Lectures 9-16

Lecture 9: Population Genetics

The factors that change allele frequency

Polyphenism example - suppose the sex of the offspring of a species of fish is determined by water temperature

Population: group of individuals of same species living in the same area

• interbreed, produce fertile offspring

Genotypes → allele combinations

Phenotypes → influenced by genotype and the environment

• can be behaviour, morphological, processing, metabolism, etc

4 processes that affect allele frequencies:

• mutation: modifies allele frequencies but continually introducing new alleles

• genetic drift: causes allele frequencies to change randomly

• gene flow: individuals leave one population, join another, & breed

• natural selection: increases the frequency of alleles that contribute to reproductive success in a particular environment

  • only process that can produce adaptation

Mendel: consequences of mating two individuals with certain genotypes

• mated individuals himself and looked at their offspring

Hardy & Weinberg: analyze frequencies of alleles where individuals in a population mate and produce offspring

• looked on a population level

• population-thinking

Gene pool: all alleles from all gametes go into a single group

• Hardy & Weinberg calculated what happened if these gametes paired randomly and mated, they estimated each pair produced

• genotypes of offspring

Allele frequency (for two alleles): p + q = 1

• p: The frequency of one allele (usually the dominant allele) in a population.

• q: The frequency of the other allele (usually the recessive allele) in the population.

• 1: The sum of the allele frequencies in a population must always equal 1 because there are only two possible alleles in this simple model (or all alleles combined must account for 100% of the genetic variation).

Genotype frequency (for two alleles): p² + 2pq +q² = 1

• p² represents the frequency of individuals who are homozygous dominant (having two copies of the dominant allele).

• 2pq represents the frequency of individuals who are heterozygous (having one dominant and one recessive allele).

• q² represents the frequency of individuals who are homozygous recessive (having two copies of the recessive allele).

Hardy-Weinberg Equilibrium:

• used as a reference point

• compare this “expectation” to observations

• when alleles transmitted via meiosis and a random combination of gametes

• allele frequencies do not change

• assumptions:

  • diploid organisms

  • no overlapping generations → parents are gone in the next generation

  • no mutations

  • population is indefinitely large → no random allele frequencies

  • no gene flow

  • no natural selection

  • mating is random with respect to genotypes

• acts as a null hypothesis

If the difference between the expected (Hardy-Weinberg Equilibrium) and the observed is large, then then questions are raised about evolution in the populations

Genetic drift:

• the largest influence is the size of the population

• if a population has 1000 individuals (mix of red and white) and you randomly selected 2, it won’t be surprising if both are red

• but if you select a large population, then it is more likely that you will get 50% red and 50% white

• Buri (experimented on fruit flies)

  • bw = white eyes

  • bw^{75 =} red eyes

  • initially there were 16 heterozygotes (bw⁷⁵/bw)

  • by chance, eventually they separated into two different populations

    • one only with bw alleles

    • and the other with only bw⁷⁵

• small populations experience strong drift

• some alleles become fixed

  • others disappear

Genetic Drift: Genetic Bottleneck

• results in non-representative set of alleles

• even after the population size rebounds

• random that certain individuals survived

• not because some alleles were stronger than others

• catastrophic reduction in population

• Elephant seals: hunting for blubber

  • Northern: only 30 survived

    • today, all 124000 are descendants of the 30 that survived

    • “genetically identical”

    • 2 variability

  • Southern: weaker bottleneck, with 1000 surviving

    • 23 variability

• probability of an allele surviving a bottleneck depends on:

  • frequency of the allele before

  • severity of bottleneck

DNA sequence alignment:

• take many individuals and see if their nucleotides match up

• if they don’t then there is polymorphism

Genetic Drift: Founder Effect

• small umber of individuals colonize new, isolated habitat

• new populations started from small number of individuals

• none of the populations are representative of the original population

• Zebra finch, branched off and only 9 individuals left

  • in the new population, everyone is a descendant of the 9 individuals

Pennsylvania Amish Community:

• all descendants of 100 individuals

• high degree of inbreeding

• reduced heterozygosity

• 12 generations

Ellis-Van Creveld Syndrome:

• polydactyly

• recessive mutation in ECV locus

• 7& frequency in Amish

• more frequent than in North America or Europe

Lecture 10: Population Genetics

Darwin and Wallace:

• both recognized that natural selection occurs when there is a variation in phenotypes and this variation can cause some individuals to outperform others

Fitness: survival and reproductive success of an individual with a particular phenotype

• to measure you fitness, count the number of grandchildren

• components of fitness:

  • survival to reproductive age

  • mating success

  • fecundity

• relative fitness: fitness of individuals of one genotype compared with population average or most fit genotype

  • most fit will get w=1

Selection and Population Size

• beneficial allele starts at a frequency of 0.1 in each population (n=10, n=100, n=1000, n=10000)

• the effects of drift are lower when the population size is higher

• larger populations will have a steady rise to fixation of beneficial allele

• selection is more powerful in large populations and drift is more powerful in small populations

Pleiotrophy: multiple phenotypic traits associated with a single gene

• most genes take part many roles

Antagonistic pleiotrophy: beneficial effects for one trait but detrimental effects for another trait of that gene

• trade-off

• ex. grass-hoppers that produce large wings and large flight muscles produce fewer eggs

• ex. Ester1 allele confers insecticide resistance on mosquitoes

  • high frequency in coastal areas (where insecticides are used more heavily)

  • but in inland proved detrimental effects to avoiding predators

  • rise of Ester4 (mutant)

    • less protection against insecticides

    • but not as susceptible to predators

Additivity: allelic effects can be predicted by summing number of copies present

• selection acts upon this

• only one that can reach fixation

Dominance: dominant allele masks presence of recessive allele in heterozygotes

• selection does not act on this

• not very common

• never actually becomes fixed because selection cannot decipher between homozygous dominant and heterozygous

Balancing selection: maintenance of diversity, why we see polymorphisms

• negative frequency-dependent selection: common phenotypes selected against, rare phenotypes are favored

• heterozygote advantage: heterozygosity confers greater fitness than homozygosity

NFDS in fruit flies:

• maggots come in two forms:

  • rovers

  • sitters

• these different behavioural phenotypes are food-dependent

• fruit flies feed on the yeast that breaks down food

• GFP - a green fluorescent protein used to determine if rover or sitter

• 70% rover, 30% sitter

• sitters survived best when rovers were more frequent

• rovers survived best when sitters were more frequent

• they had a lower but equal fitness when they both were present equally

Heterozygote Advantage in Cystic Fibrosis:

• autosomal recessive in chromosome 7, CFTR gene

  • transmembrane chloride channel receptor

  • 90% have a single amino acid deletion (3 nucleotides)

  • mutated version does not fold properly

• leads to excessive mucous production and causes damage

• pancreatic disruption leads to poor nutrient absorption

• why is the mutation not selected out?

  • many carriers

  • carriers experience an advantage in dealing with cholera, typhoid fever, lactose intolerance, and tuberculosis

Inbreeding:

• high frequency of homozygotes

• low frequency of heterozygotes

• allele frequencies do not change but genotype frequencies change

  • does not directly cause evolution

• inbreeding depression: high degree of homozygosity exposes deleterious alleles

• allele frequencies remain the same but heterozygosity is lost through generations

• inbreeding coefficient (F): probability that two alleles at any locus are identical by descent

  • Charles II had a higher F than an offspring of parents that are brother and sister

  • as the inbreeding coefficient increases, survival decreases

Population Subdivision:

• depends on landscape features and gene flow

• when organisms occupy discontinuous ranges, it can lead to population differentiation

• F_ST is the measure of population differentiation

  • extent of subdivision among subpopulations (genetic distance)

  • influenced by time since divergence and population size

  • differentiation occurs quickly for small populations

  • increase over generations

Gene flow: counteract drift

• extreme gene flow can eliminate differentiation

• Stag beetle:

  • subpopulations vary in size

  • some populations experience more gene flow than others

• Lynx:

  • extensive movement: so you can just group them together as one big populations with alleles spread apart

  • low F_ST

• Bighorn sheep:

  • little movement

  • high F_ST

  • subpopulations are very distinct

  • live on the tops of mountains so they mate within themselves

  • with a barrier, gene flow is low

Lecture 11: Quantitative Genetics

Simple/discrete traits → qualitative (ex. wrinkled/round)

• infrequent

Complex traits → quantitative (ex. height)

• abundant

Quantitative traits have continuous phenotypic variation

• normal distribution

• influenced by many genes

• strong genetic component and environmental component

• ex. Maya individuals had reduced height because of a poor diet in that area

  • while Ladinos individuals were larger due to good quality diets

Average and a variation around the mean

H-W polygenic traits

• the greater the number of genes, the more variable, the greater the distribution

• when there is low, moderate, and high variance, the mean is the same but the spread is different

Phenotypic Variation: V_P = V_G + V_E

• total phenotypic variance is the combination of genetic differences and environmental differences

The more loci involved, the more continuous a trait becomes

The more environment involved the more continuous a trait becomes

More genes and more environmental variation leads to continuous distribution

Broad sense heritability: proportion of phenotypic variation of a trait that is attributable to genetic differences among individuals

• how much of the total variance in phenotype contributes to genetics

• includes variation due to dominant/recessive, additive, epistasis (product of two genes interact)

Narrow sense heritability: proportion of phenotypic variance explained by the additive effects of alleles

• how to measure: parent-offspring regression

  • measure males and females and pair them up to mate

  • take average of mom and dad (midpoint) and plot on the X-axis

  • measure lengths of offspring and plot on Y-axis

  • slope = 1, direct correlation between size of parents and size of offspring

  • slope = 0, no correlation

  • slope represents narrow sense heritability

Modes of Selection:

• directional selection: favoring one extreme

  • oil content (artificial selection): breeder selects for individuals with higher oil content

  • selection can drive traits to evolve beyond optimal range

  • large populations evolve faster and farther than small populations

  • selection moves faster in large populations

• stabilizing selection: mean is favored, over time variance decreases

• disruptive selection: best to be at either extreme, bimodal distribution results

  • populations start to diverge

  • like the fruit flies (scutellar bristles)

Evolutionary response to selection: Breeders equation

• depends on selection differential and heritability of trait (narrow-sense heritability)

• strong selection occurs when heritability is high and selection is high

• weak selection occurs when heritability is low and selection is low

• S = strength of selection (how far the mean wants to change from the entire population)

Lecture 12: Quantitative Genetics

Recombination rate “r”:

• probability of recombination occurs between a given pair of loci

• 50% is the maximum value with recombination

Linkage equilibrium (LE):

• allele at one locus is independent of presence or absence of allele at a second locus

  • loci on different chromosomes

  • no linkage

Linkage disequilibrium (LD):

• allele at one locus is nonrandomly associated with the presence or absence of allele at a second locus

  • two adjacent genes

• physical linakge

• extent of disequilibrium

  • D_A1A2 = P_A1A2 - P_A1*P_AB

• in equilibrium, D=0

Supergene: group of functionally related genes close enough to segregate as a unit

• costal flowers are cool, perennial → large flowers

• inland flowers must flower before it gets too hot → small flowers

• inversion stops hybridization

• coastal flowers inverse to avoid recombination, selection favors keeping them together

Recombinant Inbred Lines:

• large fish and small fish

• shuffle “large” with “small”

• line them up by markers

QLT map: identify which genes are associated to “large” and “small” fish

• found that at least 5 genes contribute to size

• peaks → association between marker and trait

• can map numerous traits

• coat color in mice is dependent on Agouti and Mc1r (epistasis)

  • when agouti is present, Mc1r expression stops → pheomelanin (light color)

  • when agouti is absent, Mc1r is expressed → eumelanin (dark color)

  • agouti is expressed lower in mainland mice than beach mice

GWAS map: identify which genes in the entire genome are associated with human disease

• identify where genes differ

Phenotypic plasticity: chanign phenotype based on environment

• melanin protects UV radiation

• but when melanized, you are more conspicuous to predators

• high plasticity when predators are absent (changes in melanin production based on intensity of UV)

• low plasticity (rarely any changes in melanin) when predators are present

Behavioural plasticity: rovers behave like sitters when food is scarce

• less likely to leave

Caste polyphenism (ants)

• extreme form of plasticity

• multiple discrete phenotypes from single genotype in response to environmental cues

  • major worker - larger

  • queen - large with wings

  • minor worker - small

• based on environment → larval nutrition

A reaction norm is a concept in biology that describes the range of phenotypic expressions (traits) of a single genotype across a range of different environmental conditions.

Genotype x Environment (GxE)

• when different genotypes response differently to different environments

• in nematode worms, some genotypes produce less eggs at low temperatures while other produce less eggs at high temperatures

• X on the graph

Lecture 13: History of Genes

New mutations have existed for shorter period, they have undergone fewer recomination events, leading to larger regions of LD compared to older alleles which have had more opportunities for recombination to shuffle the surrounding gene

GWAS begins with large numbers of individuals sampled from within a single population

Homologous character:

• morphological: presence or absence of feathers

• DNA: presence of “A” or “G” on a codon

  • leading to changes in protein

Not all alleles get transmitted to the next generation

Mutations can get passed on and increase in frequency

• creates polymorphism in populaition

Synapomoprhy: shared, derived trait

Coalescence: tracking history of alleles through time

• move backwards to determine when and where alleles arose

• when alleles come together at a common ancestor

Gene trees do not always match species trees

• genes evolve at different rates than species

• Incomplete linage sorting: genetic variation present in a species' ancestors is not fully sorted into distinct lineages during speciation

• a lot of our DNA is still very similar to both chimpanzees and gorillas

Molecular phylogenetic methods:

• maximum parsimony: minimize the amount of changes

• distance matrix (neighbor-joining): closely related sequences grouped together, the result get added on by distant

• maximum likelihood: determines the probability of data, given an evolutionary model and hypothetical tree

  • bootstrapping assigns measures of accuracy to sample

• Bayesian method: determines the probability of a tree given the evolutionary model and data

Geographic origin of humans:

• Multiregional model: gradually evolved across the entire Old World

• Out-of-Africa model: evolved from Africa (once)

• Americans are more “inbred” than African populations

  • high variation in Africa

Kimura: neutral theory of molecular evolution

• deleterious mutations tend to be eliminated

• neutral mutations rise due to drift

  • can be fixed by drift

  • and outcast beneficial mutations fixed by drift

  • mutation rate = rate of molecular evolution

• molecular clock: the longer species were separated the more differences there will be

• synonymous mutations rise at a faster rate due to drift than nonsynonymous due to selection

• coding regions evolve slower because there is more chance of nonsynonymous mutations → selected against → does not contribute to evolution

Selective sweep: elimination of polymorphism near beneficial mutation that has spread to fixation

• hitchhikers come along for the ride

  • ex. selection selects for unbranded in shells, but those also happen to be pink

  • so “pink alleles” are hitchhikers

When nonsynonymous substitutions experience faster evolution than synonymous, it is positive selection

• purifying selection when it is experiencing slower evolution

dN/dS ratio: rate of nonsynonymous to synonymous

• > 1 → positive selection

• = 1 → no selection (neutral drift)

• < 1 → purifying selection

Threonine amino acid: A-C-T

• A-C-C → threonine (synonymous substitution)

• G-C-C → alanine (nonsynonymous substitution)

BRCA1:

• mutations play a role in breast cancer

• non-mutated plays an important role in DNA damage repair

• positive selection in humans because of its role in DNA damage repair

F_ST outlier: a measure of heterozygosity in one population compared to another

SNP Analysis: outliers to identify positive selection

Lecture 14: Evolution and Development

Gene regulatory network: expression of one gene is dependent on the expression of another gene

Gene control region: upstream section of DNA

• promoter region

• influences transcription

Repressor:

• binds to DNA or RNA sequences to inhibit the expression of one or more genes

Transcription factors:

• protein that binds to specific DNA sequences and turns on or off

• contributes to expression

Complex adaptation:

• coexpressed traits

• experience selection for a common function

• multiple components must be expressed together for the trait to function

• involves regulatory networks

• ex. when bacteria experiences stress → forms spores

  • many things turn off and others turn on

  • during pressure, they form a septum

  • then buds off to form pre-spore

  • if the stress is really bad, the bacteria will die and the spore will stay

  • eventually when the stress is gone, the bacteria will grow again

Hox genes:

• determine body segment identity

• arranged in order of expression

• mutations can have drastic effects

Duplication:

• can lead to novel functions

• pleiotropic genes have multiple functions

• gene recruitment: co-option of gene or network for novel function as a result of mutation

• before duplication: each role wouldn’t function at the same time

• genes duplicated into two regions → one copy mutated and one regular → one gene evolved new regulation and function while the other functions as the original gene

Evolution of E.coli

• survive on glucose normally under aerobic conditions

• set up an experiment where glucose is limited

• one flask out of 12 began to “explode”

  • number of E.coli increased

  • citrate (backup source of energy during anaerobic conditions) was expressed during aerobic conditions

  • cit promoter activates citT/G under anaerobic conditions to metabolize citrate

  • mutation caused duplicated where cit rnk promoter (aerobic promoter) activated citT/G under normal conditions

Snake venom

• evolved through duplication and co-option

• original copies of defensin genes produced in skin

  • duplicated to produce defensins in snake pancreas and other organs

  • recruitment: then evolved crotamine venom that is only expressed in the venom glands in mouths

  • additional duplications and losses as venom diversify in different lineages

• evolved before snakes had evolved

Dorsal-ventral patterning

• Dpp in insects and Bmp4 in mice are orthologs

  • digestive system

  • dorsal in insects

  • ventral in mice

• Sog in insects and Chordin in mice are orthologs

  • nervous system

  • ventral in insects

  • dorsal in mice

• mirror images

• independent evolutions

Dll (insects) and FSFs (mouse) are leg genes

• blocking Shh expression could lead to incomplete limb formation

• on the proximal-distal axis

Hoxd13 expression in zebrafish and mice

• Hoxa11

  • short bones in zebrafish

  • limb elements in mice

• Hoxd13

  • digits in mice

  • fin rays in zebrafish

• artificially express Hoxd13 in zebrafish

  • began to form what a limb would be

Antagonistic pleiotrophy

• cervical vertebrae in the neck (7)

• including giraffes

• which make them harder to bend

• recurrent laryngeal nerve is built from what was there in fish

Convergent evolution

• independent evolution leading to similar traits

  • similar selection pressures

  • homoplasies

Lecture 15: Natural Selection

Artificial selection:

• “hand” (breeder) driving selection imposes incredibly strong directional selection

Natural selection:

• hand is survival and reproductive successes

Galapagos Archipelago

• Darwin spent 5 weeks

• very different species form mainland

• eventually, found that the finches are not different birds, but are all finches

• Peter and Rosemary Grant: naturalists that trap and tag every single bird on the islands

• many different types of feeders:

  • nectar

  • larvae

  • eggs

  • soft seeds

  • blood-sucking

  • small parasites

• group of islands from Ecuador

• Daphne Major experienced the harshest environments

  • small

  • undisturbed

  • non new species, low vegetation

  • G. fortis (medium ground finch)

    • seed feeder (spurges) but when those were around fed on caltrop

    • variation in beak size

    • competitor: G. magnirostris

  • beak depth and beak length had a high degree of heritability and variability

  • drought: all the food gone

    • only hard seeds remained

    • forced to feed on Tribulus (caltrop)

    • larger beak sizes survived

  • after rainfalls

    • seeds replanted

    • selection for large beaks was reversed

Dark mice survive against predators in mainland (dark environment) and white mice survive against predators in the sand

• multiple origins or light color on opposite sides of the coast

Snowshoe hares:

• adaptation → shed coats during seasons

• climate-driven selection

• warmer winters occurred along the coast so Washington species did not change their fur color

  • hypothesis: agouti allele acquired by hybridization with jackrabbits

  • changes in agouti sequence is underlying the non-transition between white to brown

  • genome-wide tree groups Washington hares with all the other hares

  • but local Agouti tree suggests Washington hares grouped with Jackrabbits

Lecture 16: Natural Selection

Adaptation only results from natural selection

Eurosta solidanginis

• female flies that lay their eggs in golden rods

• when the larvae grows, it grows a gall to protect it and feed from it

• gall size is heritable

• two predators:

  • woodpecker → feeds on galls and eats the larvae inside

    • try to find larger galls for more food

  • female wasp → lays eggs right next to larvae

    • try to find smaller galls so its easier to plant eggs

• stabilizing selection as both extremes occur at same rates

Parallel environmental changes

• three-spined stickleback

  • when a predator tries to attack them, the spines get in the way

• marine organisms are born in freshwater and spend most of their life in the ocean, then return to freshwater to mate

• freshwater organisms spend their entire lives in freshwater

• heavy armor in marine organisms because of differences in Eda gene

  • low-Eda favored in freshwater where predation is less, so less energy is put into that

  • complete-Eda in marinewater

• lake lobourg

  • essentially all low-Eda now

Artificial selection

• selective breeding of cobs with large and many kernel

• pesticides and herbicides

  • after a few years, insects become resistant

  • ESPSP enzyme in Roundup produces glyphophate that disrupts amino acids in the plants

  • some plants become resistant to it with mutations in the enzyme

• Bt Balcillus thurigienesis

  • organic pesticide

  • crystalline protein toxins that damage insect gut

  • Bt-free refuges slow the evolution of resistance because it favour insects without the Bt-resistant allele, and slows the selection of the allele

  • now required by law to slow the resistance response

• Cane toad

  • had no predators and started to take over

  • selected for larger body size to help reduce the risk of predation

  • toxic gland so that predators don’t hunt it

  • new predator: Australian snake

    • increase in body size to lower concentrations of the toxins

    • evolved smaller jaws so they cant swallow large toads which tend to be toxic

• trophy hunting → larger horns

  • so they decreased horn sizes to prevent getting hunted

  • after hunting was banned, they increased sizes again

• fishing

  • larger fish are usually fished for

  • selected for alleles that led to early maturation and smaller size to reduce getting hunted and maximize fitness

  • but small fish produce fewer eggs

  • after fishing was banned they began to increase body size