Beyond Mendel's laws of Inheritance.pdfa
- 1. TOPIC: BEYOND MENDEL’S LAW OF INHERITANCE REVIEW OF MENDEL’S PRINCIPLES • Genes are passed parents → offspring; get one allele from each parent • During Meiosis, the alleles for a gene segregate from each other • During Meiosis, genes independently assort with each other DOMINANCE • A relationship between alleles of one gene, in which one allele is expressed over a second allele at the same locus • The first allele is dominant and the second allele is recessive • Dominance is a key concept of Mendelian I. EXTENDING MENDELIAN GEN • Mendel worked with a simple system o Peas are genetically simple o Traits are controlled by a single gene o Each gene has only 2 alleles, 1 of which is completely dominant to the other • The relationship between genotype and phenotype is rarely that simple • Transmission patterns of a visible trait are not consistent with a mode of inheritance: o autosomal dominant o autosomal recessive • Alleles interact • Genes interact • Non-nuclear genes • Segregation of genes on same chromosome The following are several circumstances in which phenotypic ratios appear to contradict Mendel’s laws --- although the laws actually still apply. INCOMPLETE DOMINANCE/SEMI DOMINANCE/PARTIAL DOMINANCE • When a dominant allele forms a gene, does not completely mask the effects of a recessive alleles, and the organism’s resulting physical appearance shows a blending of both alleles. Notes • Heterozygote shows an intermediate, blended phenotype Example: RR = red flowers rr = white flowers Rr = pink flowers ➔ Make 50% less color • The dominant allele form of a gene does not completely mask the effect of the recessive allele; • Neither allele is dominant over the other • Expression of both alleles is observed as an intermediate phenotype (blending) in the heterozygous individual The difference in color between the RR and Rr genotypes is proposed to be a dosage effect, where the presence of one allele allows the production of half as much pigment as the presence of two alleles. The genotypic ratio (1:2:1) of the F2 generation is identical to that of Mendel’s monohybrid cross.
- 2. But, since neither allele is dominant, the phenotypic ratio is identical to the genotypic ratio. WHY DOES INCOMPLETE DOMINANCE OCCUR? 1. Because neither of the 2 alleles is fully dominant over the other OR the dominant allele does not fully dominate the recessive allele 2. Phenotype appears to the a mixture of both FAMILIAL HYPERCHOLESTEROLEMIA (FH) An example of incomplete dominance in humans. • A person with two disease-causing alleles lacks receptors on liver cells that take up the low-density lipoprotein (LDL) form of cholesterol from the blood stream. TWO MUTANT ALLELES Die as children of heart attacks. ONE MUTANT ALLELE May suffer heart attacks in young adulthood. TWO WILD TYPE ALLELES Do not develop this inherited form of disease. TAY-SACHS DISEASE • Caused by recessive trait • An important enzyme (protein) is missing that breaks down lipids (fat) in the central nervous system. • Fat (lipids) accumulates in the CNS causing damage • is an example showing both complete and incomplete dominance – depending on how one evaluates the phenotype. COMPLETE DOMINANCE (ON A WHOLE- BODY LEVEL) Because the heterozygote (carrier) is as healthy as a homozygous dominant individual. INCOMPLETE DOMINANCE (PHENOTYPE IS BASED ON ENZYME LEVEL) The heterozygote is intermediate between the homozygous dominant (full enzyme level) and homozygous recessive (no enzyme). Half the normal amount of enzyme is sufficient for health, which is why at the whole-person level, the wild type allele is completely dominant. MULTIPLE ALLELES “The presence of three or more alleles of the same gene in a population of organisms” • An individual diploid organism has at most, two homologous gene loci that may be occupied by different alleles of the same gene. o A diploid individual can carry any two of these alleles o Different allele combinations can produce variations in phenotype. WHY IS ABO BLOOD GROUP IN HUMANS CONSIDERED AN EXAMPLE OF MULTIPLE ALLELES? Example ABO blood group in humans • discovered by Karl Landsteiner (in the early 1900s) • has three alleles (A, B and O) • leading to four phenotypes: o type A, o type B, o type AB, and o type O blood
- 3. ABO SYSTEM LIKE THE MN BLOOD GROUP • is characterized by the presence of antigens on the surface of the red blood cells. • the A and B antigens are distinct from MN antigens and are under the control of different gene, located on chromosome 9. • One combination of alleles in the ABO system exhibits codominant mode of inheritance. ABO BLOOD GROUPS • Blood types are determined by the patterns of cell surface on RBCs. • Most of these molecules are proteins embedded in the plasma membrane with attached sugars (antigens) that extend from the cell surface. • Antigen is the molecule that is recognized by the immune system. • In the past, ABO blood types have been described as variants of a gene called “I” (isoagglutinogen) another term for antigen. • The older I system is easier to understand. CODOMINANCE • Different alleles that are both expressed. o Neither allele is dominant over the other o Expression of both alleles is observed as a distinct phenotype in the heterozygous individual Example 1: 1. type AB blood Alleles IA and IB are dominant to Io but are codominant to each other. Codominant alleles are observed simultaneously The ABO gene encodes a cell surface protein. • Allele A makes A protein • Allele B makes B protein • Allele O makes no protein Alleles A and B can be present on the cell surface at the same time. • Alleles A and B are codominant.
- 4. • Allele O is recessive to both A and B alleles. Example 2 MN Blood Group in humans • is characterized by an antigen called a glycoprotein, found on the surface of red blood cells. • In the human population, two forms of this glycoprotein exist, designated M and N: an individual may exhibit either one or both of them. • The MN system is under the control of an autosomal locus found on chromosome 4 and two alleles designated LM and LN . • Humans are diploid, so three combinations are possible each resulting in a distinct blood type. Codominant inheritance is characterized by distinct expression of the gene products of both alleles. In Incomplete dominance, heterozygotes express an intermediate, blended phenotype. Example 3 The two alleles are equally, but separately expressed: Ex: Roan horses & cattle, B = brown hair, b = white
- 5. LETHAL ALLELES • Genes which result in viability reduction of individual or become a cause for death of individuals carrying them. • It causes death before the individual can reproduce, (which prevents passage of his or her genes to the next generation). • Some lethal genes cause death of zygote or the early embryonic stage while some express their effect in later stages of development. HISTORY • Lucien Cuenot – discovered Lethal Genes while studying the inheritance of coat color in mice • Lucien expected a phenotype ratio from a cross of 3 yellow:1 white, but the observed ratio was 2:1 • Allele was lethal in homozygous dominant condition TYPES OF LETHAL GENES RECESSIVE LG • Lucian and Baur discovered these genes when they altered Mendelian Inheritance ratios. • Can code for either dominant or recessive traits, but they do not actually cause death UNLESS an organism carries 2 copies of the lethal alleles. DOMINANT LG • DLG are expressed in BOTH homozygotes and heterozygotes. • DLG are rarely detected due to their rapid elimination from populations. An example of this is Huntington’s disease. HUNTINGTON’S DISEASE A neurological disorder that reduces life expectancy. • The onset of this disease is slow therefore individuals carrying the allele can pass it on to their offspring. This allows the allele to be maintained in the population. Dominant traits can also be maintained in the population through recurrent mutations. Notes about the disease: • Degeneration of Nerve Cells (neurons) • Cognitive impairment • Inability to focus • Muscle rigidity • No treatment • Death in 1-5 years • Neuron Apoptosis (neurons die) EXAMPLE 2 Mexican hairless dogs result from a mutation in a gene that shows lethality
- 6. • hh (hairy, the wildtype trait) • Hh (hairless, one mutation present creates a visible phenotype) • HH (dies two mutations are lethal) EXAMPLE 3 In a cross of two heterozygous flies, the homozygous recessive progeny dies as embryo, leaving only the heterozygous and homozygous dominant flies. EXAMPLE 4 In humans, early-acting lethal alleles cause “spontaneous abortion (miscarriages, if they occur after the embryonic period.) • When a man and woman each carries a recessive lethal allele for the same gene, each pregnancy has a 25 percent chance of spontaneously aborting a proportion representing the homozygous recessive class. EXAMPLE 5 Inheritance patterns in three crosses involving the normal wild-type agouti allele (A) and the mutant yellow allele (Ay ) in the mouse. Note that the mutant allele behaves dominantly to the normal allele in controlling coat color, but it also behaves as a homozygous recessive lethal allele. The genotype Ay Ay does not survive. EPISTASIS (Greek for “stoppage”). • best examples of gene interaction. • occurs when the expression of one gene or gene pair masks or modifies the expression of another gene or gene pair. • Sometimes the genes involved control the expression of the same general phenotypic characteristics in an antagonistic manner, as when masking occurs. • In other cases, the genes involved exert their influence on one another in a complementary, or cooperative, fashion. FOR EXAMPLE the homozygous presence of a recessive allele prevents or overrides the expression of other alleles at a second locus. • In this case, the alleles at the first locus are said to be epistatic to those at the second locus, and the alleles at the second locus are hypostatic to those at the first locus.
- 7. IN ANOTHER EXAMPLE, a single dominant allele at the first locus influences the expression of the alleles at a second gene locus. IN A THIRD EXAMPLE, two gene pairs complement one another such that at least one dominant allele at each locus is required to express a particular phenotype. THE BOMBAY PHENOTYPE • The biochemical basis of the ABO blood-type system has been carefully worked out. • the A and B antigens are carbohydrate groups (sugars) that are bound to lipid molecules (fatty acids) protruding from the membrane of the red blood cell. • The specificity of the A and B antigens is based on the terminal sugar of the carbohydrate group. • Both A and B antigens are derived from a precursor molecule called the H substance, to which one or two terminal sugars are added. • Bombay phenotype was first recognized in a woman in Bombay in 1952, wherein the H substance is incompletely formed. • as a result, it is an inadequate substrate for the enzyme that normally adds the terminal sugar. This condition results in the expression of blood type O and is called the Bombay phenotype. • This condition is due to a rare recessive mutation at a locus separate from that controlling the A and B antigens. • The gene is now designated as FUT1 (encoding an enzyme, fucosyl transferase). • Individuals that are homozygous for the mutation cannot synthesize the complete H substance. • Thus, even they may have the IA and the IB alleles, neither the A nor B antigen can be added to the cell surface. H GENE IS EPISTATIC TO THE ABO GENE. • H protein attaches the A or B protein to the cell surface. • hh genotype = no H protein. • All ABO genotypes appear as type O.
- 8. A partial pedigree of a woman with the Bombay phenotype. Functionally, her ABO blood group behaves as type O. Genetically, she is type B. More examples If many such individuals have children, the phenotypic ratio of 3A: 6AB: 3B: 4 O is expected of their offspring. SEX-LINKED TRAITS SEX-LINKED INHERITANCE Sex-Linked Inheritance means that a gene (or multiple genes) is carried on one of the sex chromosomes • Genes are on sex chromosomes as opposed to autosomal chromosomes • first discovered by T.H. Morgan at Columbia U. • Drosophila breeding o good genetic subject ▪ prolific o 2-week generations o 4 pairs of chromosomes o XX=female, XY=male
- 9. Notes: 1. Males have only 1 X chromosome, a single recessive allele on that X chromosome will act as pseudo dominance and cause the disease 2. Females have 2 X chromosomes, so 2 copies of the recessive allele are required for the disease to express in females 3. Males NEVER pass the disease to their sons because there is no male-to-male transmission of the X chromosome 4. Males pass the defective X chromosome to all of their daughters, who are described as obligate carriers. 5. Transmission of the sex-linked disease from affected males to male grand children through carrier daughters is described as a “Nasse’s Law.” 6. Female carriers pass the defective X chromosome to half their sons. GENES ON SEX CHROMOSOMES Y-LINKED TRAITS • Very rare • has very few genes - mainly those that contribute to male characteristics (Only about 87 genes total.) • few genes other than SRY o sex-determining region o master regulator for maleness o turns on genes for production of male hormones • Transmitted male to male (female does not have Y chromosome) • No affected females • Defined Y-linked traits involve infertility and are not transmitted Y-LINKED GENES –caused by gene found on Y chromosome that is not homologous with X chromosome (called holandric gene = genes present in Y chromosome) • Not many holandric genes (17 genes are present in the non-homologous portion of human Y chromosome) EXAMPLES HYPERTRICHOSIS PINNAE AURIS A genetic disorder that causes hairy ears X-LINKED TRAITS • more genetic information – for gender and other characteristics (About 2050 genes!) • other genes/traits beyond sex determination o mutations: ▪ hemophilia ▪ Duchenne muscular dystrophy ▪ color-blindness • more than 60 diseases traced to genes on X chromosome WHO IS USUALLY AFFECTED BY SEX- LINKED DISORDERS? MEN! Genes for certain traits are on the X chromosome only… • Since Men only have one X chromosome then they are more likely to have the disorder • Women are somewhat protected since they have two X chromosomes and are less likely to inherit receive disorders. o If women receive a recessive gene on one X chromosome, they are called “carriers” because they “carry” the gene but don’t express the disorder SEX-LINKED DISORDERS • Affected males never pass the disease to their sons o Men give their “Y” to their sons!
- 10. • Affected males pass the defective X chromosome to all of their daughters, who are described as carriers o This means they carry the disease-causing allele but generally show no symptoms • Female carriers pass the defective X chromosome to… o half their sons (affected by the disease) o half their daughters (who are carriers) o The other children inherit the normal copy of the chromosome TYPES OF X-LINKED DISEASES X-LINKED DOMINANT DISEASE • Expressed in females with one copy • Males are often more severely affected • Typically associated with miscarriage or lethality in males • Passed from male to all daughters but not to sons Examples 1. X-linked hypophosphatemia – an X- linked dominant form of rickets. It can cause bone deformity including short stature. 2. Rett syndrome – a rare genetic neurological disorder of the grey matter of the brain. 3. Alport syndrome – a genetic disorder affected around 1 in 50,000 children characterized by end-stage kidney disease, and loss 4. Incontinentia pigmenti – a genetic disorder that affects the skin, hair, teeth, nails, and CNS. It is named due to its microscopic appearance. X-LINKED RECESSIVE DISEASE • More common than X-linked dominant • Female homozygotes show the trait but female heterozygotes do not • Affected males: inherited from mother who is homozygote or heterozygote • Affected females: affected fathers, affected or heterozygous mothers Note: • Without a biochemical test, an unaffected woman would not know she is a carrier for an X-linked recessive trait unless she has an affected son. • An X-linked recessive trait generally is more prevalent in males than in females. • A genetic counselor can estimate a potential carrier’s risk using probabilities derived from Mendel’s laws combined with knowledge of X-linked inheritance patterns.
- 11. Examples 1. Color blindness: the decreased ability to see color or differences in color. 2. Hemophilia: H.A is a genetic deficiency in clotting factor 8 3. HB: mutation of the factor 9 gene 4. Duchenne muscular dystrophy: results to muscle degeneration and premature death; mutation in gene dystrophin 5. Glucose-6-phosphate dehydrogenase deficiency: inborn error of metabolism that predisposes to hemolysis HOW DO YOU SOLVE SEX-LINKED PROBLEMS? WHAT ARE SOME X-LINKED DISORDERS? ALD (Adrenoleukodystrophy) X-linked recessive • A deadly genetic disease that is a result of fatty acid buildup caused by the enzymes not functioning properly • Causes damage to the nerves, resulting in neurological issues and, later, death. Hypertrichosis X-linked dominant • An abnormal amount of hair growth over the body o Informally called werewolf syndrome, because the appearance is similar to the mythical werewolf Menke’s Disease (Kinky Hair Syndrome) X-linked recessive • Rapid deterioration of the nervous system. • Weak muscle tone, sagging facial features, seizures, developmental delay, and intellectual disability caused by enzymes not functioning • Children with Menkes syndrome typically begin to develop symptoms during infancy and often do not live past age 6 Hemophilia X-linked recessive • The “Royal Blood Disease” impairs the body's ability to make blood clots o Clots are needed to stop bleeding • This results in people bleeding longer after an injury and an increased risk of bleeding inside joints or the brain Duchene Muscular Dystrophy X-linked recessive • a genetic disorder characterized by progressive muscle degeneration and weakness • Until relatively recently, boys with DMD usually did not survive much beyond their teen years o Advances in cardiac and respiratory care means that survival into the early 30s is becoming more common
- 12. SUMMARY MENDEL • 1st law – Law of Segregation – alleles segregate into gametes • 2nd law – Law of Independent Assortment – During metaphase I of meiosis, homologous pairs line up randomly on the equator – there is no pattern and it happens differently each time • Complete dominance BEYOND MENDEL • Incomplete dominance (blended colors) • Co-dominance (equal but separate expression) • Sex-linked traits (usually x-linked) • Pleiotropy (one gene many phenotypes) • Polygenic inheritance (many genes 1 pheno.) • Epistasis (one gene completely masks another)