Tuesday, June 14, 2016

GeneSeek Meeting: GGP-F250 SNP Chip

Jerry Taylor
University of Missouri

Why did we create a new SNP chip?
There have been four large USDA research grants that Taylor has been a part of. From theses grants, there has actually been a synergy, the sum has been greater than the individual parts.

In one grant they planned to genotype 4,000 variants in 10,000 cattle to look for variants causing embryo losses due to broken genes. The feed efficiency project and the bovine respiratory disease complex projects both budgeted to test 1,000 variants in 2,000 cattle. With a fourth project, they won additional funds to create a SNP chip to look at 200,000 DNA variants in over 17,000 cattle, thus tying all four projects together.

If a DNA variant is lethal, meaning it causes an embryo which carries two copies of the variant to be aborted, then we will never see an animal carrying two copies of that DNA variant. We can look at the inheritance of DNA variants through pedigrees and identify DNA variants that we should observe animals with two copies, but we never observe an animal with two copies of the DNA variant. These DNA variants are then strong candidates as lethal variants.

We also need to identify causal variants for quantitative traits. This is very hard to do; in his 30 year career, Jerry Taylor has found one causal variant. Why are we chasing causal variants in beef cattle? Unlike dairy cattle, we have lots of breeds represented in the beef industry and knowing the causal variants should allow us to create genomic predictions across cattle breeds.

There is a process, called imputation, that allows us to use lots of DNA variants in our search for causal variants. The DNA variants on chromosomes are inherited in patterns. We can use these patterns to infer or predict the genotype for DNA variants that we did test in genotyped animals using DNA sequence data from other animals with whole genome sequences. Now, we can look for causal variants in analyses with over 10 million variants.

This imputation process is improved by using the GGP-F250 SNP chip. The 200,000 DNA variants on this chip are located in genes, not evenly spaced like mile markes, and are at lower frequencies in cattle breeds. If we are trying to impute rare variants, having rare DNA variants on our SNP chip should help us do this imputation.

The GGP-F250 chip contains DNA variants that change the make up or length of proteins encoded by genes.

Most of the amino acid substitutions (protein sequence changes) are very rare in the population. They are likely to be under selection because they are harmful not helpful. [Evolution in action!] These rare amino acid substitutions may be responsible for hybrid vigor; when we cross two animals from two different breeds the progeny are never carry two copies of these bad amino acid changes. Thus, these crossbred progeny perform better than expected base on the parental averages.

There are about 2,200 DNA variants that we should have seen has homozygotes (two copies). One reason is that the DNA variant is not genotyping correctly. Even when we correct for lots of statistical tests, we see 1,772 variants that we never see as homozygotes (two copies). For many of these variants that appear to be lethal, the SNPs in the surrounding DNA are also not inherited in patterns that we would expect (deviations from Hardy-Weinberg equilibrium).

"We can now look at the things that are actually changing proteins," Taylor stated.

Decker's Take Home Message
The GGP-F250 chip is going to be a great tool for scientists. The GGP-F250 will allow scientists to create new tools for cattle breeders to use to select better cattle.

Further, it appears there are many more lethal variants causing embryonic loss than we recently expected.


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