MGI 404 Exam 4: Population Genetics, Gene Mapping, and Variant Classification

Vocabulary practice flashcards covering Hardy-Weinberg equilibrium, population genetics mechanisms, linkage and association analysis methods, study statistics, sequencing strategies, and ACMG variant classifications.

Hardy-Weinberg Equilibrium (HWE)

The principle stating that allele frequencies will remain constant from generation to generation when equilibrium assumptions (random mating, a sufficiently large population, no selection, no mutation, and no migration) are met.

$$p$$

The frequency of the $A$ allele (large).

$$q$$

The frequency of the $a$ allele (small).

$$p + q = 1$$

The principle that all allele frequencies at a two-allele locus add up to $100\%$.

Binomial expansion equation

$(p+q)^2 = p^2 + 2pq + q^2$, which predicts genotype frequencies for $AA$, $Aa$, and $aa$.

Non-random mating (assortative)

Choosing mates according to genetic constituency; for example, individuals with congenital deafness or achondroplasia having a higher than random probability of mating with others who have the same condition.

Consanguinity / inbreeding / high-kinship

Mating within families or small closed populations (e.g., Amish).

Population stratification

Non-random mating with respect to population sub-groups based on potential isolation due to geography, religion, or language (e.g., Tay Sachs mutation frequency being high in the Ashkenazi Jewish population but low outside).

Genetic drift

Random changes in allele frequencies across generations, especially prominent in small populations.

Founder effects

Genetic drift that occurs when a new population is established by a small number of individuals carrying only a subset of the original population's genetic variation.

Heterozygous advantage

A condition in which heterozygotes have a higher fitness than either homozygote (e.g., sickle-cell trait providing protection against severe malaria).

Selection coefficient ($s$)

Measures the reduction in fitness relative to the most fit genotype; commonly calculated as $s = 1 - w$ (or $1 - f$), where $w$ is relative fitness.

Fitness coefficient ($f$)

Often written as $w$; measures reproductive success relative to other genotypes, where a value of $1$ represents the reference maximum fitness.

Functional cloning

Identifying a gene by starting with its known function or the protein it produces.

Positional cloning

Identifying a gene by first locating its chromosomal position, often using genetic markers and linkage analysis.

Linkage analysis

A method that tracks genetic markers through families to determine whether a marker and a disease-causing gene are inherited together.

Genome wide Association study (GWAS)

An approach that examines genetic variants across the genome in many people to identify variants statistically associated with a trait or disease.

Phase

Specifies which alleles are located together on the same chromosome.

Haplotype

A group of alleles inherited together on one chromosome.

Recombinant

An offspring whose allele combination differs from the parental combinations because crossing over occurred between loci.

Non-recombinant

An offspring that retains the original parental allele combinations.

LOD score (log of odds)

The log-base-10 ratio comparing the likelihood of linkage at a specified recombination fraction with no linkage; a score $\ge 3$ is conventionally considered strong evidence supporting linkage.

$Z$ and $Z_{\max}$

In linkage analysis, $Z(\theta)$ is the LOD score at a given recombination fraction, and $Z_{\max}$ is the highest LOD score across the tested recombination fractions.

Theta ($\theta$) and $\theta_{\max}$

$\theta$ is the recombination fraction between two loci (ranging from $0$ to $0.5$); $\theta_{\max}$ is the value of $\theta$ that produces the maximum LOD score.

$$\theta = 0$$

Indicates that no recombination is observed in the model.

$$\theta = 0.5$$

Indicates that the loci behave as unlinked.

Coupling

A state where two alleles of interest are located on the same chromosome, such as $AB/ab$.

Association

A simple statistical test comparing two groups (case/control) and two exposures minimally; association does not prove causation.

Case/control study

A study that compares people with a disease (cases) to people without it (controls) to investigate differences in genetic variants or exposures.

Necessary condition

A factor or condition that must be present for an outcome to occur.

Sufficient condition

A factor or condition that, when present, is enough to produce an outcome.

Forest plot

A graph displaying effect estimates and confidence intervals from multiple studies, often used in meta-analysis.

Point estimate

A single best estimate of a population value, such as an odds ratio or relative risk.

Confidence interval

A range of plausible values for a population value, such as an odds ratio or relative risk.

Linkage disequilibrium

Non-random association of alleles at different loci in a population, where certain allele combinations occur more or less often than expected.

Haplotype block

A chromosome region where groups of nearby variants are commonly inherited together, often with limited historical recombination.

Manhattan plot

A GWAS graph displaying genomic positions on the x-axis and $-\log_{10}(p)$ values on the y-axis, where taller peaks indicate stronger statistical associations.

WES (whole exome sequencing)

Sequencing technique that targets the exome, which consists of the protein-coding portions of genes.

WGS (whole genome sequencing)

Sequencing technique that covers nearly the entire genome, including both coding and noncoding regions.

Critical region

A specific part of a chromosome or gene where changes can cause a particular disorder or affect its function.

“Sequence First”

A genetics approach where DNA is sequenced first to identify variants that could explain a patient's condition.

Pathogenic

An ACMG classification for a genetic variant that causes disease.

Benign

An ACMG classification for a genetic variant that does not cause disease.

VUF (variant of unknown function)

A genetic variant whose effect on gene or protein function is not yet known.