September 11, 2012
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Horse locomotion and speed is one of the most complex behaviors that people seem to be interested in (for obvious reasons). There is some correlation between how a horse runs and how fast it runs. In other words, it seems that there are successful styles of running and these styles can be treated as phenotypes (or traits) and effectively studied through genetics. In general, genetic studies of dogs or horses have been significantly more successful than those of human, partly due to very controlled mating across the breeds and also excellent record keeping by the breeders throughout many generations. Now there is a paper out in Nature that looks at pacing in icelandic horses, which has a high heritability in this breed, and successfully maps this phenotype to a nonsense mutation in Dmr3.
The study contains an association study between 30 horses that don’t pace and 40 that do which resulted in the discovery of a highly significant SNP (single-nucleotide polymorphism) on chromosome 23. Genome re-sequencing in this region showed a nonsense mutation in Dmr3 as the likely candidate.
What distinguishes this study from similar ones I had read over the years is the fact that they closely follow up on the functionality of Dmr3 and its mutated form. They make the case that this protein functions in neural development using mouse models. And this is the part that gets me excited… this study sets a bar for genetic projects. It’s not enough to just list mutations in a bunch of genes along with their contribution to the phenotype. We need more mechanistic and functional results that can actually augment our knowledge to a degree that a simple gene/mutation list cannot. I am sure this is not a perfect project either and if we look closely there are things that could be done differently/better. Nevertheless, it signals the arrival of a new kind of genetic studies, one that is more function oriented.
September 10, 2012
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A recent paper in Science perfectly captures the post-ENCODE mood of the community. It seems like we suddenly realized the coding genome is not actually that important. We have remarked over and over in the past couple of weeks that the majority of whole-genome association studies (GWAS) actually map to non-coding DNA as opposed to coding sequences. And now, armed with the knowledge that the non-coding genome has far-reaching regulatory consequences, it is very likely that the genetic component of many complex human diseases are in fact driven by regulatory interactions. And this Science paper very clearly portrays this idea. They use DNAse I hypersensitivity data as a proxy for the parts of the genome are bound by proteins in vivo. They then look at the overlap between DNase I hypersensitive sites (DHSs) and the available phenotypic and disease data. They show that many variants at these sites have regulatory consequences and they make the case that the role of regulatory genome in disease is ubiquitous and profound.
As I said, this study very well captures the consensus view-point of the community and I think we’ll see an explosion in these type of studies that would put the regulatory genome front and center as opposed to the coding DNA. With the low-hanging fruits already discovered in genetic studies, and the emergence of effective methods based on high-throughput sequencing, we are now poised to better understand regulatory networks in all their glory.