MCB Lecture 10 - Population Genetics and Evolution

Are allele frequencies constant?

NO.

Populations have different frequencies of alleles

• In widely dispersed populations, allele frequency varies within sub populations

• Ex: Human Brown vs. Blue Eye Color

What is an example of allele frequency inconsistency

• Ex: Human Brown vs. Blue Eye Color

Why do allele frequencies change?

• Natural populations rarely meet Hardy-Weinburg assumptions

  • NO POPULATION IS INFINITELY LARGE

  • New mutations at each locus arise occasionally

  • Migrations of small groups of individuals does occur

  • Mating isn’t random

  • Genotype-specific differences in fitness

What is the Hardy-Weinberg equation useful for?

Estimating population changes through a few generations

(Not as useful for predicting long term changes but does provide foundation for modeling)

What do Monte Carlo Simulations do?

• Perform random sampling of inputs to produce probability distribution

  • Useful for modeling systems where inputs have high uncertainty or the mathematics is intractable/too complex

  • Named after Monte Carlo Casino

What is Monte Carlo Simulations specifically used for in Population Genetics

Used to model changes in allele frequencies

• Starting population has a defined number of individuals that are homozygous/heterozygous

• Experiment runs for specified number of generations

• Multiple, independent experiments performed

At each generation in the simulation (4 things - Monte Carlo)

• Random mating pairs chosen

• Genotypes of offspring based on probabilities

• Continues until total offspring number = parental population size

• Parental generation is discarded, offspring are parents of next generation

Monte Carlo - What does each simulation represent?

A possible pathway of genetic drift

What is Genetic Drift?

Change in allele frequencies as a consequence of randomness in inheritance due to sampling error from one generation to the next

Six Monte Carlo simulations were run with 2 initial populations of heterozygous individuals, what happened?

• NO SELECTION

• Small population with 10 individuals had more genetic drift than larger population with 500 individuals

What is Fixation?

Fixation: When only one allele in a population has survived and all individuals are homozygous for that allele

• Fixed because no further changes can occur (in absence of migration of mutation)

How big are the changes in allele frequencies each generation?

• Relatively small

• Over many generations can accumulate (once tiled, easier)

What is the Founder effect?

A few individuals separate from a larger populations and establish a new population

What are population bottlenecks?

• A large proportion of individuals die, resulting in a smaller population

What are population bottlenecks?

A large proportion of individuals die, resulting in smaller population

What happens in both founder effects and bottlenecks?

A small subset is taken from a large population and then grows

2 places to introduce allele change:

• Random subset may not be representative

• Small population causes rapid genetic drift

What are mutations?

Variant DNA sequence in individual genome that wasn’t present in either parent

• Deleterious: Reduce fitness

• Beneficial: Increase fitness

• Neutral: No benefit/harm

What is molecular clock?

• Mutations accumulate in populations at fairly constant rate over time

• DNA differences between organisms can be used to estimate how long ago they shared common ancestor

How does mutating allele affect allele frequency?

VERY DIRECTLY

• EXTREME EX: 100% AA individuals in population, single mutation makes it 99.999% AA, 0.01% Aa

• ANOTHER EX: 25% A1A1, 50% A1A2, 25% A2A2, mutation adds a new allele A3, changing all 3 frequencies

When generally isolated populations exchange individuals…

Allele frequencies and ratios can change!

(This is most noticeable when a new allele is added)

The amount of change in allelic frequency due to migration between populations depends on:

• Difference in allelic frequency

• Extent of migration

What are examples of nonrandom mating?

• Positive assortative mating

  • a tendency of phenotypically like individuals to mate

• Negative assortative mating

  • a tendency of phenotypically unlike individuals to mate

• Inbreeding vs. Outcrossing

  • Crossing btw. closely related vs. unrelated individuals

  • (Based on genotype, not phenotype)

• Inbreeding coefficient

  • Probability that 2 alleles at any locus are identical by descent of a common ancestor of 2 parents

• Inbreeding depression

  • Reduced fitness due to loss of genetic diversity

  • Ex: Corn, loss fitness and smaller corns, fewer seeds, etc)

What is positive assortative mating?

• Positive assortative mating

  • a tendency of phenotypically like individuals to mate

What is Negative assortative mating?

• Negative assortative mating

  • a tendency of phenotypically unlike individuals to mate

What is inbreeding v. outcrossing?

• Inbreeding vs. Outcrossing

  • Crossing btw. closely related vs. unrelated individuals

  • (Based on genotype, not phenotype)

What is inbreeding coefficient?

• Inbreeding coefficient

  • Probability that 2 alleles at any locus are identical by descent of a common ancestor of 2 parents

What is inbreeding depression?

• Inbreeding depression

  • Reduced fitness due to loss of genetic diversity

What are the effects of inbreeding on homozygosity?

• Starting at 50% homozygotes in population rapidly reduces heterozygosity

  • Basic math: prob of 2 siblings sharing given allele from 1 parent is ½ so change of passing down is ¼

  • Cousins: 1/16, slower but still non-random

• Deviation from HWE that AA and aa frequency are higher than expected from p and q

Elaborate on inbreeding/homozygosity

When progeny, the change of them being homozygous is 0.36 for p and 0.16 for q and the heterozygote is remainder

When inbreeding, odds become more skewed, if homozygote and relative, the odds that the relative homozygous for same allele higher

it’s also more likely to be a heterozygous - higher than expected

inbreeding, closely related they are, the more likely to be homozygotes in their progeny than population at odds

What is fitness?

An individual’s relative ability to survive and transmit its genes to the next generation

• Statistical measure of all individuals with that genotype in population not a single individual

• Two basic components: viability and reproductive success

• Represented as probability from 0-1 where 0 is no change of offspring and 1 is guaranteed offspring

What is Natural Selection?

Process that increases fitness over generations

• Individuals whose fitness is higher are parents of larger portion of next generation

• Occurs in all natural populations

What is an example of Natural Selection?

• Pocket mice in New Mexico live in rocky areas

• Mice living in sandy rock areas tend to have sandy colored fur

• Mice living in dark, lava rock areas tend to have darker fur

• Likely due to increased predation of individuals that don’t blend

What is Sexual Selection?

• Evolution is driven by mate choice or competition for mates

• Sexual selection rapidly drives shifts in allele frequency by violating 2 HWE assumptions:

  • Non-random mating

  • Impact on fitness

• Directly impacts the reproductive success, sometimes at expensive of viability

How does fitness and hardy weinburg intertwine?

• Once fitness is involved, HWE no longer possible

• However, Hardy-Weinburg formula can still make predictions

  • Ex Population with 2 alleles (A and a)

    • Relative fitness (W) of each genotype

    • Relative frequencies of each at adulthood

What are relative fitness used to determine?

The effective adult population size/frequency

• If you have 100 AA individuals with 0.75 fitness, then only 75 will reproduce

• After fitness is applied, genotype frequencies no longer add up to 1

What is the Normalization Factor?

• The effective total adult population size/frequency and is used to make frequencies add to 1 again

What does p’ and q’ represent?

• Allele frequencies after 1 generation of selection

What is the formula for change in allele frequencies

What does the rate of decrease depend on?

Allele frequencies

As q approaches 0, what happens?

Rate of decrease gets slower

Think of an example with recessive lethal and low q.

• As 1 decreases, the frequency of homozygotes born decreases

• So as long as there is no selective disadvantage for heterozygote, those alleles are “safe” from selection

• With low q, heterozygotes are more likely to mate with p homozygotes

In a population with 500 individuals and 1 new mutation…

What are some human examples?

• H. sapiens migrated out of Africa 60,000-80,000 years ago

• Exposure to UV rays decreases with increasing distance from equator

  • Affects Vitamin D production and skin cancer incidence

  • Close to equator, dark skin protects against skin cancer

  • Farther from equator, lighter skin allows more UV for sufficient vitamin D production

• Skin pigmentation is a complex quantitative trait determined by alleles at many genes

• Alleles of several genes show strong associations with different populations around the world

What is Sickle Cell and Malaria relations to Monte Carlo

• Sickle cell anemia is recessive trait caused by mutations in B-globin locus

• Heterozygous advantage: individuals that are carriers of sickel-cell are resistant to malaria

• Sickle-cell allele distribution matches malaria distribution

What is balancing selection?

What’s the formula for balancing selection?

Natural Selection - Ex: Pesticide Resistance

• Large-scale use of DDT and other synthetic insecticides began in 1940s

  • DDT is nerve toxin in insects

  • Dominant mutations in single gene confer resistance through detoxification of DDT

  • With insecticide application, strong selection favors heterozygotes

  • Resistance to every known insecticide has evolved with 10 years of its commercial introduction

Describe DDT resistance in mosquitos

• Use of DDT Bangkok to control A. aegytpi mosquitos - began in 1964 and discontinued in 1967

  • R DOMINANT, RESISTANT, r is SUSPECTIBILITY

  • RR Genotype - Fitness cost

  • Absence of insecticide, resistance is subject to negative selection

What is Biological Ancestry?

• Each person alive today has 2^k biological ancestors k generators ago, assuming ancestors were not related

What is Genetic Ancestry?

• Inheritance of segments of DNA from biological ancestors

• At each genetic locus there are only 2 genetic ancestors (one allele from each parent)

What is the Most Recent Common Ancestor (MRCA)

• In this pedigree, the genetic pedigrees coalesce to one ancestral allele: the MRCA

Is MRCA is genome region specific?

YES.

• Different genome regions have different MRCAs because of recombination

• Exceptions: Y-Chromosome and mtDNA

  • Y-Chromosome don’t recombine and are paternal only

  • Mitochondrial genome is inherited maternally

How do Genetic Ancestry and mutations relate?

• An unbroken line of descent connects the MRCA with all modern humans

• The modern sequences are not identical, because mutations occur along the lineages

Where did Modern humans originate?

• Most recent common ancestral mtDNA from mitochondrial Eve: lived no more than 200,000 years ago in Africa

• Similarly, Y chromosome Adam lived 200,000 to 300,000 years ago in Africa

• Did not interact and were likely separated by thousands of years

How do Mitochondrial Haplotypes work?

• MITOCHODRIA DON’T RECOMBINE

• Only new way is to generate new haplotypes

What is Mitochondrial Eve? What does Mitochondrial haplotypes provide?

• By looking at mitochondrial haplotypes - can see how closely related various populations are

• Estimating based on molecular clock and ancient DNA can provide information about when different events happened

How does Human Migration and mtDNA relate?

• By plotting the mitochondrial haplotypes on a map along the information about when they diverged, we can trace migrations

Y Chromosomal Adam - What is this?

• Y-Chromosome has the same trait of almost all change in haplotype from mutation

• Lets us perform same experiment

• Result is very similar

What are Founder Effects in H. sapiens migration

• African populations have more DNA sequence diversity than other populations

• As small populations left, founder effect reduced genetic diversity

What are some bottlenecks in human history?

• Significant bottleneck occured 50,000 years ago in non-African populations

• Estimated effective population size dipped below 2500

What are Neanderthal & Denisovan Genomes

• Genomic DNA sequence was determined from bone samples

• DNA sequence of certain genes allows predictions of appearance

What are some DNA Markers of inbreeding?

• Various populations have markers found in Neanderthal and Denisovan genomes

• Non-African humans have Neanderthal markers

• Asian populations have Denisovan markers