Genetics Exam 4-

allele

different version of a gene at a specific location in the chromosome

Genotype

the combination of alleles an individual has at a particular gene

Frequency

how common an allele or genotype is in a population

SSR (simple sequence repeats)

short DNA sequence repeated multiple times in a row; high variable and useful for identifying individuals (can have multiple alleles)

SNP (single nucleotide polymorphism)

single base change in the DNA sequence; most common type of genetic variation

Microarray

technology used to detect thousands of SNPs at once by analyzing DNA samples on a chip

Segregating Variant

A genetic variant that shows different alleles in a population - not fixed and can help distinguish individuals

Allele

different version of a gene at a specific location in the chromosome

Genotype

the combination of alleles an individual has at a particular gene

Frequency

how common an allele or genotype is in a population

SSR (simple sequence repeats)

short DNA sequence repeated multiple times in a row; high variable and useful for identifying individuals (can have multiple alleles)

SNP (single nucleotide polymorphism)

single base change in the DNA sequence; most common type of genetic variation

Microarray

technology used to detect thousands of SNPs at once by analyzing DNA samples on a chip

Segregating Variant

A genetic variant that shows different alleles in a population - not fixed and can help distinguish individuals

Drift

random changes in allele frequency, stronger in small population

Natural Selection: process where traits that improve survival/reproduction increase in frequency

Population size: number of individuals in a population, affects drift and selection strength

Neutral mutation: mutation with no effect on fitness

Deleterious mutation: a harmful mutation that lowers fitness

Beneficial mutation: a helpful mutation that increases fitness

Positive selection: natural selection that increases the frequency of beneficial alleles

Balancing selection: natural selection that maintains multiple alleles in a population

Polymorphism

a genetic variation that exists WITHIN a population

Substitution

a mutation that has become fixed in a population (all individuals and offspring will have the mutation)

MK Test

a method that compares nonsynonymous vs synonymous polymorphisms and substitutions to detect selection

Mean

average value of a trait in a population

Variance

a measure of how much individuals in a population differ from the mean

VA (additive genetic variance)

genetic variance due to the sum of individual allele effects that can be passed to offspring

VP (phenotypic variance)

total variation in a trait including both genetic and environmental factors

VG (genetic variance)

phenotypic variance caused by genetic differences in individuals

Narrow sense heritability

the proportion of phenotypic variance due to addition variance (VA/VP)-- just additive

Broad sense heritability

proportion of phenotypic variance due to all genetic variance, including additive, dominance, etc. (VG/VP)-- all genetic variance

G×E (Genotype by-Environment interaction)

When the effect of a genotype on a trait depends on the environment in which it is expressed.

Marker

A known DNA sequence or variant (like a SNP or RFLP) used to track inheritance patterns in genetic studies.

QTL (Quantitative Trait Locus)

A region of the genome that is statistically associated with variation in a quantitative trait.

Backcross

A genetic cross between a hybrid individual and one of its original parents (or a genetically similar line), used to recover parental traits.

Intercross

A mating between F₁ hybrids to increase recombination and genetic variation in a population.

GWAS (Genome Wide Association Study)

A method that scans the genome to find statistical associations between genetic variants and traits in a population.

LD (Linkage Disequilibrium)

The non-random association of alleles at different loci, meaning they are inherited together more often than expected by chance.

Haplotype

A set of alleles or SNPs that are inherited together on the same chromosome segment.

Chisq (Chi square)

A statistical test that measures whether the observed genotype-phenotype associations differ from what's expected by chance.

Odds

Ratio-A number that tells you how much more (or less) likely a trait is in people with a particular allele compared to those without it.

Polygenic Risk Score

A number that estimates a person's genetic predisposition for a trait based on the combined effects of many SNPs.

1. What is the difference between synonymous and nonsynonymous polymorphism?

Synonymous polymorphism - DNA mutation that DOES NOT change the amino acid sequence (no change in protein)

GAA - glutamic acid

GAG - glutamic acid

** still get a change in nucleotide just doesn't change the amino acid

Nonsynonymous polymorphism - results in a change to the amino acid sequence

Syn= same amino acid

Non= new amino acid

2. Why are SSRs more efficient than SNPs for linking DNA to an individual in a population?

SSR are highly variable as they have many different alleles. Much better for distinguishing against individuals and doesn’t cause as high of a false positive rate.

3. What is the relationship between the Punnett square and Hardy-Weinberg equations?

Punnett squares are how alleles combine in individuals' offspring while Hardy Weinberg predicts allele and genotype frequencies for an ENTIRE POPULATION.

Punnett square= one generation of mating

Hardy- Weinberg= whole population

4. Approximately how many SNPs would be required to achieve the same false positive rate in

genetic forensics as 1 microsat locus? (assume that all SNPs are biallelic with allele frequency p equal to 50%, the microsat has 10 alleles each at 10%, and that the sampled individual is heterozygous at either all of the SNPs, or at the microsat).

(2 (1/10) (1/10))= 0.02 (Microstat heterozygous)

2(½)(½)=0.5 (simple SNPS)

1 SNP= 50%

2 SNP = 0.5 x 0.5= 25%

3 SNP …

5 SNP 0.5 ^ 5 = 0.031

6 SNP 0.5 ^6= 0.015

5 or 6 SNPS

1. Why is the mutation rate from wild-type to albino mice higher than the mutation rate from

wild-type to brown mice?

Albino mutation is often a single base pair change in the pigmentation gene, whereas in brown mice, you typically get a mutation in the MC1R gene which is more complex and variable making the mutation rate for this much lower.

2. What is the probability that a mutation at the Thr codon ACA will be a missense mutation

When looking at the codon chart, if you switch the first or second nucleotide you will have a non synonymous mutation. Knowing this you have a 66% chance that a mutation at the ACA codon will result in a non synonymous change.

What is the expected frequency of missense mutations based on the codon table? What is

the expected frequency of synonymous mutations based on the codon table? (you don't need to calculate it exactly, but what is the general average?) In most natural populations,

non-synonymous mutations are less frequent than synonymous mutations. What does this

discrepancy tell you about the difference between the de-novo mutation rate and the

standing mutation rate?

For codon ACA

There are 9 ways a codon can change (3 in first nucleotide, 3 in second, 3 in third)

Write the different ways that you can change and see if it changes the nucleotide or not

7/9 will make a new amino acid

2/9 will keep the amino acid

In most populations though, missense mutations are less frequent than synonymous mutations; this is because nonsynonymous mutations are removed by natural selection because they are deleterious.

Use the wf_model app to calculate the rate of loss & fixation for neutral vs beneficial

mutations. Does this rate differ? Why?

Neutral mutations are mostly lost due to genetic drift (random), especially in small populations

Beneficial mutations have a higher chance of fixation due to positive selection

Yes the rate of fixation differs because beneficial mutations are fixed (spread to a whole population) more often while neutral ones are often lost.

1. Why does the substitution rate (mutation spreads through the whole population) equal the mutation rate (rate at which mutations happen)? FOR NEUTRAL MUTATIONS ONLY

most neutral mutations are lost by chance, each one has a small chance of becoming fixed in the population. Because so many neutral mutations arise each generation, on average one will fix and this makes the substitution rate equal to the neutral mutation rate over time

2. Why does the rate of adaptive substitution vary among species?

Different species have different population sizes, mutation rates, and selection pressure. Bigger populations have more beneficial mutations and stronger selection which means more adaptive substitutions (the chance that these mutations get passed from parent to offspring).

More differences=more time since they shared a common ancestor

3. What is the molecular clock?

The idea that neutral mutations accumulate at a constant rate over time, the number of differences in a species can be used to estimate how long ago they diverged

Why does dn/ds = pn/ps suggest neutral evolution?

Fixed differences versus variation within a species

If evolution is neutral- mutations are not affected by selection (they're not selected for or against), they are spreading by drift not natural selection

5. Using the MK-test framework what type of signature would balancing selection leave?

In the MK-test, balancing selection looks like more nonsynonymous polymorphisms (pn) than expected, and fewer nonsynonymous substitutions (dn) — because selection is keeping diversity within the species, not between them.

1. If parents resemble their offspring does that mean that variation in the trait is determined by

genetic factors?

Not necessarily, parent-offspring resemblance can be due to shared environment (like lifestyle, diet, etc.) or genetics. You would need a controlled study to separate genetic and environmental effects

2. How does heritability change if the allele frequency of the causal SNPs change?

As allele frequencies shift, the amount of genetic variance in a population changes. If alleles become very common or rare, there is less variation to explain so heritability usually decreases because there's less genetic contribution to trait differences in the population

3. Why is natural & artificial selection better able to act on additives compared to dominance variance?

Additive genetic variance is important because it makes it easier for selection to work. When genes each add a small, predictable effect to a trait, like height or speed, we can tell which individuals are likely to pass on those traits to their kids. That’s why parents with high trait values, like being tall, usually have kids that are tall too. Over time, if we keep choosing the individuals with the best versions of these genes, the population will keep improving — this is how breeding works. Additive effects are also easier to measure and predict because they don’t depend on complicated interactions like dominance, where one gene hides another.

4. Can heritability change? Is heritability a property of a population or an individual?

Yes, heritability can change depending on the environment and the genetic variation in a population. Heritability is not about one person, it's a population level measure that tells us how much of the differences in a trait across individuals are due to genetics rather than environment

1. In the slide above, which phenotype (rows) in which truss (column) show the greatest G×E? Why?

D, lines cross best performing genotype in one experiment is the worst in another

2. If you want more resolution in a QTL study (i.e., a smaller candidate QTL window), what do

do you need more of it? Hint: there are two things that need to increase.

-Sample Size: Increasing the sample size of the study population allows for more statistical power and precision in identifying QTLs (With a larger sample size, researchers can detect smaller effects and reduce the margin of error in estimating the QTL location)

-Marker Density: Marker density refers to the number of genetic markers used in the QTL study (By increasing the density of markers across the genome, researchers can capture more genetic variation and obtain finer resolution)

3. QTL mapping as an approach emerged in the mid 1980s, well before the release of any

complete genome. QTL mapping was successful because it can work without knowledge of the

genome and because it provides you with information about the genome structure. What aspect

of genome structure can QTL mapping tell you? (hint, think about the location of your markers

along the genome).

QTL mapping tells you about the linkage relationships and relative positions of markers on chromosomes, creating a genetic map of genome structure.

1. How is a QTL study different from GWAS?

QTL studies typically use controlled crosses in model organisms to identify genomic regions affecting traits, while GWAS examines natural variation across many unrelated individuals in a population.

2. Why does LD decay with physical distance?

LD (linkage disequilibrium) decays with distance because recombination is more likely to occur between loci that are farther apart, breaking the association between alleles.

3. Does LD decay with more generations of recombination or less?

LD decays with more generations of recombination, because each generation introduces opportunities to shuffle alleles.

4. What does LD have to do with GWAS?

GWAS relies on LD to detect associations — it tests markers that are linked to causal variants, not necessarily the causal variant itself.

5. Common alleles (>5%) tend to have small effect sizes on phenotypes. What does that imply about their effect on fitness?

It implies they likely have little or no negative effect on fitness, since harmful alleles with big effects tend to be removed by natural selection and thus stay rare.

6. Why is the predictive capacity of GWAS so bad when applied to a population with a different ancestry than the training population?

Because LD patterns, allele frequencies, and environmental interactions vary across ancestries, so markers identified in one group may not tag the same causal variants in another.

Principal components

A mathematical method used to reduce genetic data into axes that summarize the major sources of variation, often used in population structure analysis.

Mitochondrial Eve

The most recent common ancestor of all living humans through maternal mitochondrial lineages.

Genealogy

The family tree of genetic lineages, tracing how alleles or individuals are related through time.

TMRCA (Time to Most Recent Common Ancestor)

The time in the past when all sampled gene copies last shared a common ancestor.

Site-frequency spectrum

A summary of how frequently mutations of different frequencies occur in a sample, often used to infer demographic history or selection.

Ancestry painting

A method of showing which parts of an individual's genome were inherited from different ancestral populations.

How does the TMRCA relate to population size

TMRCA is longer in larger populations because it takes more generations for genetic lineages to coalesce due to weaker genetic drift.

Are rare alleles or common alleles more likely to be lost during a bottleneck

Rare alleles are more likely to be lost because strong genetic drift in small populations tends to eliminate low-frequency variants.

Are new, recessive deleterious mutations more or less likely to persist in populations if the population is expanding? Why

More likely, because weaker drift and heterozygote masking allow them to persist longer without being removed by selection.

The TMRCA of the mitochondria going back in time is ~150K years. Will it take another ~150K years for the mitochondria in one present day individual to be the ancestor of all future mitochondria? Will it take more, or less and why

It will take more than 150K years because the current population is large, and with more individuals, it takes longer for one lineage to randomly drift to fixation.

GRM (Genomic Relationship Matrix)

A matrix that quantifies the genetic similarity between individuals based on genome-wide SNP data.

Dynastic effects

When parental genotypes influence offspring traits indirectly through the environment they create.

Assortative mating

A non-random mating pattern where individuals with similar traits or genotypes are more likely to mate.

Population stratification

Differences in allele frequencies and traits across subpopulations due to ancestry, leading to biased genetic associations.

Biobank

A large, structured collection of biological and health data (including genetic data) from many individuals, used for research.

1. What is a confounding effect

A confounding effect is a factor that influences both the genotype and phenotype in a way that creates a false or inflated genetic association.

2. What are three types of confounding effects that we discussed today

Dynastic effects - when parental genotypes affect offspring phenotype through the environment (e.g., educated parents provide enriched learning environments). Assortative mating - when individuals with similar phenotypes/genotypes are more likely to mate, increasing genetic correlations. Population stratification - when allele frequencies and trait values differ across ancestral subgroups, creating spurious associations.

3. Why do these confounding effects inflate estimates of heritability

Because they introduce environmental or non-genetic structures that mimic genetic effects, making it seem like more of the trait is explained by genetics than actually is.

4. Do the same processes also inflate metrics of association between genotype and phenotype? Why

Yes, because they can create spurious correlations between specific genetic variants and traits that are actually due to shared environment, ancestry, or mating patterns rather than true causal relationships.