Intro popgen spring 2015
- 1. Hasan Alhaddad, Ph.D. Guest lecturer: Molecular Genetics (342) In Faculty of Allied Health Sciences (LT2-123) April 1st 2015 (12:30 - 2:30) A Brief Introduction to Population Genetics
- 2. AIMS • Review Mendelian genetics and its relation to population genetics. • Review evolution and its relation to population genetics. • Introduce the field of population genetics and its significance. • Introduce the most basic model in population genetics (HW equation). • Run some beanbag experiments.
- 3. Who am I? • My name is Hasan Alhaddad. • Ph.D. in Genetics from UC Davis. • I studied insects and cats and I do population and evolutionary genetics for fun. • I love science and I like to share this love with everybody especially you.
- 4. Who am I? • Check my website for more information or if you need to contact me. hagenetics.org
- 5. Population genetics Population Genetics Evolutionary biologyMolecular Biology Mendelianism DNA RNA protein Darwinism dominant recessive co-dominant mutation mutation species neo-darwinism genetic drift mutation rate substitution deletion natural selection speciation fitness reproduction survival insertion transversion transition allele frequency selection gene allele Mendeldiscrete continuous locus loci chromosome different by state identical by state variation polymorphism homozygous heterozygous segregation monomorphic morphology haploid diploid biallelic multi-allelic Darwin immigration migration isolation population phlyogenetics phylogeny taxonomy genotype phenotype A T C G U replication transcription translation population structure genotype frequency N 2N pangenesis hybridization blending inheritance visual traits biochemical traits Mendel’s first law Mendel’s second law Fst Fis Inbreeding inbreeding depression mRNA tRNA rRNA gene expression splicing P F1 F2 filial generation parental generation adaptation polyploidy recombination rate Fisher Wright sympatric speciation allopatric speciation genome chromatin histone H3 H4 H2A H2B LD Ne generation p q 2pq variance continous epigenetics motif cis trans promoter exon intron transcriptome proteome double helix bp Kb Mb Gb nucleotide amino acid alpha helix Beta sheet
- 6. Population genetics is the field that results from combining Genetics and Evolution We need to review both genetics and evolution to properly cover concepts pertain to population genetics
- 7. Traditions of Genetics Natural selection of small changes Darwin Mendel Transmission of large differences Evolution and Population Genetics Analytical Genetics
- 8. Traditions of Genetics Pearson Darwin Mendel Biometricians Mendelists Yule Punnett Bateson Hardy Weinberg “one cannot help feeling that the speculations would have had more value had he kept his emotions under better control; the style and method of the religious revivalist are ill-suited to scientific controversy” (Edwards, 2008) Yule to Bateson (1902)
- 9. Mendel and the general theory of inheritance and basic laws
- 10. The chief motives to understand heredity and the bases of it were: 1. Speciation 2. Hybridization 3. Similarities between parents and offsprings Scientific motives
- 11. What were the theories of inheritance at the time?
- 12. Theories of inheritance Before Mendel the only proposed theory of inheritance was “blending inheritance”
- 13. Theories of inheritance How traits are passed on? Two hypotheses
- 14. Theories of inheritance What happens to characters when they are blended every generation?
- 15. Theories of inheritance Darwin’s hypothesis of Pangenesis “Gemmules” travel from every part of the body to the reproductive system to pass the traits to future generation. Hypothesis NOT supported by scientific evidence. O'Connor, C. & Miko, I. (2008) Developing the chromosome theory. Nature Education 1(1):44
- 16. Mendel and his peas Gregor Mendel (Johann) studied heredity by the systematic breeding experiments of garden pea (Pisum sativum)
- 17. Why Pea plants? Clear and distinct visual Traits/characters Mendel’s Peas
- 18. What kind of traits/characters are these? Why should we care?
- 19. Traits and characters Traits can be continuous or discontinuous (also called discrete)
- 20. Traits
- 21. OK!? What is the connection to Darwin and Mendel?
- 22. Mendel’s characters vs. Darwin’s Mendel focused on variation of large effect while Darwin observed small variations that affect fitness
- 23. Lost? Do not worry We will get to Darwin in a bit
- 24. Mendel’s discrete characters Mendel chose seven discrete characters that can be easily be visualized and identified. Miko, I. (2008) Gregor Mendel and the principles of inheritance. Nature Education 1(1):134
- 25. Mendel’s pure single trait lines 1) Establish pure lines of each character Which characters?
- 26. What are pure lines? Homozygous? Identical by state?
- 27. 2) Cross breed the pure lines. 3) Resulting plants are hybrids. 4) Inspect the phenotypes of the first generation. How do we inspect the phenotype? Why? First generation
- 28. Observations and findings: • All resulting plants exhibits the phenotype of one of the parents. • One of the parental phenotypes disappears in the first hybrid generation. First generation
- 29. 5) Self cross the F1 individuals. 6) Inspect the phenotypes of the resulting F2 generation. Second generation
- 30. How did Mendel inspect the phenotypes of the F2 generation? Second generation
- 32. Observations and findings: • The selfing of the first generation results in the reappearance of one of the parents’ characteristics. • A factor/particle is within the plant that results in the appearance of the plant. • Both male and female contribute equally to the phenotype. • The absence or appearance of a specific character depends on the combination of factors. Mendel’s Monohybrid Experiment
- 33. Observations and findings: • The “factor” that appeared in all individuals of the first generation is the “dominant” factor. • The “factor” that disappeared in the first generation is the “recessive” factor. Factor’s type
- 34. • The P generation is a pure bred contains each with two factors of the same type (homozygous). • The F1 generation is a hybrid and as a result contains two different “factors” one from each of the parents (heterozygous). Genotype
- 35. • “Factors” within a plant separate during the formation of gametes. • “Factors” unite during fertilization randomly. • The phenotype of resulting union is determined by the combination of factors. Segregation of factors (alleles) Mendel’s 1st law
- 36. • Yellow : Green 3:1 • Round : Wrinkled 3:1 What is the ratio of each phenotype independently? Mendel’s 2nd law • Each factor segregate independently. Independent Assortment
- 37. • What is “dominant” and “recessive” a description of? • What is a phenotype? • What is a genotype? • What is a homozygous? • Identical by state? • What is a heterozygous? • Different by state? • Did Mendel observe or infer genotype? • Did Mendel observe or infer phenotype? Review
- 39. What is an allele? Alleles are Mendel’s factors that he could not see but infer by crosses Do not get it? They are the (A) and (a) that are being passed into gametes and unite to give the genotype of an individual.
- 40. What is an allele?
- 41. Alleles on chromosomes? Where? Same location? Same chromosome?
- 42. Locus • A specific location in the genome is called locus (plural loci). • Alleles at the same locus are inherited each from one parent.
- 43. Alleles at a locus • DNA at a specific locus may differ in one individual. • How? • What are the alleles in the figure?
- 44. Mendel’s work Important contributions by Mendel to biology: 1.Genotypic notation. 2.Quantitative framework.
- 45. Now we need to review some evolution What is evolution? What is to evolve?
- 46. Evolution in general Change through time Non-biological Biological Is evolution a fact or a theory? Evolution (biological and non-biological) is a fact that is explained by theories Not buying it?
- 47. Evolution in general Can you think of a theory that explains the evolution of: 1) Food and cuisine (ex. Machboos) 2) Cars (ex. Ferrari) 3) Houses and cities (ex. skyscrapers) 4) Clothes and fashion (ex. Deshdasha)
- 48. So what about biological evolution? Let’s start with the theory before Darwin
- 49. Lamarckian inheritance and evolution Jean Baptiste Lamarck Lamarck proposed the inheritance of acquired characteristics
- 50. Testing Lamarck’s idea August F. Weismann • Weismann tested Lamarck’s idea using mice. • Cutting mice tails and breeding them. • 5 generations! What happened?
- 51. Natural selection Darwin and Wallace, independently, proposed a theory of biological evolution and called it “Natural selection” Charles Darwin Alfred Russel Wallace
- 52. Variation!
- 53. 1) Individuals within a population are variable. 2) Variation is heritable (passed to offsprings). 3) Differential survival and reproduction. 4) Survival and reproduction is not random (individuals with best variation produce more offsprings). Natural selection
- 54. It is all about variation!
- 55. Did Darwin answer where variation come from? Did he know about heredity? Did he know about genes/factors? Did evolutionary biology stop and end with Darwin’s theory? Is natural selection the only force of evolution? The field of evolutionary biology has itself evolved and evolutionary studies have gone way beyond Darwin
- 56. Population genetics is the answer
- 57. Some significance “Nothing in biology makes sense except in the light of evolution” Theodosius Dobzhansky, 1973
- 58. Some significance “Nothing in evolution makes sense except in the light of population genetics” Jeffrey Ross-Ibarra (2010 citing his mentor)
- 59. It is the study of the evolutionary historical record of a group of individuals documented in the DNA of their descendants What is population genetics?
- 60. Why population genetics? 1) Understand and refine theory
- 61. Why population genetics? 2) Understand the history of genes Opazo, J. C., Hofmann, F. G. & Storz, J. F. (2008) Genomic evidence for independent origins of β-like globin genes in monotremes and therian mammals. Proceedings of the National Academy of Sciences (105): 1590–1595
- 62. Why population genetics? 3) Understand the history of populations/ organisms 21. J. Parsonnet, in Microbes and Malignancy, J. Parsonnet, Ed. (Oxford Univ. Press, New York, 1999), pp. 3–18. 22. Y. Xu et al., Genomics 81, 329 (2003). 23. We thank the National Cancer Institute–supported Cooperative Human Tissue Network for tissues used in this study, M. Aquafondata for tissue staining, P. S. Schnable for sharing cDNA data sets used in DTS pilot testing, O. Gjoerup and R. D. Wood for helpful comments, and J. Zawinul for help with the manuscript. Supported in part by funds from NIH R33CA120726 and the Pennsylvania Department of Health. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. Supporting Online Material www.sciencemag.org/cgi/content/full/1152586/DC1 Materials and Methods Figs. S1 to S3 Tables S1 to S5 References 5 November 2007; accepted 8 January 2008 Published online 17 January 2008; 10.1126/science.1152586 Include this information when citing this paper. Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation Jun Z. Li,1,2 *† Devin M. Absher,1,2 * Hua Tang,1 Audrey M. Southwick,1,2 Amanda M. Casto,1 Sohini Ramachandran,4 Howard M. Cann,5 Gregory S. Barsh,1,3 Marcus Feldman,4 ‡ Luigi L. Cavalli-Sforza,1 ‡ Richard M. Myers1,2 ‡ Human genetic diversity is shaped by both demographic and biological factors and has fundamental implications for understanding the genetic basis of diseases. We studied 938 unrelated individuals from 51 populations of the Human Genome Diversity Panel at 650,000 common single-nucleotide polymorphism loci. Individual ancestry and population substructure were detectable with very high resolution. The relationship between haplotype heterozygosity and geography was consistent with the hypothesis of a serial founder effect with a single origin in sub-Saharan Africa. In addition, we observed a pattern of ancestral allele frequency distributions that reflects variation in population dynamics among geographic regions. This data set allows the most comprehensive characterization to date of human genetic variation. I n the past 30 years, the ability to study DNA sequence variation has dramatically increased our knowledge of the relationships among and history of human populations. Analyses of limited populations, or both, and yield an in- complete picture of the relative importance of mutation, recombination, migration, demogra- phy, selection, and random drift (7–10). To Europe, the Middle East, South/Central Asia, East Asia, Oceania, and the Americas (11). This data set is freely available (12) and allows a detailed characterization of worldwide genetic variation. We first studied genetic ancestry of each individual without using his/her population identity. This analysis considers each person’s genome as having originated from K ancestral but unobserved populations whose contributions are described by K coefficients that sum to 1 for each individual. To increase computational effi- ciency, we developed new software, frappe, that implements a maximum likelihood method (13) to analyze all 642,690 autosomal SNPs in 938 unrelated and successfully genotyped HGDP- CEPH individuals (14). Figure 1A shows the results for K = 7; those for K = 2 through 6 are in fig. S1. At K = 5, the 938 individuals segregate into five continental groups, similar to those re- 1 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305–5120, USA. 2 Stanford Human Genome Center, Stanford University School of Medicine, Stanford, CA 94305–5120, USA. 3 Department of Pediatrics, Stanford University School of Medicine, Stanford, 4 Various body site tissues Total MCV negative (%) 54/59 (92) Total MCV positive (%) 5/59 (8) Appendix control 1 –/+ Appendix control 2 –/+ Gall bladder –/+ Bowel –/+ Hemorrhoid –/+ Skin and skin tumor tissues Total MCV negative (%) 21/25 (84) Total MCV positive (%) 4/25 (16) Skin –/+ KS skin tumor 1 –/+ KS skin tumor 2 –/+ KS skin tumor 3 –/+
- 63. Why population genetics? 4) Understand the relationship between organisms
- 64. Why population genetics? 5) Classify groups of living organisms
- 65. Why population genetics? 6) Understand the evolutionary forces that shape life forms
- 66. Why population genetics? 7) Reconstruct the history and the timing of evolutionary events
- 67. Why population genetics? 8) Find cool stuff! Genome-wide Association studies (GWAS)
- 68. Redefining evolution Evolution is the change in allele frequency at a locus in a population over time Change in frequency Time Allele frequencies? populations? Evolutionary forces act on an individuals, correct? Why populations?
- 69. Redefining evolution Evolutionary forces act on the individuals but the affects are seen in populations in the form of changes in allele frequency So what exactly do we do? We study the effects of evolutionary forces on the frequency of a mutant allele Ya Rabbi What are all these terms? I am lost
- 70. Redefining evolution One more thing about the changes Molecular changes vs. Morphological changes Small effects on fitness large effects on fitness If they have small effects, then we will have to deal with chance We need models to understand stochastic/random forces vs.
- 71. (1) Edwards, 2008 Hardy-Weinberg Principle “ The answer was in Mendel’s paper all the time”1 The first and most basic model in population genetics
- 72. Hardy-Weinberg Law Weinberg Hardy • Wilhelm Weinberg • (1862-1937) • German Physician • Godfrey H. Hardy • (1877-1947 ) • English mathematician
- 73. (1) Edwards, 2008 (2) Jewett,1914 How did a mathematician, Hardy, get involved? • February 28th 1908, Punnett gave a lecture on “Mendelism in relation to disease” 1. •The lecture discusses brachydactylism. • Brachydactylism means short- fingeredness 2. • Shortness in fingers and toes relative to other body parts. • The genetics disease is a dominant trait.
- 74. (1) Edwards, 2008 • Yule: if brachydactyl is a dominant trait (assuming random mating) ➔ 3:1 brachydactyl : normal. 1 • Yule misinterpreted Mendel’s theory. In order to get the 3:1 ratio, the gene frequency must be ½. • Punnett: interpreted Yules remarks as “why the nation was not becoming ….. Brachydactylous”. 1 • Punnett was puzzled “why the dominant did not continually increase in frequency?” 1 • Hardy ….. Help! How did a mathematician, Hardy, get involved?
- 75. (1) Hardy, 1908 Mendelian Proportions in a Mixed Population 1 • Assumptions: Aa is a Mendelian characters. The numbers of genotypes pure dominant (AA), heterozygotes (Aa), and pure recessives (aa) are 1:2:1 respectively. • Conditions: “ … suppose that the numbers are fairly large, so that mating may be regarded as random, that the sexes are evenly distributed among the three varieties, and that all are equally fertile.”1 • Using “a little mathematics …” the allele frequencies in the next generation will be “ .. unchanged after the second generation.” • “ I have … considered only the very simplest hypotheses possible.” 1
- 76. Assumptions • Single locus / Biallelic locus • Diploid organism / Equal sexes. • No natural selection: equal survival rates and reproductive success • No mutation: no alleles created or converted • No migration/gene flow: individuals do not move into or out of the population
- 77. Assumptions • No genetic drift. • Population is infinitely large: sampling errors and random effects insignificant. • No population subdivision. • Random mating (no inbreeding). • Non overlapping generations.
- 78. The idea Allele 2 (a) Allele 1 (A) Single locus and two alleles q = frequency of Allele 2 q = p = frequency of Allele 1 p = What is the frequency of all alleles in a population? p + q = # of allele 1 # allele 1+allele 2 # of allele 2 # allele 1+allele 2 # of allele 1 # allele 1+allele 2 # of allele 2 # allele 1+allele 2 + = # allele 1+allele 2 # allele 1+allele 2
- 79. Hardy-Weinberg Principle (1) p + q = 1 A (p) a (q) a (q) AA (p2) Aa (pq) Aa (pq) aa (q2) (2) p2+2pq+q2=1 Predictions (1) Allele frequency do not change over time (2) Genotype frequencies can be calculated A (p)
- 80. (1) Klug et al., Concepts of Genetics Relationship between genotype and allele frequency 1 p2+ 2pq + q2 =1 p2 = (0.8)2 = 0.64 2pq = 2*(0.8)*(0.2) = 0.32 q2 = (0.2)2 = 0.04 Population is at HW equilibrium at this locus
- 81. What happens in frequencies ARE NOT in HW equilibrium? We test which assumption of HW was violated and may, as a result, explain the evolution of the population at this particular locus
- 82. Not so brief introduction after all Sorry :-)
- 83. REPRINTS AND REFLECTIONS A Defense of Beanbag Genetics* JBS Haldane My friend Professor Ernst Mayr, of Harvard University, in his recent book Animal Species and Evolution1 , which I find admirable, though I disagree with quite a lot of it, has the following sentences on page 263. The Mendelian was apt to compare the genetic contents of a population to a bag full of colored beans. Mutation was the exchange of one kind of bean for another. This conceptualization has been referred to as ‘‘beanbag genetics’’. Work in population and developmental genetics has shown, however, that the thinking of beanbag genetics is in many ways quite misleading. To consider genes as independent units is meaningless from the physiological as well as the evolutionary viewpoint. Any kind of thinking whatever is misleading out of its context. Thus ethical thinking involves the concept of duty, or some equivalent, such as right- eousness or dharma. Without such a concept one is lost in the present world, and, according to the religions, in the next also. Joule, in his classical papers on the mechanical equivalent of heat, wrote of the duty of a steam engine. We now write of its horsepower. It is of course possible that as I have been officially informed that I for a visa for entering the United State dead, but when alive preferred attack Wright is one of the gentlest men I ha and if he defends himself, will not counte leaves me to hold the fort, and that by w than speech. Now, in the first place I deny that the m theory of population genetics is at all im least to a mathematician. On the contr Fisher, and I all made simplifying assum allowed us to pose problems soluble by tary mathematics at our disposal, and e not always fully solve the simple prob ourselves. Our mathematics may impre but do not greatly impress mathematic give a simple example. We want to kn frequency of a gene in a population ch natural selection. I made the following assumptions3 : 1. The population is infinite, so the each generation is exactly that calcula somewhere near it. 2. Generations are separate. This is minority only of animal and plant s even in so-called annual plants a fe Published by Oxford University Press on behalf of the International Epidemiological Association ß The Author 2008; all rights reserved. International Journal of Epidemiolog doi: REPRINTS AND REFLECTIONS A Defense of Beanbag Genetics* JBS Haldane My friend Professor Ernst Mayr, of Harvard University, in his recent book Animal Species and Evolution1 , which I find admirable, though I disagree with quite a lot of it, has the following sentences on page 263. The Mendelian was apt to compare the genetic contents of a population to a bag full of colored beans. Mutation was the exchange of one kind of bean for another. This conceptualization has been referred to as ‘‘beanbag genetics’’. Work in population and developmental genetics has shown, however, that the thinking of beanbag genetics is in many ways quite misleading. To consider genes as independent units is meaningless from the physiological as well as the evolutionary viewpoint. Any kind of thinking whatever is misleading out of its context. Thus ethical thinking involves the concept of duty, or some equivalent, such as right- eousness or dharma. Without such a concept one is lost in the present world, and, according to the religions, in the next also. Joule, in his classical papers on the mechanical equivalent of heat, wrote of the duty of a steam engine. We now write of its horsepower. It is of course possible that ethical conceptions will in future be applied to electronic calculators, which may be given built-in consciences! as I have been officially informed that I am ineligible for a visa for entering the United Statesy . Fisher is dead, but when alive preferred attack to defense. Wright is one of the gentlest men I have ever met, and if he defends himself, will not counterattack. This leaves me to hold the fort, and that by writing rather than speech. Now, in the first place I deny that the mathematical theory of population genetics is at all impressive, at least to a mathematician. On the contrary, Wright, Fisher, and I all made simplifying assumptions which allowed us to pose problems soluble by the elemen- tary mathematics at our disposal, and even then did not always fully solve the simple problems we set ourselves. Our mathematics may impress zoologists but do not greatly impress mathematicians. Let me give a simple example. We want to know how the frequency of a gene in a population changes under natural selection. I made the following simplifying assumptions3 : 1. The population is infinite, so the frequency in each generation is exactly that calculated, not just somewhere near it. 2. Generations are separate. This is true for a minority only of animal and plant species. Thus even in so-called annual plants a few seeds can survive for several years. 3. Mating is at random. In fact, it was not hard to allow for inbreeding once Wright had given a Published by Oxford University Press on behalf of the International Epidemiological Association ß The Author 2008; all rights reserved. International Journal of Epidemiology 2008;37:435–442 doi:10.1093/ije/dyn056 Let’s do beanbag genetics
- 84. Let’s do beanbag genetics