Evolution and Population Genetics Xiaole Shirley Liu STAT115 / STAT215

Evolution Evolution is a gradual change in genetic makeup from one generation to the next Evolution: Natural Selection Mutation Genetic Drift … Natural selection and genetic drift are the two most important causes of allele substitution in populations Nonrandom process Random processes

Evolution Evolution creates species-specific and population-specific differences Are they all selected for advantages to the species or population? Some definitions: Locus: position on chromosome where a sequence or a gene is located Allele: alternative form of DNA on a locus Written as A vs a, or A vs B

What about transgenerational epigenetic inheritance? Natural Selection What about transgenerational epigenetic inheritance? Controversial

Phenotypic vs Molecular Evolution Motoo Kimura Phenotypic evolution is controlled by natural selection Molecular mutations are selectively neutral in the strict sense as that their fate in evolution is largely determined by random genetic drift Genetic drift due to sampling errors

Random Fluctuation in Allele Frequencies Metapopulation Neutral alleles Deme p q p' pt … time Drunk traveler staggering on a train platform with tracks on both sides… will eventually fall off the edge of the platform onto one or the other track

Genetic Drift p q Deme Metapopulation p' pt Neutral alleles … time Over time, allele frequency in each sub-population will fluctuate, diversity in each sub-population will decrease till an allele is fixed (100%) or lost (0%)

Factors Influencing Genetic Drift Deme: a population consisting of closely related species that can typically breed within Initial mutation (allele) occurs in a deme of N individuals (effective population size) Assuming neutral evolution, its probably of being sampled in the offspring is 1/2N The likelihood of a mutation being fixed is its initial frequency (1 / 2N): smaller population, more likely fix; larger population more likely lost Founder effect: new colony starts from few members (small N) of initial population

Factors Influencing Genetic Drift An allele’s probability of fixation equals its frequency at that time and is not affected by its previous history In a diploid population, the average time to fixation of a newly arisen neutral allele that does become fixed is 4N generations: evolution by genetic drift proceeds faster in small than in large populations Bottleneck: drastic population decrease for at least one generation  accelerate fixation p'

Factors Influencing Genetic Drift Initially genetically identical demes can evolve by chance to have different genetic constitutions Pb (mutation X will fix) = allele frequency Among genetically identical demes in a metapopulation, average allele frequency does not change but heterogeneity in each declines to 0 Metapopulation Neutral alleles Deme p q p' pt …

The Neutral Theory of Molecular Evolution Most mutations (genetic variations) are fixed from genetic drifts: neutrally selected and lacks adaptive significance Some mutations are disadvantageous and eliminated Only minority of mutations are advantageous and fixed from natural selection Break

By comparing DNA changes among populations we can trace their history Population 1: A T G T A A C G T T A T A Population 2: A C G T A A C G T T A T A Population 3: A C G A A A C G T T A T A Population 4: A C G A A A C C T T A T A 1 2 3 4 How can we trace our ancestry with DNA? DNA changes (or “mutates”) over time, and these changes are passed from parent to child. As these changes build up over time, and populations migrate around the globe, each population will have some changes (which we refer to as “markers”) that are specific to their area and others that reflect where that population came from [click 4 times to show changes building up over time and placement of populations on tree]. The more DNA markers two populations have in common, the more closely related those populations are likely to be. In this example, populations 3 and 4 are more closely related (ie share a more recent common ancestor), than populations 1 and 4. By comparing the number of DNA changes over time, and calibrating this with the fossil record, researchers can estimate how many years have passed since two populations split.

From Phylogeny to Selection The protein-coding portion of DNA has synonymous and nonsynonymous substitutions. Thus, some DNA changes do not have corresponding protein changes. If the synonymous substitution rate (dS) is greater than the nonsynonymous substitution rate (dN), the DNA sequence is under negative (purifying) selection. If dS < dN, positive selection occurs. E.g. a duplicated gene may evolve rapidly to assume new functions.

Molecular Clock Molecular evolutionary substitutions proceed at ~constant rate, sequence difference between species  a molecular clock If sequences evolve at constant rates (big if), they can be used to estimate the times that sequences diverged. ~Dating fossils by radioactive decay.

Molecular Clock L = number of nucleotides compared between two sequences N = total number of substitutions K = N / L, number of substitutions per nucleotide E.g. K = 0.093 for rat versus human r = rate of substitution (mutations) = 0.56 x 10-9 per site per year r = K / 2T  T = .093 / (2)(0.56 x 10-9) = 80 million years Graur and Li (1999)

Factors Influencing Mutation Rate / Molecular Clock Generation time (age to reproduction) Population size (stronger drifts in small populations) Intensity of natural selection Species-specific differences When two species are way too different, over a sufficiently long time some sites experience repeated base substitutions, so the observed number of differences will plateau.

Factors Influencing Mutation Rate / Molecular Clock Generation time (age to reproduction) Population size (stronger drifts in small populations) Intensity of natural selection Species-specific differences Change in protein function

Constant Mutation Rate? Page & Holmes

Where did we come from? Two competing hypotheses Multiregional evolution (1 millions years ago, Homo erectus left Africa, and evolve into modern humans in different parts of the Old World) The Out of Africa hypothesis: Homo erectus were displaced by new populations of modern humans that left Africa 100K to 50K years ago.

Break National Geographic Story Jan 2014 If a fragment of DNA is shared by Neanderthals and non-Africans, but not Africans or other primates, it is likely to be a Neanderthal heirloom. People living outside Africa carries 1-4% of Neanderthal DNA (skin, hair, etc). Break

Polymorphism Polymorphism: sites/genes with “common” variation, less common allele frequency >= 1%, otherwise called rare variant and not polymorphic Single Nucleotide Polymorphism Come from DNA-replication mistake individual germ line cell, then transmitted ~90% of human genetic variation Copy number variations May or may not be genetic STAT115

Why Should We Care Disease gene discovery Personalized Medicine Association studies, e.g. certain SNPs are susceptible for diabetes Chromosome aberrations, duplication / deletion might cause cancer Personalized Medicine Drug only effective if you have one allele STAT115

SNP Distribution Most common, 1 SNP / 100-300 bp Balance between mutation introduction rate and polymorphism lost rate Most mutations lost within a few generations 2/3 are CT differences In non-coding regions, often less SNPs at more conserved regions In coding regions, often more synonymous than non-synonymous SNPs STAT115

SNP Characteristics: Allele Frequency Distribution Most alleles are rare (minor allele frequency < 10%) STAT115

SNP Characteristics: Linkage Disequilibrium Hardy-Weinberg equilibrium In a population with genotypes AA, aa, and Aa, if p = freq(A), q =freq(a), the frequency of AA, aa and Aa will be p2, q2, and 2 pq respectively at equilibrium. Similarly with two loci, each two alleles Aa, Bb STAT115

SNP Characteristics: Linkage Disequilibrium Equilibrium Disequilibrium LD: If Alleles occur together more often than can be accounted for by chance, then indicate two alleles are physically close on the DNA In mammals, LD is often lost at ~100 KB In fly, LD often decays within a few hundred bases 0.26 ab STAT115

SNP Characteristics: Linkage Disequilibrium Statistical Significance of LD Chi-square test (or Fisher’s exact test) eij = ni. n.j / nT B1 B2 Total A1 n11 n12 n1. A2 n21 n22 n2. n.1 n.2 nT STAT115

SNP Characteristics: Linkage Disequilibrium Haplotype block: a cluster of linked SNPs Haplotype boundary: blocks of sequence with strong LD within blocks and no LD between blocks, reflect recombination hotspots STAT115

SNP Characteristics: Linkage Disequilibrium Haplotype block: a cluster of linked SNPs Haplotype boundary: blocks of sequence with strong LD within blocks and no LD between blocks, reflect recombination hotspots Haplotype size distribution STAT115

Summary Phenotype evolution (natural selection) vs molecular evolution (neutral theory) Decrease of genetic variation over time Fixation: population size, probability Positive and negative selection (dN / dS ratio) Molecular clock and migration patterns Genome variations: SNP and CNV Linkage disequilibrium from recombination

Acknowledgement Francisco Ubeda Jun Liu