Linkage analysis

Question 1

What methods can be used to see if a disease/trait is genetic?

Answer 1

• Twin studies: compare concordance rates of monozygotic (genetically identical) and dizygotic twins (1/2 genome shared)
• Family segregation: compare frequency of diseases among first degree relatives of affected individuals with frequency of the disease in general population

Question 2

What are the general approaches in gene identification?

Answer 2

1. Functional cloning: disease > function > gene > map

2. Positional cloning (reverse genetics): disease > map > gene > function

Question 3

What are the strengths and weaknesses of positional cloning?

Answer 3

Strengths: no knowledge of gene product required; good for single gene disorders

Weakness: understanding of function not a certain outcome; poor track record with complex diseases

Question 4

What is the candidate gene approach? What is it limited to?

Answer 4

Candidate genes are located in a chromosome region suspected of being involved in the expression of disease traits. Limited to the known biological functions of a particular disease

Question 5

What is the whole genome scan approach?

Answer 5

Scan the whole genome without prior info. Can discover potential genes playing roles for disease

Question 6

What is Linkage mapping?

Answer 6

Measures the segregation of alleles and a phenotype within a family. Using cross-over during meiosis I (genes physically close are more likely to be co-inherited that those far apart)

Question 7

What is Linkage disequilibrium?

Answer 7

Evaluate the evidence of a direct correlation between a marker allele and a disease risk allele. Loci that are close together tend to be inherited together (in LD)

Question 8

What are some genetic molecular markers?

Answer 8

• SNPs and microsatellites

Question 9

What happens during meiosis?

Answer 9

The chromosomes duplicate, then cross over (recombine) to produce a haploid gamete.

Question 10

How do you measure linkage?

Answer 10

Degree of linkage is a measure of genetic distance. It’s measured by the recombination fraction 0 (proportion if recombinants). 0 = 0 (complete linkage. 0 = 0.5 (no linkage). Further apart 2 loci, the more likely a crossover event will occur (0 value increases)

Question 11

What is cM?

Answer 11

Centimorgan is genetic distance unit. 1cM = 1% chance of recombination.

Question 12

What is linkage analysis?

Answer 12

The determination of the ~ location of disease predisposing genes using a genetic marker map. Looks for co-segregation with a marker. Great for Mendelian disease