1. Evolution and Population Genetics
Xiaole Shirley Liu
STAT115 / STAT215

2. 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

3. 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

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

5. 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

6. 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

7. 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%)

8. 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

9. 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'

10. 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 …

11. 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

12. 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.

13. 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.

14. 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.

15. 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 = 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)

16. 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.

17. 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

18. Constant Mutation Rate?
Page & Holmes

19. 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.

20. 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

21. 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

22. 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

23. 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

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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. Acknowledgement
Francisco Ubeda
Jun Liu