Ch. 10 Strategies for Identifying Genes and Genetic Mapping

Flashcards based on lecture notes about strategies for identifying genes, linkage analysis, recombination frequency, genetic maps, and genome sequencing.

What are the three main strategies for identifying genes?

Linkage analysis, association analysis, and genome sequencing

1. Which method of Genetic mapping is family based?

1. Linkage Analysis

Describe linkage analysis

• tests for consistent, repeated inheritance of diseases with a particular genomic or specific variant such as markers (SNPs or microsatellites) that co-segregate with the disease

• Used in families

• Need “linked” genes for variation among gametes

  • If two genes follow independent assortment, their inheritance patterns will appear unlinked in pedigrees

• Recombination freq will be used to calculate how closely linked a marker is to the disease gene

According to Nussbaum et al. (2016), what is the nature of a child's chromosome in terms of their grandparents' chromosomes?

The child's chromosome is a mosaic of all four of his grandparents' chromosomes.

Genes that reside on the same chromosome are ______

syntenic - on the same thread

If 2 syntenic loci are far enough apart on the same chromosome to ensure that 1 crossover between them occurs every meiosis, the ratio of recombinant to non-recombinant will be ______

1:1 - the same

1 to 4 crossovers between homologous chromosomes occur during meiosis I.

1. Define non-recombinant

2. Define recombinant

1. Non-recombinant is no crossing over between 2 loci, the chromosomes in the gametes will be same as parental chromosome (most likely further apart chromosomes)

2. Recombinant - at least 1 crossover occurs and gametes will be recombinant

How does the distance between loci affect recombination frequency and the ratio of recombinants to non-recombinants?

If loci are far apart, at least 1 crossover will occur, and recombinants and non-recombinants are 50/50. If loci are so close together that crossovers never occur, all gametes are all non-recombinants.

How does the proximity of two loci affect the likelihood of a crossover occurring between them?

The closer two loci are to each other, the lower the likelihood that a cross-over will occur between them.

Define linkage

Tendency for alleles at loci that are close together on the same chromosome to be transmitted together through meiosis

Do not assort independently

Ranges from 0 (so close togther there is no recombination) to 0.5 (assort independently - unlinked)

T/F: Hotspots of recombination (places more likely to encounter crossover) occupy 6% of genome but account for 60% of meiotic recombination

true

Linkage equilibrium vs Linkage disequilibrium

L Equilibrium - two alleles at different loci are inherited independently

• occurs because loci are either far apart on the same chromosome or on different chromosomes

L Disequilibrium - two alleles at different loci are inherited together more often than expected by chance, often due to their physical proximity on the same chromosome

• used to build haplotypes - blocks of DNA inherited together

What is the odds ratio (OR), what type of studies is it used in, and what does an OR of 1 signify?

Calculated association between disease and genotype, used in case-control studies. OR = 1 indicates no association between genotype and disease.

What is relative risk (RR), what type of studies is it used in, and what does RR = 1 signify?

Measure of the strength of an association, used in cross-sectional or cohort studies. RR = 1 indicates no association.

An association study uses unrelated, affected individuals and controls.

1. What is the purpose?

2. If the results move further away from RR and OR being one, what does that mean?

1. looks for statistical association between genetic variants and disease status (genotype vs phenotype)

2. there is a greater effect of the genetic variant on the association between genotype and phenotype

Define confidence interval

• way of expressing statistical significance

• range within which one would expect the OR or RR to fall 95% of the time by chance alone

What is a Genome Wide Association study (GWAS)

• A study that examines the entire genome to identify genetic variants associated with specific diseases or traits (with SNPs), often involving large sample sizes to detect small effects. (uses haplotype mapping)

  • compared to controlled alleles

• Related to linkage disequilibrium

What are pitfalls to GWAS?

• population stratificaiton

• False positives due to less strict test for statistical significance

• If associations are found between a disease and a marker allele, one cannot infer that the allele has a functional role in the disease

What is population stratification, and how can it lead to incorrect associations in GWAS?

Members of 1 subpopulation rarely mate with members of other subpopulation. A disease that happens to be more common in a subpopulation can incorrectly appear to be associated with any alleles that also happen to be more popular in that same subpopulation

What does finding genes responsible for disease by genome sequencing involve?

Involves direct genome sequencing of affected individuals and their parents, includes whole genome sequencing (WGS) and whole exome sequencing (WES).

Name some strategies in filtering sequence data to find potential causative variants.

Ignore variants deep within introns or intergenic regions, ignore common variants, ignore silent/synonymous mutations, and look for consistency with likely inheritance Pattern

What is the importance of associations discovered with GWS?

GWAS results how many associations, most with very modest effect size (OR of 1.2)

Finding genes responsible for disease by genome sequencing involves sequencing of affected individuals and their parents with which types of sequencing?

• considered next generation sequencing - novel and rare

Whole genome sequencing WGS

Whole Exome Sequencing WES - exons account for 2% of genome and most cost effective alternative

• limitation to WES is that important regulatory regions in the UTS and introns would be ignored

Filtering sequence methods are able to ignore which factors about which variants are more likely to be responsible for the disease include …(4)

AKA their limiting factors

1. Ignore variants deep within introns or intergenic regions

2. Ignore common variants (“80% of population…)

3. Ignore silent/synonymous mutations

4. Look for consistency with likely inheritance pattern

In linkage analysis, what are parental combinations?

Allele combinations that remain the same as in the parents

What does the HapMap project focus on?

Collecting and characterizing SNP loci for use of genetic markers

What is population stratification in context of GWAS studies?

The separation of populations into subgroups that rarely intermate

When genes sort independently, what is their recombination frequency?

0.5

Why might silent or synonymous mutations be important despite not changing amino acid sequences?

They may affect transcription factor binding or gene expression