLPs. Restriction fragment length
t
Cut
t
Cut
polymorphisms (RFLPs) are playing
an increasingly important role in
genetic identification. In (a), the
restriction endonuclease cuts the
Long-length fragment DNA molecule in three places,
producing two fragments. In (b), the
mutation of a single nucleotide from
G to A (see top fragment) alters a
Long-length fragment restriction endonuclease cutting site.
Now the enzyme no longer cuts the

i
DNA molecule at that site. As a
result, a single long fragment is
_^___^J obtained, rather than two shorter
Long -*• Short ones. Such a change is easy to detect
(b) Mutation Gel electrophoresis when the fragments are subjected to a
technique called gel electrophoresis.

To test for certain genetic disorders, genetic counselors that, by chance, occur at about the same place as the muta-
can look for three things in the cultures of cells obtained tions that cause those disorders. By testing for the presence
from amniocentesis or chorionic villi sampling. First, of these other mutations, a genetic counselor can identify
analysis of the karyotype can reveal aneuploidy and gross individuals with a high probability of possessing the disorder-
chromosomal alterations. Second, in many cases it is possi- causing mutations. Finding such mutations in the first place
ble to test directly for the proper functioning of enzymes in- is a little like searching for a needle in a haystack, but per-
volved in genetic disorders. The lack of normal enzymatic sistent efforts have proved successful in these three disor-
activity signals the presence of the disorder. Thus, the lack ders. The associated mutations are detectable because they
of the enzyme responsible for breaking down phenylalanine alter the length of the DNA segments that restriction en-
signals PKU, the absence of the enzyme responsible for the zymes produce when they cut strands of DNA at particular
breakdown of gangliosides indicates Tay-Sachs disease, and places (see chapter 18). Therefore, these mutations produce
so forth. what are called restriction fragment length polymor-
Third, genetic counselors can look for an association -with phisms, or RFLPs (figure 13.42).
known genetic markers. For sickle cell anemia, Huntington's
disease, and one form of muscular dystrophy (a genetic dis- Many gene defects can be detected early in pregnancy,
order characterized by weakened muscles), investigators allowing for appropriate planning by the prospective
have found other mutations on the same chromosomes parents.


Probability ana The probability that the three children
will be two boys and one girl is:
You can see that one-fourth of the chil-
dren are expected to be albino {aa). Thus,
Allele Distribution 3p2g = 3 x (И)2 x (M) = X for any given birth the probability of an
albino child is 1A. This probability can be
To test your understanding, try to esti- symbolized by q. The probability of a
mate the probability that two parents het- nonalbino child is !4, symbolized by p.
Many, although not all, alternative alleles erozygous for the recessive allele producing Therefore, the probability that there will
produce discretely different phenotypes. albinism (a) will have one albino child in a be one albino child among the three chil-
Mendel's pea plants were tall or dwarf, had family of three. First, set up a Punnett square: dren is:
purple or white flowers, and produced Ip2<j = 3 x (X4)2 x (!4) = %, or 42%
Father's
smooth or shriveled seeds. The eye color of
Gametes This means that the chance of producing
a fruit fly may be red or white, and the skin
A a one albino child in the three is 42%.
color of a human may be pigmented or al-
bino. When only two alternative alleles Mother's A AA Aa
exist for a given trait, the distribution of Gametes a Aa aa
phenotypes among the progeny of a cross is
referred to as a binomial distribution.
As an example, consider the distribution
of sexes in humans. Imagine that a couple
has chosen to have three children. How
likely is it that two of the children will be
boys and one will be a girl? The frequency
of any particular possibility is referred to as Composition Order
its probability of occurrence. Letp symbol- of Family of Birth Calculation Probability
ize the probability of having a boy at any p xp xp
3 boys bbb P1
given birth and q symbolize the probability
of having a girl. Since any birth is equally 2 boys and 1 girl bbg pxpxq P22q
likely to produce a girl or boy: bgb pxgxp P i 1P 4 2

p-f.M gbb qxpxp P2q
Table 13.A shows eight possible gender 1 boy and 2 girls ggb qxqxp РЧ
2

combinations among the three children. gbg qxpxq pq2 W
2
The sum of the probabilities of the eight bgg pxq Xq pq ,
different ways must equal one. Thus: 3 girls ggg qXqXq <f
/>3 + !>p2q + 3pq2 + q* = I

A Vocabulary gene The basic unit of heredity; a se-
quence of DNA nucleotides on a chromo-
homozygote A diploid individual whose
two copies of a gene are the same. An indi-
of Genetics some that encodes a polypeptide or RNA
molecule and so determines the nature of
vidual carrying identical alleles of a gene on
both homologous chromosomes is said to
an individual's inherited traits. be homozygous for that gene.
genotype The total set of genes present locus The location of a gene on a
allele One of two or more alternative in the cells of an organism. This term is chromosome.
forms of a gene. often also used to refer to the set of alleles phenotype The realized expression of
diploid Having two sets of chromosomes, at a single gene locus. the genotype; the observable manifesta-
which are referred to as homologues. Animals haploid Having only one set of chromo- tion of a trait (affecting an individual's
are diploid as well as plants in the dominant somes. Gametes, certain animals, protists structure, physiology, or behavior) that re-
phase of their life cycle as are some protists. and fungi, and certain stages in the life cycle sults from the biological activity of the
dominant allele An allele that dictates of plants are haploid. DNA molecules.
the appearance of heterozygotes. One allele heterozygote A diploid individual carry- recessive allele An allele whose pheno-
is said to be dominant over another if a het- ing two different alleles of a gene on its two typic effect is masked in heterozygotes by
erozygous individual with one copy of that homologous chromosomes. Most human the presence of a dominant allele.
allele has the same appearance as a homozy- beings are heterozygous for many genes.
gous individual with two copies of it.


13.1 Mendel solved the mystery of heredity. predicted by Mendel. This is particularly true in epistatic
situations, where the product of one gene masks another.
• Koelreuter noted the basic facts of heredity a century
before Mendel. He found that alternative traits Genes are on chromosomes.
segregate in crosses and may mask each other's
appearance. Mendel, however, was the first to quantify The first clear evidence that genes reside on
his data, counting the numbers of each alternative type chromosomes was provided by Thomas Hunt Morgan,
among the progeny of crosses. who demonstrated that the segregation of the white-eye
trait in Drosophila is associated with the segregation of me
• By counting progeny types, Mendel learned that the
X chromosome, which is involved in sex determination.
alternatives that were masked in hybrids (the FI
generation) appeared only 2 5 % of the time in the p2 The first genetic evidence that crossing over occurs
generation. This finding, which led directly to Mendel's between chromosomes was provided by Curt Stern, who
model of heredity, is usually referred to as the showed that when two Mendelian traits exchange during
Mendelian ratio of 3:1 dominant-to-recessive traits. a cross, so do visible abnormalities on the ends of the
chromosomes bearing those traits.
• Mendel deduced from the 3:1 ratio that traits are
specified by discrete "factors" that do not blend. He The frequency of crossing over between genes can
deduced that pea plants contain two factors for each trait be used to construct genetic maps, which are
diat he studied (we now know this is because the plants representations of the physical locations of genes on
are diploid). When a plant is heterozygous for a trait, chromosomes, inferred from the frequency of crossing
the two factors for that trait are not the same, and one over between particular pairs of genes.
factor, which Mendel described as dominant, determines
the appearance, or phenotype, of the individual. We Human genetics follows Mendelian principles.
now refer to Mendel's factors as genes and to alternative Primary nondisjunction results when chromosomes do not
forms of genes as alleles. separate during meiosis, leading to gametes with missing
• When two heterozygous individuals mate, an individual or extra chromosomes. In humans, the loss of an autosome
offspring has a 50% (that is, random) chance of obtaining is invariably fatal. Gaining an extra autosome, which leads
me dominant allele from the father and a 50% chance to a condition called trisomy, is also fatal, wirn only two
of obtaining the dominant allele from the mother; exceptions: trisomy of chromosomes 21 and 22.
dierefore, the probability of being homozygous recessive Some genetic disorders are relatively common in human
is 25%. The progeny thus appear as % dominant and populations; others are rare. Many of the most important
14 recessive, a dominant-to-recessive ratio of 3:1. genetic disorders are associated with recessive alleles,
• When two genes are located on different chromosomes, which may lead to the production of defective versions of
the alleles included in an individual gamete are enzymes that normally perform critical functions.
distributed at random. The allele for one gene included Because such traits are determined by recessive alleles
in the gamete has no influence on which allele of the and, therefore, are not expressed in heterozygotes, the
other gene is included in the gamete. Such genes are alleles are not eliminated from the human population,
said to assort independently. even though their effects in homozygotes may be lethal.
• Because phenotypes are often influenced by more than While there are no cures for any genetic disorder at
one gene, the ratios of alternative phenotypes observed present, many of these conditions can be identified
in crosses sometimes deviate from the simple ratios through genetic therapy.

Homozygous/heterozygous Different versions of the 3. The chromosomal theory of inheritance Mendelian
same gene are called alleles; each diploid offspring traits are usually the result of the expression of particular
receives one allele from each parent. A diploid individual genes located on chromosomes. Each gene is a segment
containing two copies of the same allele is homozygous; of DNA encoding a protein.
an individual containing two different alleles is 4. Nondisjunction Errors during meiosis may yield
heterozygous. gametes with either extra or missing chromosomes. In a
Dominance In many cases, one (dominant) allele will few instances, these gametes can produce zygotes that
"mask" the presence of another (recessive) allele in a develop into individuals with mild to profound
heterozygous individual, so that the individual shows the abnormalities.
dominant trait.


1. How did Koelreuter's experiments on tobacco plants conflict with 5. In л dihybrid cross, what is the ratio of expected phenotypes?
the ideas regarding heredity that were prevalent at that time? Why What fraction of the offspring should be homozygous recessive
weren't the implications of his results recognized for a century? for both traits? What fraction of the offspring should be
2. What characteristics of the garden pea made this organism a homozygous dominant for both traits?
good choice for Mendel's experiments on heredity? 6. What is primary nondisjunction? How is it related to Down
3. How did Mendel produce self-fertilization in the garden pea? syndrome? hi humans, how are the age and sex of an individual related
How did he produce cross-fertilization? to me likelihood of producing gametes affected by nondisjunction?

4. To determine whether a purple-flowered pea plant of unknown 7. What is the sex chromosome genotype of an individual with
genotype is homozygous or heterozygous, what type of plant Klinefelter syndrome? Is such an individual genetically male or
should it be crossed with? What would the offspring of this cross female? Why? Would such an individual usually have male or
be like if the plant with unknown genotype were homozygous? female body characteristics?
What would the offspring be like if it were heterozygous? 8. Is Huntington's disease a dominant or a recessive genetic
disorder? Why is it maintained at its current frequency in human
populations?

1. Why did Mendel observe only two alleles of any given trait in 3. If a heterozygous, Rh-positive woman and a homozygous, Rh-
the crosses that he carried out? negative man produce an Rh-negative fetus, will the fetus develop
2. How might Mendel's results and the model he formulated have antibodies against the Rh antigens and kill the mother? Explain
been different if the traits he chose to study were governed by your reasoning.
alleles exhibiting incomplete dominance or codominance?

'
Mendel Online Mendelian Inheritance in Man
http://ww.stg.brown.edu/MendelWeb/ http://www3.ncbi.nlm.nih.gov/omim
An outstanding site from Brown University for those interested in The single largest resource on human genetics, this site, maintained by
Mendel and his experiments, ivith excellent supplementary materials. the National Center of Biotechnology Information of the NIH, provides
Classic Papers in Mendelian Genetics an extensive data base of genetic disorders and information on individual
http://www.esp.org/foundations/genetics/classical/ human genes. Over 9,300 genes are included, with roughly 50 new
A -wonderful collection of original historically-significant papers, includ- genes added each month.
ing key papers by Mendel, Eateson, Morgan, and many others. Searching For a Cure
Virtual Drosophila Crosses http://www.hhmi.org/GeneticTrail/
http://uflylab.calstatela.edu/edesktop/VirtApps/Vrflylab BLAZING A GENETIC TRAIL provides a -wonderful account of
IntroVflylab.html human hereditary disorders, their causes, and the on-going search for cures.
The VIRTUAL FLY LAB allows you to learn the principles of genetic Prepared by the Howard Hughes Medical Institute. Highly Recommended.
inheritance by mating virtual fruit flies and analyzing the offspring.

Blixt, S.: "Why Didn't Gregor Mendel Find Linkage?" Nature, Morgan, Т. Н.: "Sex-Limited Inheritance in Drosophila," Science,
vol. 256, 1975, page 206. Modern information on the chromo- vol. 32, 1910, pages 120-22. Morgan's original account of his fa-
somal location of the genes Mendel studied. mous analysis of the inheritance of the white-eye trait.
Corcos, A., and F. Monaghan: "Mendel's Work and Its Rediscovery: A Mulligan, R.: "The Basic Science of Gene Therapy," Science,
New Perspective," Critical Reviews in Plant Sciences, vol. 9, May 1990, vol. 260, May 14, 1993, pages 926-32. An overview of gene ther-
pages 197-212. An evaluation of the myths surrounding Mendel's work. apy, how far we've come, and how it works.
Diamond, J.: "Blood, Genes, and Malaria," Natural History, February Patterson, D.: "The Causes of Down Syndrome," Scientific Ameri-
1989. An account of the evolutionary history of sickle cell anemia. can, August 1987, pages 52-60. A cluster of genes on chromosome
Mendel, G.: "Experiments on Plant Hybridization," 21 associated with Down syndrome are being identified and studied.
(1866), translated and reprinted in The Origins of Genetics: A Verma, L: "Gene Therapy," Scientific American, November 1990,
Mendel Source Book, C. Stern and E. Sherwood (eds.), W. H. Free- pages 68-84. Treatment of genetic disorders by introducing
man, San Francisco, 1966. Mendel's original research, largely healthy genes into the body of an affected individual is producing
ignored for over 30 years. exciting results.


Mendelian Genetics Problems mine that no cow in the herd has horns. Some of
the calves born that year, however, grow horns.
1. The illustration describes Mendel's cross of wrinkled You remove them from the herd and make certain
and round seed characters. (Hint: Do you expect all that no horned adult has gotten into your pasture.
the seeds in a pod to be the same?) What is wrong Despite your efforts, more horned calves are born
with this diagram? the next year. What is the reason for the appear-
ance of the horned calves? If your goal is to main-
tain a herd consisting entirely of polled cattle, what
should you do?
4. An inherited trait among humans in Norway causes
affected individuals to have very wavy hair, not unlike
that of a sheep. The trait, called woolly, is very evident
when it occurs in families; no child possesses woolly
hair unless at least one parent does. Imagine you are a
Norwegian judge, and you have before you a woolly-
haired man suing his normal-haired wife for divorce
because their first child has woolly hair but their sec-
ond child has normal hair. The husband claims this
F1 generation
(all round seeds) constitutes evidence of his wife's infidelity. Do you
accept his claim? Justify your decision.
5. In human beings, Down syndrome, a serious develop-
mental abnormality, results from the presence of
three copies of chromosome 21 rather than the usual
two copies. If a female exhibiting Down syndrome
mates with a normal male, what proportion of her
offspring would you expect to be affected?
6. Many animals and plants bear recessive alleles for al-
binism, a condition in which homozygous individuals
lack certain pigments. An albino plant, for example,
lacks chlorophyll and is white, and an albino human
lacks melanin. If two normally pigmented persons het-
erozygous for the same albinism allele marry, what pro-
portion of their children would you expect to be albino?
7. You inherit a racehorse and decide to put him out to
stud. In looking over the stud book, however, you
Round seeds (3) Wrinkled seeds (1) discover that the horse's grandfather exhibited a rare
disorder that causes brittle bones. The disorder is
hereditary and results from homozygosity for a reces-
The annual plant Haplopappus gradlis has two pairs of sive allele. If your horse is heterozygous for the allele,
chromosomes 1 and 2. In this species, the probability it will not be possible to use him for stud, since the
that two traits a and b selected at random will be on genetic defect may be passed on. How would you de-
the same chromosome is equal to the probability that termine whether your horse carries this allele?
they will both be on chromosome 1 (]A x И = У-t, or 8. In the fly Drosophila, the allele for dumpy wings (d) is
0.25), plus the probability that they will both be on recessive to the normal long-wing allele (d+), and the
chromosome 2 (also !4 x И = К, or 0.25), for an overall allele for white eye (w) is recessive to the normal red-
probability of И, or 0.5. In general, the probability eye allele (w+). In a cross of d+d+w+w x d+divw, what
that two randomly selected traits will be on the same proportion of the offspring are expected to be "nor-
chromosome is equal to % where n is the number mal" (long wings, red eyes)? What proportion are ex-
of chromosome pairs. Humans have 23 pairs of chro- pected to have dumpy wings and white eyes?
mosomes. What is the probability that any two 9. Your instructor presents you with a Drosophila with
human traits selected at random will be on the same red eyes, as well as a stock of white-eyed flies and an-
chromosome? other stock of flies homozygous for the red-eye allele.
Among Hereford cattle there is a dominant allele You know that the presence of white eyes in Drosophila
called polled; the individuals that have this allele is caused by homozygosity for a recessive allele. How
lack horns. Suppose you acquire a herd consisting would you determine whether the single red-eyed fly
entirely of polled cattle, and you carefully deter- was heterozygous for the white-eye allele?


10. Some children are born with recessive traits (and, that a mix-up occurred at the hospital, they check the
therefore, must be homozygous for the recessive al- blood type of the infant. It is type O. As the father is
lele specifying the trait), even though neither of the type A and the mother type B, they conclude a mix-
parents exhibits the trait. What can account for this? up must have occurred. Are they correct?
11. You collect two individuals of Drosophila, one a young 15. Mabel's sister died of cystic fibrosis as a child. Mabel
male and the other a young, unmated female. Both does not have the disease, and neither do her par-
are normal in appearance, with the red eyes typical of ents. Mabel is pregnant with her first child. If you
Drosophila. You keep the two flies in the same bottle, were a genetic counselor, what would you tell her
where they mate. Two weeks later, the offspring they about the probability that her child will have cystic
have produced all have red eyes. From among the off- fibrosis?
spring, you select 100 individuals, some male and 16. How many chromosomes would you expect to find in
some female. You cross each individually with a fly the karyotype of a person with Turner syndrome?
you know to be homozygous for the recessive allele 17. A woman is married for the second time. Her first
sepia, which produces black eyes when homozygous. husband has blood type A and her child by that mar-
Examining the results of your 100 crosses, you ob- riage has type O. Her new husband has type В blood,
serve that in about half of the crosses, only red-eyed and when they have a child its blood type is AB.
flies were produced. In the other half, however, the What is the woman's blood genotype and blood type?
progeny of each cross consists of about 50% red-eyed 18. Two intensely freckled parents have five children.
flies and 50% black-eyed flies. What were the geno- Three eventually become intensely freckled and two
types of your original two flies? do not. Assuming this trait is governed by a single
12. Hemophilia is a recessive sex-linked human blood pair of alleles, is the expression of intense freckles
disease that leads to failure of blood to clot normally. best explained as an example of dominant or recessive
One form of hemophilia has been traced to the royal inheritance?
family of England, from which it spread throughout 19. Total color blindness is a rare hereditary disorder
the royal families of Europe. For the purposes of this among humans. Affected individuals can see no col-
problem, assume that it originated as a mutation ei- ors, only shades of gray. It occurs in individuals ho-
ther in Prince Albert or in his wife, Queen Victoria. mozygous for a recessive allele, and it is not sex-
a. Prince Albert did not have hemophilia. If the dis- linked. A man whose father is totally color blind
ease is a sex-linked recessive abnormality, how intends to marry a woman whose mother is totally
could it have originated in Prince Albert, a male, color blind. What are the chances they will produce
who would have been expected to exhibit sex- offspring who are totally color blind?
linked recessive traits? 20. A normally pigmented man marries an albino woman.
b. Alexis, the son of Czar Nicholas II of Russia and They have three children, one of whom is an albino.
Empress Alexandra (a granddaughter of Victoria), What is the genotype of the father?
had hemophilia, but their daughter Anastasia did 21. Four babies are born in a hospital, and each has a dif-
not. Anastasia died, a victim of the Russian revolu- ferent blood type: A, B, AB, and O. The parents of
tion, before she had any children. Can we assume these babies have the following pairs of blood groups:
that Anastasia would have been a carrier of the dis- A and В, О and O, AB and O, and В and B. Which
ease? Would your answer be different if the dis- baby belongs to which parents?
ease had originated in Nicholas II or in Alexandra? 22. A couple both work in an atomic energy plant, and
13. In 1986, National Geographic magazine conducted a bom are exposed daily to low-level background radiation.
survey of its readers' abilities to detect odors. About After several years, they have a child who has
7% of Caucasians in the United States could not Duchenne muscular dystrophy, a recessive genetic
smell the odor of musk. If neither parent could smell defect caused by a mutation on the X chromosome.
musk, none of their children were able to smell it. On Neither the parents nor the grandparents have the
the other hand, if the two parents could smell musk, disease. The couple sue the plant, claiming that
their children generally could smell it, too, but a few the abnormality in their child is the direct result of
of the children in those families were unable to smell radiation-induced mutation of their gametes, and that
it. Assuming that a single pair of alleles governs this the company should have protected them from this
trait, is the ability to smell musk best explained as an radiation. Before reaching a decision, the judge hear-
example of dominant or recessive inheritance? ing the case insists on knowing the sex of the child.
14. A couple with a newborn baby is troubled that the Which sex would be more likely to result in an award
child does not resemble either of them. Suspecting of damages, and why?


Patterns of inheritance

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Patterns of inheritance