Selection against A 2 (upper row, s = 0.004) and for A 2 (lower row, s = ) N = 25 N = 250 N = 2500

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Why mitochondrial DN is simple Mitochondrial DN and the History of Population Size lan R Rogers January 4, 8 inherited from mother only no recombination evolves fast mean pairwise difference: average

$pairwise diff: between\within\net Major Human Populations European sian frican (N = ) (N = 7) (N = ) Eur 94 8 s 8 37 5 f 94 3 38 Chimpanzee Subspecies Pts Ptt Ptv (N = 4) (N = 8) (N = 8) Pts 9 3 37$ recently Eurasian populations less ancient 3 / 5 4 / 5 Movies of drift versus selection (N, s, and the fates of mutations) Selection against (upper row, s = 4) and for (lower row, s = -4) Each panel

recently Eurasian populations less ancient 3 / 5 4 / 5 Movies of drift versus selection (N, s, and the fates of mutations) Selection against (upper row, s = 4) and for (lower row, s = -4) Each panel

1 Why mitochondrial DN is simple Mitochondrial DN and the History of Population Size lan R Rogers January 4, 8 inherited from mother only no recombination evolves fast mean pairwise difference: average number of nucleotide site differences between mitochondria of pairs of individuals we will look at about 3 base pairs of mitochondrial DN / 5 / 5 Mitochondrial nucleotide differences (D-loop) Mean pairwise diff: between\within\net Major Human Populations European sian frican (N = ) (N = 7) (N = ) Eur 94 8 s f Chimpanzee Subspecies Pts Ptt Ptv (N = 4) (N = 8) (N = 8) Pts Ptt Ptv Genetic differences between human mitochondria are small between populations small within Eurasian populations somewhat larger within frica Suggests populations separated recently Eurasian populations less ancient 3 / 5 4 / 5 Movies of drift versus selection (N, s, and the fates of mutations) Selection against (upper row, s = 4) and for (lower row, s = -4) Each panel shows allele-freuency histories for a given N, s, and initial freuency Each history runs for generations or until fixation occurs Within each row of three panels, the population sizes are 5, 5, and 5 N = 5 N = 5 N = W( ) =, W( ) = -½s, and W( ) = -s The first set of cases (below) is a neutral control for the experiments in subseuent slides s =, = ½ (neutral case, pure drift) N = 5 fixations for : 48 N = 5 N = fixations for : 5 generations 4 generations generations 48 5 generations generations generations 5 / 5 Ns = Ns = Ns = 6 / 5

2 s = 4 = /N N = 5 N = 5 N = 5 Genealogy of genes s = -4 = /N s = - = /N N 99 7 / 5 8 / 5 Genealogy of 3 genes Genealogy of 4 genes C C N/3 N ( 3 + ) D N/6 N ( 6 + ) 3 N ( ) 9 / 5 / 5 Simulated gene genealogy of a sample of size 5 from a population of constant size Principles The expected length of a coalescent interval is long in large populations if there are only a few lineages What if the population changes in size? Terminal branches are short asal branch is long dditional samples don t tell us much about the ancient past / 5 / 5

Population Size Population Size N Effect of a population explosion 7 4 Mutational time before present Genealogy Mismatch Distribution Middle: comb-shaped (or star-shaped) genealogy of 5 individuals;

3 Population Size Population Size N Effect of a population explosion 7 4 Mutational time before present Genealogy Mismatch Distribution Middle: comb-shaped (or star-shaped) genealogy of 5 individuals; dots are mutations mutational diff per time unit ottom: = simulated data, line = theory Wave peaks at population expansion Mutational time before present Genealogy Mismatch Distribution Simulation of euilibrium population No history of growth Deep genealogy Ragged mismatch distribution 7 4 Site Differences Site Differences 3 / 5 4 / 5 Mitochondrial Mismatch Distribution i ˆN =, 3 ˆN = 9, ˆt = 68, 7 open circles: data of Cann, Stoneking, & Wilson (7) solid line: fit to expansion model (Rogers & Harpending 99) implies expansion 7 kyr ago (or so we thought then) revised molecular clock: 45 kyr ago coincident with origin of modern humans Mismatch Distribution: 77 sian Subjects i open circles: sian data solid line: fit to expansion model (Rogers & Harpending 99) implies expansion 45 kyr ago coincident with origin of modern humans 5 / 5 6 / 5 Mismatch Distributions of merindian mtdn Haplogroups Genealogies of merindian mtdn Haplogroups Fagundes et al 8 Fagundes et al 8 7 / 5 8 / 5

Skyline Plot Hepatitus C virus in Egypt (Drummond et al 5) Use mutations to estimate length of each interval Long intervals imply large population size Won t work with nuclear DN: too few mutations

Suppose that a favorable mitochondrial mutation arose 6, years ago, and increased in freuency until everyone had it This is called a selective sweep Effect on mitochondrial variation is

4 Skyline Plot Hepatitus C virus in Egypt (Drummond et al 5) Use mutations to estimate length of each interval Long intervals imply large population size Won t work with nuclear DN: too few mutations per tree (Drummond et al 5) 9 / 5 / 5 Estimated Size of merindian Population Estimated Size of ison Population Fagundes et al 8 / 5 / 5 The Selection Hypothesis Problems with mitochondrial clock Suppose that a favorable mitochondrial mutation arose 6, years ago, and increased in freuency until everyone had it This is called a selective sweep Effect on mitochondrial variation is indistinguishable from that of population growth No recombination: deleterious mutations are hard to get rid of Hang around in mtdn longer than in ndn t short time scales, we overestimate the count of neutral differences Overestimate dates within past, years 3 / 5 4 / 5

5 Summary History of population size affects depth of gene trees, genetic variation, and length of MRC segments We can use these facts to infer the history of population size Mitochondrial DN suggest that human populations were small during the last ice age With mitochondrial DN, it is hard to distinguish the effect of population growth from that of selection 5 / 5

Neutral Theory of Molecular Evolution

Neutral Theory of Molecular Evolution Kimura Nature (968) 7:64-66 King and Jukes Science (969) 64:788-798 (Non-Darwinian Evolution) Neutral Theory of Molecular Evolution Describes the source of variation