Mendelian Genetics in Populations

Flashcards covering the vocabulary of Mendelian Genetics in Populations.

Modern synthesis of evolution and genetics

In the 1930s through 1960s, geneticists, systematists, and paleontologists reconciled Darwin’s theory of evolution by natural selection with the emerging facts of genetics. Began using mathematical theory and hypothesis testing as important components of scientific inquiry.

Modern synthesis founded

The field of population genetics

Darwin’s Four Postulates

1. Individuals within a species are variable 2. Some variation is passed on to offspring 3. More young are born than can survive 4. Individuals with most favorable variations survive to reproduce more Natural selection, or non-random survival and reproduction

Darwin’s four postulates, restated in population genetics terms

1. Allelic variation exists among individuals 2. Alleles are passed down from parent to offspring by meiosis and fertilization 3. More young are born than can survive 4. Some allelic combinations are more fit than others and these survive to reproduce more often = Natural selection, or non-random survival and reproduction based on allelic variants

New definition of evolution

Change in frequency of alleles in a population over generations

Microevolution

Evolution at the population level = the level at which evolution acts

Hardy-Weinberg Equilibrium Principle

Null model of how populations act when evolution is not occurring

Hardy-Weinberg Equilibrium Principle

The model specifies what will happen to frequencies of alleles and genotypes. Applies to all diploid sexual organisms

Population

group of interbreeding individuals and their offspring

Gene pool

Adults produce gametes, Gametes combine to make zygotes, Zygotes grow up to become next generation of adults, Track fate of Mendelian genes across generations in a population. Find out if particular alleles become more or less common over time

Hardy-Weinberg Equilibrium Principle-mice example

Assume adults choose their mates at random from within the gene pool. Diploid organisms, so each has two alleles for A locus. One allele is in each gamete for the A locus

Blind luck

sampling error = Random Genetic Drift

Hardy-Weinberg Equilibrium Principle-numerical example

Imagine 60% of eggs and sperm received allele A and 40% received allele a. Frequency of A allele in gene pool = 0.6, a allele = 0.4. When egg and sperm meet, what proportion of genotypes will be AA? 60% egg will be A, 60% sperm will be A 0.6 X 0.6 = 0.36 36% of zygotes will have genotype AA

Frequency of A in next generation

0.36 + (1/2)0.48 = 0.6

Frequency of a will be

0.16 + (1/2)0.48 = 0.4

Conditions if a population is in Hardy-Weinberg Equilibrium

it will never evolve. Regardless of starting frequencies

Allele frequencies

A is called p, allele B is called q, p + q = 1

Genotype frequencies in Hardy-Weinberg Equilibrium

p2 + 2pq + q2 = 1

Hardy-Weinberg Equilibrium Principle-conclusions

Conclusion 1: the allele frequencies in a population will not change, generation after generation. Conclusion 2: if the allele frequencies in a population are given by p and q, the genotype frequencies will be given by p2, 2pq, and q2

Why do we use Hardy-Weinberg Equilibrium Principle?

Shows when evolution does not happen. Gives specific set of testable assumptions. If an assumption is violated, the conclusions do not hold. Is a null model to test evolution against

Assumptions of Hardy-Weinberg

1. There is no selection (all members contribute equally to gene pool), 2. There is no mutation (no new alleles are created), 3. There is no migration (all alleles stay in gene pool), 4. There is an infinitely large population size (no random events = no genetic drift), 5. Panmixia (mates are chosen randomly)

Why use HWE?

Allows prediction of genotype frequencies given allele frequencies. Genotypes will approximate a binomial distribution [a.k.a. HWE, a.k.a. (p + q)2 = 1] after 1 generation of random mating. If we know the allele frequencies in generation 1, we can predict the genotype frequencies in generation 2. Allele and genotype frequencies will not change as long as the assumptions are met

Simple phenotypic example with DOMINANCE

Cats typically have 5 toes per hand, but can also be polydactyl with 6-7 toes per hand – This form of polydactyly is an autosomal dominant trait caused by a variant of the Pd gene

Simple phenotypic example polydactl and normal frequencies

If a population of 100 cats has 60 polydactl and 40 normal individuals…. – Then the frequencies of polydactyl and normal phenotypes are 0.60 and 0.40, respectively N allele → 12-14 fingers n → 10 fingers

convention dominant and recessive allele-pq

The dominant allele (N) is designated p, The recessive allele (n) is designated q, p + q = 1 The Hardy-Weinberg equilibrium can be written as an equation (p + q)2 = p2 + 2pq + q2. Individuals homozygous for allele N. Individuals heterozygous for alleles N and n. Individuals homozygous for allele n

Binomial expansion

(p + q)2 = 12 p2 + 2pq + q2 = 1

Calculation of allele frequencies (only with assumption that population is in Hardy-Weinberg Equilibrium)

Frequency of normal (nn) cats = 40/100 = 0.40 bb = q2 = 0.40 q = √0.40 = 0.63 p + q = 1 => p = 1 – q = 1 – 0.63 = 0.37

What about genotype frequencies?

Frequency of the homozygous dominant genotype is p2 = (0.37)2 = 0.14. Frequency of the heterozygous genotype is 2pq = 2(0.37)(0.63) = 0.46. 14 out of 100 cats are homozygote polydactl (NN) 46 out of 100 cats are heterozygote polydactyl (Nn)

By having explicit assumptions, the violations of assumptions can be used to determine which forces are causing disequilibrium

evolution. We will examine what occurs if assumptions are broken due to one or more microevolutionary process

Evolution

in terms of H-W is change in allele frequency over time

Test if Hardy-Weinberg Equilibrium holds or is broken

= Chi-squared test: 2 =  (observed – expected)2/expected. Expected is the calculation using the Hardy-Weinberg equations. Must use whole numbers, not frequencies. Degrees of freedom is 1

Chi-squared test

Degrees of freedom (df)is 1 , Look up critical values online or in statistics textbook

Testing HWE assumptions

What happens when assumptions are broken? No selection, No mutation, No migration, Large population size, Random mating ,No selection

Testing HWE assumptions: Selection

Individuals with particular phenotypes survive to reproduce more than others. Differential reproductive success. Phenotypes must be heritable. Can selection change the frequencies of alleles in the gene pool from one generation to the next? Does violation of the no-selection assumption violate conclusion 1 of Hardy-Weinberg Equilibrium?

Testing HWE assumptions: Selection example

B locus affects probability of survival. Frequency of B1 = 0.6. Frequency of B2 = 0.4. After random mating, genotype frequencies are 0.36, 0.48, and 0.16. Will use a population of 1000 individuals B1B1 = 360 individuals B1B2 = 480 B2B2 = 160

Testing HWE assumptions: Selection example

Incorporate selection. All B1B1 individuals survive. 75% B1B2 individuals survive. 50% B2B2 individuals survive. Now 800 adults left 360 B1B1 360 B1B2 80 B2B2

Testing HWE assumptions: Selection example

Frequencies of genotypes are: B1B1 360/800 = 0.45, B1B2 360/800 = 0.45, B2B2 80/800 = 0.1. When they produce gametes B1 = 0.45 + (1/2)0.45 = 0.675, B2 = (1/2)0.45 + 0.1 = 0.325. Allele frequencies Frequency of B1 rose by 7.5% Frequency of B2 fell by 7.5%

Testing HWE assumptions: Selection

Population evolved in response to selection. Rarely is selection so strong. Usually requires many generations to change allele frequencies much

Testing HWE assumptions: Selection

Two alleles for alcohol dehydrogenase locus. AdhF and AdhS. Break down alcohol at different rates. Maintained two populations of flies spiked with alcohol and two controls without alcohol .At each generation took random sample of flies and determined their genotypes

Testing HWE assumptions: Selection

Empirical study of Drosophila. Two alleles for alcohol dehydrogenase locus AdhF and AdhS. Control populations appeared to be in Hardy-Weinberg Equilibrium. Allele frequencies did not change. Populations under selection pressure (alcohol) showed a decline in AdhS allele. Hardy-Weinberg Conclusion 1 did not hold in experimental populations. The populations evolved because of selection for better ability to break down alcohol

How does selection affect conclusion 2?

Can we still calculate genotype frequencies by multiplying allele frequencies. Sometimes conclusion 2 is violated. Allele frequencies do not change but genotype frequencies cannot be calculated by Hardy-Weinberg equation

Testing HWE assumptions: Selection Malaria example notes

Pregnant woman are more susceptible to malaria (more attractive to mosquitos and impaired parasite control mechanisms).If a pregnant woman contracts the parasite, it then invades the placenta.Causes placental inflammation and usually death of the child (accounts for 3-8% of infant deaths in malaria-endemic areas of Africa).Hinges on fetus’s genotype of VEGFR1 (= fms-like tyrosine kinase 1).Influences placenta development and inflammation.SS and SL produce more of the protein than LL

observed genotypic frequencies?

SS=0.211 SL=0.658 LL=0.132

predicted genotypic frequencies?

SS=0.291 SL=0.497 LL=0.213

selection How do we determine significant difference between actual genotype frequencies and HWE expected genotype frequencies?

Chi-square test

For a two allele system degrees of freedom

there are three classes and one independent value, thus there is 1 degree of freedom. d.f. = 3 – 1 – 1

Testing HWE assumptions: Selection CCR5-32

HIV. Will the frequency of the allele increase in response to HIV epidemic.Three potential models

Testing HWE assumptions: Selection CCR5-32 Model 1

Frequency of allele 20%. 1/4 of people with genotype +/+ or +/32 die before reproducing. All 32/32 individuals survive. After 40 generations (1000 years) the 32 allele is nearly 100%

Testing HWE assumptions: Selection CCR5-32 Model 2

Frequency of allele 20%. HIV infection rate less than 1%. All 32/32 individuals survive. After 40 generations (1000 years) the 32 allele is still at 20%. Selection is too weak to cause a large change in allele frequencies

Testing HWE assumptions: Selection CCR5-32 Model 3

Frequency of allele 1%. 1/4 of people with genotype +/+ or +/32 die before reproducing. All 32/32 individuals survive. After 40 generations (1000 years) the 32 allele is still at 1%. Most copies of 32 would be heterozygotes and hidden from selection

Dominant and Recessive alleles Flour beetles with l locus

Two alleles: + and l. Individuals with genotype +/+ or +/l are normal. Individuals with genotype l/l do not survive. Recessive lethal allele. Dawson started colonies with heterozygotes. Allele frequencies 0.5 for each

Testing HWE assumptions: Selection Flour beetles with l locus dominance and allele frequency

Because l/l have lower fitness, expect population to evolve to lower l frequencies. Measured allele frequency over 12 generations. Frequency of l allele dropped to 0.10 but was not eliminated. Dominance and allele frequency interaction: If recessive is common, evolution is rapid. When recessive is rare, evolution is very slow. When rare, recessive allele is usually hidden from selection

Testing HWE assumptions: SelectionSelection coefficientselection against and for

w = fitness of an allele, ranges from 0 - 1. s = strength of selection on an allele. w++, w+l, wll. For negative selection on recessive phenotypes: w++ = 1, w+l = 1, wll = 1 - s. s gives strength of selection on homozygous recessive phenotype. Positive s is selection in favor of phenotype. Negative s is selection against phenotype

Testing HWE assumptions: SelectionSelection coefficient

For negative selection on dominant phenotypes: w++ = 1 - s, w+l = 1 - s, wll = 1. “s” is the amount of selection against phenotype

When one allele is dominant and one is recessive, heterozygote fitness is equal to that of one kind of homozygote

Other scenarios possible = more complex. Sometimes heterozygote fitness is intermediate to two homozygotes. Changes rate of evolution. Eventually one allele (the one that confers higher fitness) may become fixed and the other lost. Sometimes heterozygote fitness is superior or inferior to either homozygote. Different evolutionary outcomes produced

Frequency Dependant-Selection

We have assumed selection is constant over time. Direction of selection may fluctuate. One allele favored and then the other. Example: Perissodus microlepis in Lake Tanganyika rip scales off of other fish for food. They attack from behind, grab scales of flank, and dart away

If right-handed fish are more abundant

prey will be more vigilant from left side and vice versa. Therefore, it is better to be the rarer type to catch prey unawares. Rarer type is a more successful predator and is more fit, leaving more offspring. Thus, population is always evolving for a higher frequency of rarer type. Both types should be equally abundant at any point in time

What happens when assumptions are broken?

HWE assumptions No selection, No mutation, No migration, Large population size, Random mating

Testing HWE assumptions: Mutation

How do deleterious alleles like cystic fibrosis remain at high frequencies in populations? Heterozygote superiority? Introduced anew by mutation? Mutation introduces new alleles into a population. How effective is mutation as a force of evolution? Can mutation violate conclusions of Hardy-Weinberg Equilibrium Principle?

Testing HWE assumptions: Mutation

Mutation alone is not a potent evolutionary force. Model mouse population. Locus A. Frequency of allele A = 0.9. Frequency of allele a = 0.1. a is recessive loss-of-function mutation. Copies of A are converted to a at a rate of 1 copy per 10,000 generations. Very high mutation rate

Testing HWE assumptions: Mutation

Model mouse population. Back mutations to A are negligible. .Assume all mutations happen in gametes in gene pool. Adult genotype frequencies AA = 0.81. Aa = 0.18. aa = 0.01. In Hardy-Weinberg proportions Alleles in gametes are still 0.9 and 0.1

How do you determine what the frequency of a particular allele will be in the future based on a particular mutation rate?

pn = p0e-mn Where pn = frequency of A in generation n p0 = frequency of A in generation 0 m = mutation rate. Determines frequency of dominant allele in future

Lenski’ s E. coli study

Fitness and cell size increased in response to natural selection. Fitness increases occurred in jumps. Beneficial mutations swept through population to fixation. Mutations caused bacteria to divide faster and increase in size. Mutation is ultimate source of genetic variation

Mutation Selection Balance

Most mutations are deleterious. Selection eliminates these mutations (= negative or purifying selection). Mutations are created anew. When rate of deleterious alleles being eliminated by selection equals rate of creation by mutation: Mutation-Selection Balance. Mutation is the ultimate source of genetic variation

Testing HWE assumptions: MutationRecessive loss-of-function allele is at equilibrium when

^ = / m q √ s. m = mutation rate. s = selection coefficient Between 0 and 1 expressing strength of selection. If selection is small and mutation is high, equilibrium frequency of allele will be high. If selection is high and mutation is low, equilibrium frequency will be low

Cystic fibrosis

Researchers discovered that the high frequency is maintained by heterozygote advantage. Heterozygotes were partially resistant to typhoid fever infection. Cystic fibrosis maintained by mutation and overdominance

Have examined how selection and mutation violate the Conclusions of the Hardy-Weinberg Equilibrium Principle

Will next examine the other three forces: Migration, Genetic Drift, Nonrandom mating

Assumptions of Hardy-Weinberg Equilibrium

1. No Selection, 2. No Mutation, 3. No Migration, 4. Large Population, 5. Random Mating

Migration

Movement of alleles among populations. Not the same as seasonal migration of animals

Gene flow

Transfer of alleles from one gene pool to another gene pool of a different population. Dispersal of adults or any other life stage

Hardy-Weinberg conclusions

Conclusion 1: the allele frequencies in a population will not change, generation after generation. Conclusion 2: if the allele frequencies in a population are given by p and q, the genotype frequencies will be given by p2 , 2pq, and q2

Migration

Movement of individuals from one population to another. Immigration: movement into a population. Emigration: movement out of a population

One-island model

Two populations, Mainland + island, Migration of alleles to continent is insignificant, Migration of alleles to island could have a large impact on allele and genotype frequencies

Gene flow is effectively one way

Locus A with two alleles: A1 and A2. Before migration frequency of A1 is 1.0. A1 is fixed in island population. No A1A2 or A2A2. 800 zygotes before migration. Continental population fixed for A2. 200 individuals migrate to island. New genotype frequencies after mating A1 = 0.8 A2 = 0.2

Migration

Homogenizes the populations within a species (unopposed by other forces). Rate of gene flow = m. A1 varies among populations (pi) resident. The average allele frequency of A1 in source population is p. Within population i (which has A1 frequency of pi), proportion m of the gene copies enter from other populations at frequency p

Water snakes of Lake Erie

Nerodia sipedon ,live on mainland and on several islands, Color pattern variable, Strongly banded to unbanded Banding controlled by a single locus with two alleles, Banded is dominant over unbanded, On mainland most snakes are banded, On island many are unbanded

What accounts for the lake erie water snakes

Banding pattern is due to natural selection, On islands snakes bask on rocks. On mainland stay closer to vegetation. Why is the unbanded allele not fixed on islands? Banded snakes migrate from mainland each generation. Bring banded alleles to island gene pool. Migration may work in opposition to natural selection

Migration

Homogenizing evolutionary force. Migration makes island and mainland snake populations more similar. If natural selection did not oppose migration for snakes, island populations would eventually fix on banded allele. Migration would homogenize the populations completely.

Red bladder campion, Silene dioica

Perennial wildflower on islands off the coast of Sweden. Recently formed islands deposited by glaciers. Rise at rate of 0.9 cm per year. Each island has different age… Red bladder campion seeds dispersed by wind or water. Populations die out after a few hundred years from competition. Metapopulation

The Hardy-Weinberg assumptions

No selection, No mutation, No migration, Large population size, Random mating. What happens when assumptions are broken?

Genetic drift

Population genetics shows us that natural selection is not the only mechanism for evolution. Evolution can happen by random chance events. This kind of evolution is not adaptive but does lead to changes in allele frequencies. Violate assumption of infinite population size.

Genetic drift

Many possibilities for genotypes of 10 zygotes. Both conclusions of Hardy-Weinberg violated. Allele frequencies change. Genotype frequencies cannot be calculated with formula.. Failure to conform to Hardy-Weinberg is only because population is small

Genetic drift

Can lead to random fixation of alleles-Effects of genetic drift over many generations can be powerful. Because of drift, one allele can rise to fixation over time. Smaller populations go to fixation faster

Genetic drift-sampling error

Random discrepancy between theoretical expectations and actual results can be called sampling error.Sampling error in production of zygotes is genetic drift. Random luck causes evolution. Drift is a result of finite population size. If the population is larger, drift is less important

Founder effect

Small group of individuals that start a new population. Allelic frequencies are, by chance, different from source population. Result of sampling error. By chance, not all alleles will be represented

Genetic bottleneck

is another phenomenon similar to the founder effect, Random events cause a population to crash to a very low level , Many alleles are eliminated from the population., The remaining population has different allelic and genotypic frequencies than the beginning

Bottleneck vs Founder Effect

Founder effect-Small group of individuals establishes a population in a new location. Bottleneck effect-A sudden decrease in population size because of extreme natural forces

Genetic drift

can produce substantial changes in allele frequencies.In combination with selection or migration, effects of genetic drift can be lessened. Important if trying to manage an endangered species

Sewall Wright demonstrated how to measure fixation

that the probability of fixation for a particular allele is the same as its original frequency – If the initial frequency of an allele is 0.8, there is 80% it will drift to fixation

FIS FIS F-statistics

is the the proportion of the variance in the subpopulation contained in an individual = Inbreeding coefficient.FIS = (Hs – HI)/Hs • HI = HO = Observed heterozygosity in a population – Count # of heterozygotes • Hs = HE = Expected heterozygosity in a population based on HWE – Hs = 2[f(A)][f(a)]

FST FST F-statistics

is the level of differentiation among a set of populations FST = (HT – Hs)/HT.HS = Average Hs among all populations – 9 (HS’ + HS”)/2. HT = Total expected heterozygosity among all populations you treat all samples from multiple populations as if they come from a single population. HT = 2[f(A)][f(a)]

EFFECTIVE POPULATION SIZE

Definition: The size of an idealized population that would lose genetic diversity at the same rate as the actual population

How does effective size differ from census size?

Any characteristic of a real population that deviates from the characteristics of an ideal population

Unequal sex-ratio -- inbreeding effective size Ne

Unequal sex-ratio--Demographic Methods:.Ne = 4NefNem/(Nef + Nem)example: 17 monkeys 12 males and 5 females:Ne=(4125)/(12+5)=14.1

EFFECTIVE POPULATION SIZE Demographic Methods B) Variation in family size

Ne = (4N – 2) / (Vk +2)

Demographic Methods: C) Fluctuations in population size

Ne = t/Σ(1/Nei) Where Nei = effective size in the ith generation and t = number of generations

Genetic drift

FST = 1/(2Ne) Increase in FST due to drift over one generation

Neutral theory of molecular evolution

A small minority of mutations in DNA sequences are advantageous and are fixed by natural selection and although some are disadvantageous and are eliminated by purifying (negative) selection.The great majority of mutations that are fixed are effectively neutral with respect to fitness, and are fixed by genetic drift

Neutral theory of molecular evolution

When sequences evolve by drift and negative (or purifying) selection, synonymous substitutions outnumber nonsynonymous substitutions. When sequences evolve by drift and positive (or diversifying) selection, nonsynonymous substitutions outnumber synonymous substitutions.

Neutral theory as null hypothesis

If changes occur that are significantly different from the predictions made by the neutral theory, there may be evidence for natural selection