Genetic Variants & Evolution
Hai Yan, MD, PhD and Greg Wray, PhDThis article originally appeared in the November/December 2004 Issue of GenomeLife.
Hai Yan and Greg Wray don't have anything against proteins or the DNA sequences that code for them. But both are quick to point out that 98 percent of our DNA does not code for protein. Thus, they contend there's a lot to be gained by studying genetic variation in that 98 percent. Variants lying outside of the protein-coding regions of DNA may not change the structure of proteins, but they can affect how much protein is made. That's because the non-coding portions of our genome regulate to what extent a gene is switched on or off.
Yan, an Assistant Professor of Pathology, sees genetic variation in the non-coding portions of the genome as key to understanding disease. Wray, Associate Professor of Biology, says such variants can teach us about our own evolutionary history.
Regulation: A Revelation
Given that gene expression is regulated by DNA sequences that lie "upstream" from the regions that code for protein, the idea that variants in those upstream regions can affect whether a gene is turned on or off is not surprising. A variant in a regulatory sequence may attenuate or boost the expression of the gene it regulates. Yan, who recently published a review on the subject, says if enough such variants accumulate in the same genome, they may make the difference between sickness and health.
In 2001, he identified a putative non-coding variant rendering certain families more susceptible to familial adenomatous polyposis (FAP), a single-gene disorder associated with multiple benign tumors in the colon. He is now working to identify variants associated with human behavior and other characteristics.
A Rapidly Evolving Story
Greg Wray is interested in the way upstream variants influence natural selection--the way in which those organisms best adapted to their environments tend to survive and transmit their genes to succeeding generations. Such genes and their corresponding traits are said to be "selected for." Recently, Wray's lab examined the evolutionary history of a variant in a gene called MMP3, which has been associated with heart disease.
Graduate student Matt Rockman, Wray and their co-authors observed that one of the two human MMP3 versions ("alleles") with variants in the noncoding region of the gene had been selected for-but only in Europe. Some 23,000 years ago, the frequency of the rarer allele shot up on the European continent, which was then in the middle of the Ice Age.
Selection, the conventional wisdom goes, implies importance: if evolution has kept a version of a gene around over a long period of time and favored it over other versions, it must be doing something important. Might the favored European MMP3 allele be protective against heart disease? Wray admits that the possibility is intriguing, especially given Europeans' heart-unhealthy carnivorous diets at the time, but he cautions that it's only speculation.
"It's true that people in Europe at that time were eating large mammals. But this gene does many other things in the body, so we can't make a convincing case that heart disease was the driving factor in one MMP3 allele being selected for."
Wray sees the MMP3 story as an important example of the power of rapid evolutionary change. Traditionally, important alleles are thought to change very slowly. However, Wray points out that when the environment changes rapidly, organisms with genes that can also evolve rapidly may have an advantage. The rapid rise of the European MMP3 allele suggests that that may have been the case 20,000 years ago.
The other lesson, Wray says, is that alleles should not be viewed in absolute terms. "There might be an allele that works better in one circumstance-say, a cold climate-and another that works better in another circumstance. It really depends on the local environment."
Upstream without a Protein
Yan and Wray have helped to establish the importance of genetic variation outside of regions of DNA that code for proteins. Both lament how little attention the subject has received in the literature. Wray attributes that to inertia.
"As scientists, we get used to thinking about how to approach a gene in a lab," he says. "It establishes a workflow for us. I've read many papers where the investigators scoured a gene for a mutation or variant and only looked at upstream non-coding sequence out of desperation. And then when they did find something [in a non-coding region], they didn't know what to do with it. But I think it's starting to resonate in the community that we need to look explicitly at these things. They are a part of the [evolutionary and medical] picture and we can't ignore them."
Further Reading
Rockman MV, Hahn MW, Soranzo N, Loisel DA, Goldstein DB, Wray GA. Positive selection on MMP3 regulation has shaped heart disease risk. Curr Biol 2004;14:1531-9.
Yan H, Zhou W. Allelic variations in gene expression. Curr Opin Oncol 2004;16:39-43.