Integrative genomics

Question 1

What were the early integrative genomic approaches?

Answer 1

• use of RIL with 2 parental strains
• F1 generation (het at many loci) are intermated to generate many different recombination events
• then each line is inbred (hom) which creates a population of genetically identical individuals
• can easily map trait
• differences between RILs can be mapped to either parental chromosome

Question 2

What is the collaborative cross?

Answer 2

• 8 genotype founder strains (parental strains)
• increased no of strains = increased no of recombination = increased mapping resolution
• result is hundreds of unique strains which all contain 1/8th of each founder genome

Question 3

What is expression profiling?

Answer 3

After population of interest established (e.g. founder strains) use microarray or RNA seq to discover expression levels of transcripts in each individual in a population

After use statistical analyses to correlate/associate variant/s that segregate with high vs low expression of the transcript

Question 4

What is a genomic map?

Answer 4

The variants (markers) found via expression profiling that segregate with the trait are used to map the genomic regions which influence expression of the trait

Question 5

What is the LOD score?

Answer 5

The likelihood that the association between the trait and the genetic marker is not due to chance (>3 is statistically significant)

Question 6

What are Cis and Tran expression QTLs?

Answer 6

Cis = QTL peak localises to the same genomic region as the transcript being measured

Trans = QTL peak localises to a different genomic region as the transcript being measured

Question 7

What is atrial fibrillation?

Answer 7

A massive cause of morbidity and mortality where abnormal electrical impulses are thought to originate in the lung, from a small population of muscle cells which surround the pulmonary veins. Thought that these muscle cells have an altered phenotype which switches from working muscle to pacemaker

Question 8

Explain how a 2-parent cross in mice was used to study atrial fibrillation

Answer 8

• Stain the muscle cells around the pulmonary veins with cardiac troponin
• then correlation analysis (find all transcripts that are correlated with cardiac troponin)
• now have gene network of correlated muscle transcripts within lung
• gene network is co-regulated

Question 9

What did the the 2-parent cross in mice studying atrial fibrillation find?

Answer 9

Found all the transcripts in the network were regulated from either one or both Ch1 or Ch2 (master regulatory loci)

Question 10

What are the challenges of integrative genomics?

Answer 10

• increasing no of individuals and SNPs to increase resolution increases the cost
• if the effect size you are mapping is small, or there are many loci controlling the trait, the more individuals needed
• increased variation between lines, also increases the risk of spurious association

Question 11

Outbred population of integrative genomics present what challenges?

Answer 11

• need to screen large no
• need high density genotyping (whole genome scan)
• need sophisticated statistical methods
• must be careful of confounding factors

Question 12

What was the San Antonio Family Heart study?

Answer 12

• Major project to find genes involved in heart disease
• 1400 members of 40 large Mexican American Families in San Antonio with high incidence of heart disease and diabetes
• aim to identify cardiovascular disease genes

Question 13

What results were found in the San Antonio Family Heart Study?

Answer 13

• results of eQTL association analysis found VNN1 had a high association with HDL-cholesterol and TG
• SNP- genotype total population for VNN1: found 2 SNPs highly associated within the promoter of the VNN1 gene
• network analysis found positive association of VNN1 and HDL-C