Tuesday, July 14, 2009

Genetics of Athletic Performance (Dog Version)

Dr. Elaine Ostrander is a geneticist at the NIH. She studies genetic variation within and between populations, and tries to identify genetic mutations that cause disease. Her lab studies dog genetics as a model for understanding the genetic structure of populations. Dogs are fairly interesting in this regard because although they are all members of the same species, different breeds show very diverse phenotypes. The size difference between a great dane and a chihuahua, for instance, is far greater than the size difference between any two people. The cause of this size difference is genetic, and the Ostrander lab traced the variation to mutations in the gene IGF-1.

As part of this research program, Ostrander’s lab published a
paper in 2007 on how a genetic mutation in whippets increased their athletic performance. Whippets are lean racing dogs that were bred from greyhounds in the late 1800s and, like amateur bike racers, they compete in categories based on racing ability. Dogs move up and down categories, ranked A to D from fast to slow, as they proceed through their careers.

Not surprisingly, an individual whippet’s physiology has a large effect on their racing ability. In particular, there is a subpopulation called “bully whippets” that show larger than normal musculature. This condition is known as “double muscling” in some breeds of cattle and, in one known case, a human. These individuals have a substantially greater number of skeletal muscle fibers. Furthermore, in bully whippets this enhanced musculature tends to appear at two different degrees – bigger and biggest. To a geneticist, this strongly suggests that the cause is a single genetic mutation that is partially recessive. Dogs with one copy of the mutant gene and one normal gene (heterozygotes) are somewhat more muscular than normal, and dogs with two copies of the mutant gene (homozygotes) are extremely muscular. Following up on this, the Ostrander lab identified a mutation in the myostatin gene (MSTN) as the cause of the bully whippet phenotype. Sure enough, dogs with two mutant copies of MSTN were double muscled, and dogs with a single mutant MSTN had enhanced musculature.

The MSTN mutation had a positive effect on racing ability, judging by the fact that mutant dogs were more likely to be Grade A racers. The MSTN gene was genotyped in 85 individuals and 13 were found to have the mutation. Nine of these 13 were Grade A racers, three were Grade B, and one was Grade D. If this mutation didn’t have an effect on race performance we would expect about 3 mutant dogs in each category; the likelihood we would get 9 or more in Grade A is 0.03%. Although it would be nicer to have more individuals and hence better statistics, this is pretty solid evidence that the MSTN mutation confers an advantage in racing.

This is interesting but not very surprising. Clearly, certain genetic variants are going to improve athletic performance, especially ones that increase muscle mass. One might ask if there are other genetic determinants of racing ability that might explain the 13 Grade A dogs that had a normal MSTN gene. Are they also genetically superior to the other grades, in a way that doesn’t directly involve MSTN?

Indeed, they are. To study this, the researchers genotyped each of the 85 dogs at 32 sites scattered across the genome and then compared the results. Based on this fairly sparse view of the genome (a dog has 39 chromosome pairs, so this is less than one site per chromosome), they computed a representative number they call pc1 for each individual (technically, the first principle component of the genotype). While one individual pc1 isn’t meaningful, we can say that two or more dogs with similar pc1 values are genetically similar. The results looked like this:

The x-axis, pc1, represents the genotype and the y-axis shows the race grade (plus a small random number to scatter the points a little). It is clear that Grade A dogs tend to have low pc1 and Grade D dogs generally have high pc1. Grade B dogs cluster in the middle, and Grade C dogs are spread into a middle and low group. This population structure is partially due to the greater inbreeding within a race grade – fast dogs are bred with other fast dogs, so fast dogs will tend to be genetically similar. It is difficult to tell how great of an effect this has on the current study since the dog’s ancestries were not reported. That caveat aside, the cluster of points in the upper left suggests that the genotypes of the Grade A dogs provide a genetic advantage over the other race grades.

This effect becomes even more clear when we consider only the dogs without the MSTN mutation:

In this second plot points have been faded for dogs with at least one MSTN mutation (bully whippets). We see that all but one of the Grade A dogs with the highest pc1 values carry the mutation, suggesting that this single genetic abnormality has turned these five slower dogs into Grade A racers. Looking only at the dark points, we see strong evidence that MSTN is not the only genetic contributor to racing ability; there are 13 Grade A dogs without the mutation, and all except for a single outlier have a genetic makeup (negative pc1 values) that sets them apart from most dogs in the other grades. The authors suggest that about 70 other genes are contributing to this genetic advantage.

So a major result of this study is a genetic signature for a fast whippet, comprised of 32 markers across the genome. In principle, if one were to give these researchers the DNA from a rookie whippet, they could probably predict to reasonable accuracy whether that dog will be Grade A based on its genotype. The test won’t be perfect, but one might significantly improve the test by including more than 32 genetic markers. Current technology can read millions of genetic markers for a few hundred dollars, so it certainly could be done.

The paper concludes by noting that the MSTN mutation also confers greater musculature in humans, and therefore is a candidate for gene doping. With only one known human case of this mutation it is impossible to predict side effects, rendering this proposition quite dangerous even if it were technically feasible. However, it is probably a matter of time before such ideas will make their way into athletics. Personally I propose an alterative use for genetics in cycling. I would like to collect DNA samples from a few hundred of my fellow amateur racers, genotype them all, and determine the genetic profile of a Cat 1/2, Cat 3, and Cat 4 racer. New racers will be forced to do their ten Cat 5 races, after which they will be genotyped and assigned to their appropriate category. No more unnecessary thrashings of the Cat 3 and 4 fields by clearly superior racers who are amassing upgrade points – just put everyone where they belong and let their training, race smarts, teams, and luck determine the outcome. It will be a new age of bike racing, brought to us by science! Are you reading this, Shawn Farrell?

No comments:

Post a Comment