The less common a gene variant is, the more likely it is to be functional, according to new research out of David Goldstein's lab at Duke University. This finding would contradict the common disease, common variant hypothesis that underpins many genome-wide association studies and instead lends credence to the idea that rare variants are behind common diseases, a theory that Goldstein has long suggested.
"There's always been debate about rare variants as the causal variants of common disease or common variants are the causal variants of common disease," says Qianqian Zhu, a postdoc in the Goldstein lab. "We think that if a variant can cause phenotypic effect, that variant is more likely to be in the genomic region that has function — for example, in the region that is coding or is regulating gene expression. Based on this idea, we ask whether rare variants or common variants are more enriched in functional genomic regions."
For their analyses, Zhu and her colleagues used SNVs from whole genome sequences of 29 unrelated people of European descent, and used three criteria — gene conservation, gene structure, and regulatory potential — as proxies for functionality. For each metric, they compared the allele frequencies for rare and common variants to look for a pattern. "We first looked at conservation to see if there is relationship between allele frequencies and conservation. We see that as the allele frequencies decrease, the corresponding genomic positions are more conserved," Zhu says.
As she and her colleagues report in The Journal of Human Genetics, they observed that same pattern for the other measures as well. "The results are consistent with our expectation that rare variants are more likely to cause phenotypic effects. What's surprising to us is that the pattern is consistent across all functional categories we examined," she says. "We think this analysis may help in the interpretation and design of association studies in humans, in particular establishing a direction for how population allele frequency can be used to both weight variants and assess the utility of functional assignments, such as the extent to which amino acid replacements affect protein function."
In addition, the researchers studied variants for which the minor allele is the ancestral one. Derived alleles, Zhu says, are more likely to be under positive selection in humans, and therefore their frequency should be on the rise — they should be becoming more common. "If the derived allele becomes the major form in human population due to positive selection, we would expect to see stronger enrichment in functional regions as the derived allele becomes more common, but that's not what we see from the data," she says. When the minor alleles are ancestral, there is no difference in the tendency of a rare or common SNV to be functional, Zhu and her colleagues report. "This suggests that positive selection is not a general pattern," she adds. Instead, those variants could be becoming common through genetic drift.