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REVIEW HUMAN POPULATION GENETICS What is population genetics and why is it important? Theories of Darwin and Mendel & The Modern Synthesis. population evolution Population structure and the Hardy-Weinberg theorem. p2 + 2pq + q2 = 1 Microevolution. The Neutral Theory of Molecular Evolution. Dr. A. Ruth Freeman Department of Genetics Trinity College Dublin. Email: [email protected] www.gen.tcd.ie/molpopgen/ruth 1 2 1) Genetic Drift Factors that disrupt Hardy-Weinberg and cause Microevolution 1) Genetic drift 2) Gene flow 3) Mutation 4) Non-random mating 5) Natural selection 700 7 300 3 • Flip a coin 1000 times Î 700 heads and 300 tails Î very suspicious. • Flip a coin 10 times Î 7 heads and 3 tails Î well within the bounds of possibility. • The smaller the sample, the greater the chance of deviations from the expected result Î sampling error Îimportant factor in the genetics of small populations. • If a new generation draws its alleles at random, then the larger the sample size, the better it will represent the gene pool of the previous generation. N.B can act together 3 4 1 Genetic Drift - population with stable size ~ 10 Generation 1: p = 0.5 q = 0.5 Genetic Drift - population with stable size ~ 10 Generation 0: p (frequency of A) = 0.7 q (frequency of a) = 0.3 AA AA AA AA AA Aa Aa Aa Aa aa AA aa AA Aa Aa aa Aa Aa aa AA 5 6 Genetic Drift Genetic Drift - population with stable size ~ 10 Generation 2: p = 1.0 q = 0.0 • In this population of wildflowers, the frequencies of the alleles for pink and white flowers fluctuate over several generations. • Only a fraction of the plants manage to leave offspring and over successive generations, genetic variation Ð (fixed for A allele). AA AA AA • Microevolution caused by genetic drift, changes in the gene pool of a small population due to chance. AA • Only luck could result in random drift improving the population’s adaptation to its environment. AA AA AA • A population must be infinitely large for drift to be ruled out as an evolutionary process. AA • Many populations are so large that drift is negligible. AA AA 7 8 2 Examples of Genetic Drift The Founder Effect An extreme form of genetic drift is called the founder effect. • Shepard et al. PNAS 2005 102(46):16717-22 Microevolution and mega-icebergs in the Antarctic Adelie penguins, 6,000 years B.P., 5 loci It is a particular example of the influence of random sampling. • Helgason et al. Ann Hum Genet. 2003 67:281-97 It was defined by Ernst Mayr as: A reassessment of genetic diversity in Icelanders: strong evidence from multiple loci for relative homogeneity caused by genetic drift. "The establishment of a new population by a few original founders (in an extreme case, by a single fertilized female) which carry only a small fraction of the total genetic variation of the parental population." >300,000 Deficit of rare HVS1 sequences – less heterogenous than other Europeans 9 Examples of the founder effect in humans 10 Hum Genet. 1994 94:479-83. •Fragile X syndrome in Finland – single founder • Amish populations in the USA are descended from a few dozen founder individuals and tend to inter-marry. •Retinitis pigmentosa on Tristan da Cunha – 15 British founders • The result Î they exhibit some traits at higher frequencies than the general population, e.g. polydactyly, microcephaly •Genghis Khan’s Ychromosome 11 12 3 The Bottleneck Effect • Natural calamities can drastically reduce a population - usually unselective. • The result Î genetic composition of small surviving population Î unlikely to be representative of the original population. The Bottleneck Effect I The Cheetah (Acinoyx jubatus) originally had a wide range across Africa and Asia. Population bottleneck at the end of the last Ice Age about 10-12000 years ago. Climate change reduced habitat. 2nd bottleneck during the last 150 years as it was hunted almost to extinction. Cheetah are so genetically similar Î almost like clones. Alleles in original population Bottleneck event Skin can individuals. Surviving population 13 be grafted between Very susceptible to disease outbreaks. 14 The Bottleneck Effect III The Bottleneck Effect II The Northern Elephant Seal (Mirounga angustirostrus) - West coast of America. • Modern humans (Homo sapiens sapiens) may also have undergone a bottleneck ~ 120,000 years ago (very low molecular genetic diversity compared to chimps, gorillas etc.) Hunted almost to extinction during the 18th century. Passed through a population bottleneck of ~ 20 individuals. Now population has recovered ~ 30,000 Very low genetic variation. 24 gene loci examined for polymorphism Î no variation, fixed for 1 allele at each gene. Southern Elephant Seal Î plenty of variation, was never bottlenecked. 15 16 4 Gene flow between populations 2) Gene Flow Fixed for the pink allele p = 1.0 q = 0.0 • HWE requires the gene pool to be a closed system - most populations are not completely isolated. AA a • Population can gain or lose alleles by gene flow —genetic exchange due to migration of fertile individuals or gametes between populations. a a AA • Gene flow tends to reduce differences between populations that have accumulated because of natural selection or genetic drift. • If gene flow is extensive enough Î amalgamate neighbouring populations. a AA AA a a AA AA AA AA Pollen blown in during a storm AA AA 17 Gene Flow in Humans Next generation after gene flow p = 0.7 q = 0.3 • Many examples. - African Americans AA Aa 18 Aa Aa - Indian caste system (Lynn Jorde) AA Aa AA Aa Aa AA 19 20 5 3) Mutation Mutation in a small wildflower population • A mutation is a change in an organism’s DNA. Fixed for the white allele • New mutation Î transmitted in gametes will immediately change the gene pool Î either completely new allele or converted to the other allele. • A mutation that causes the white-flowered plant (aa) to produce gametes bearing dominant pink allele (A) would decrease freq. of a allele and increase freq. of A allele. p = 0.0 q = 1.0 aa aa aa aa • For any one gene Î mutation does not have much of an effect on a large population in a single generation. aa aa • Mutation at any given genetic locus is usually very rare. aa • Rate of one mutation per 105 - 106 gametes is typical. aa • Example: an allele has frequency of 0.5 in the gene pool. Mutates to another allele at a rate of 0.00001 mutations per generation Î 2000 generations to reduce the frequency of the original allele from 0.50 to 0.49. aa aa 21 Mutation in a small wildflower population Next generation: Mutation p = 0.05 q = 0.95 aa aa 22 • If a new allele increases its frequency significantly in a population Î usually because it confers a selective advantage not because mutation is continually generating it. aa aa • Mutations at a particular locus Î rare. However, impact of mutation at all genes is significant - Each individual: 1000’s of genes. aa aa aa aa Aa • Mutation is the original source of genetic variation Î raw material for natural selection. aa 23 24 6 Examples of Mutations in Humans 4) Non-random mating. • For HWE to hold Î individual of any genotype must choose its mates at random from the population. Huntington’s chorea – Lake Maracaibo • In reality Î individuals usually mate with close neighbours Î promotes inbreeding. • Most extreme example of inbreeding Î self-fertilisation (selfing). Lactose tolerance – Hollox et al Am J Hum Genet 2001 68:160-172 • Inbreeding causes relative genotype frequencies to deviate from HWE. • Heterozygotes will only produce 50% heterozygotes in the next generation. 25 26 Complete selfing Non-random mating - selfing in 24 plants Generation 0: Aa Aa AA Aa p (frequency of A) = 0.5 q (frequency of a) = 0.5 Aa aa Aa aa AA AA AA aa aa AA Aa AA AA aa p2 = 0.502 = 0.25 = 6 p2 = 0.502 = 0.25 = 6 (expected) q2 = 0.502 = 0.25 = 6 q2 = 0.502 = 0.25 = 6 (expected) AA aa aa AA Aa AA Aa Aa AA aa Aa AA Aa AA Aa aa AA Aa Aa aa Aa Aa aa aa aa Aa Aa AA Generation 1: p (frequency of A) = 0.5 q (frequency of a) = 0.5 aa aa 9 observed 9 observed Not in HWE 2pq = 2 x 0.50 x 0.50 = 0.50 = 12 (expected) 6 observed 2pq = 2 x 0.50 x 0.50 = 0.50 = 12 27 28 7 Non-random mating in humans Non-random mating Inbreeding • Even in less extreme cases of inbreeding Î proportion of heterozygotes will decrease (more slowly). • From a purely phenotypic perspective Î proportion of recessive phenotypes will increase (white flowered plants). • This is essentially why inbreeding is not a good idea Î recessive disorders become more frequent. • Isolated populations - Amish • Family systems – European Royals Assortative mating • Geography e.g. • Another type of nonrandom mating Î assortative mating. patients with schizophrenia – spouse risk • Sexual selection • Assortative mating Î individuals select partners with phenotypic characters similar to themselves (e.g. height in humans). e.g. • Assortative mating Î tend to increase homozygosity at certain genes. HLA alleles and olfactory molecules (Nat Genet 2002 30:175, PNAS 1995 260:245) Similarity of features (Alvarez & Jaffe 2004 Evol Psych) 29 30 Natural selection in wildflower population with pink mutant 5) Natural selection G0 allele frequencies • HWE requires that all individuals in a population be equal in their ability to survive and produce viable offspring (very unusual in reality). aa aa • Imagine pink flowers are more visible to pollen-collecting bees. p = 0.05 q = 0.95 aa aa • Over time, the frequency of the A allele will increase and the a allele will decrease because pink flowers more likely to be visited by bees. aa aa • HWE is disturbed - population is evolving. • Microevolution environment. through natural selection Î adaptation aa to aa Aa 31 aa 32 8 Natural selection in wildflower population with pink mutant Natural selection in wildflower population with pink mutant G1 allele frequencies p = 0.15 q = 0.85 G2 allele frequencies p = 0.30 q = 0.70 Aa aa Aa Aa aa aa aa Aa aa aa aa aa aa aa Aa Aa AA aa Aa aa 33 This kind of selection is also referred to as directional selection It favours a single allele and may drive it to fixation 34 Alternatively balancing selection acts to maintain genetic polymorphism/multiple alleles in the population Most famous classical example is the peppered moth. Multiple alleles are maintained by: Common type of peppered moth found around Manchester pre 19th century is referred to as typica. - heterozygote advantage/overdominance - selective advantage of certain allele combinations Carbonaria form appeared in 1848, and reached a frequency of 98% by 1895 - frequency dependent selection – sex ratios - environmental heterogeneity New “clean air” laws introduced – frequency of carbonaria reduced 35 36 9 Genetic selection in humans I: heterozygote advantage • Relatively high frequencies of certain alleles that confer reduced fitness on homozygotes (e.g. cystic fibrosis in Caucasians and sickle-cell anaemia in Africans) have arisen because the heterozygotes (Aa) have greater evolutionary fitness than either of the homozygotes (AA or aa). • For cystic fibrosis, it seems that heterozygotes are more resistant to the dehydrating effects of diseases associated with severe diarrhoea (e.g. cholera). • For sickle-cell anaemia there is good evidence that heterozygotes for HbS have increased resistance to death from malarial infection than the normal HbAHbA homozygotes. Wild type Sickle-cell 37 38 Positive selection in humans • Genes for language – FOXP2 • Genes for brain size - Microcephalin, ASPM Science 2005 (vol 309, p 1717 and p 1720) Positive selection in some human populations • Immunity – esp. malaria (1920’s - before extensive malaria-control programmes) • AIM1 in Europeans (Soejima et al 2005 MBE) 39 40 10 Question • In a population that is in HWE, 16% of the individuals show the recessive trait. What is the frequency of the dominant allele in the population? a) 0.84 b) 0.36 c) 0.6 d) 0.4 e) 0.48 REVIEW Genetic Drift – the founder effect, bottlenecks Gene Flow Mutation Non-random mating Selection 41 42 Useful Reading The Essentials of Genetics by John Murray – Jones Karp Giddings Biology by Campbell and Reece – Pearson Education Principles of Population Genetics by Daniel L Clark and Andrew G Clark - Sinauer Genetics of Populations by Philip W. Hedrick “Genetics and the origin of species: An introducion” Ayala and Fitch PNAS, Vol. 94, p 7691-7697 43 11