Rare and common genetic variants in humans

The findings of this paper are not very surprising, but it is nice to see them formally expressed and tested.

Common variants are usually not functional; this makes sense as alleles that differ functionally from their competitors at a given locus are likely to win/lose in the evolutionary game and either become fixed, disappear, or be maintained at an extremely low frequency (and hence not be common).

The finding that major derived alleles are more functional also makes sense: a new allele at a given locus may either disappear, attain a non-trivial frequency by random drift, or even achieve a high frequency, pushing the ancestral allele to a lower one. In the latter case, the derived allele becomes the major (most frequent) allele in the population. A high frequency can be attained by either drift or selection: drift is slow and effective in small populations, whereas selection is faster, depending on the relative advantage of the new allele.

Polymorphism in the human genome can be maintained by either mutation-selection, whereby new variants appear constantly due to mutations in individuals, and selection culls many of them, or by balancing selection, whereby different variants have important functions but involve tradeoffs so that a tug-of-war between them results in an equilibrium.

What this paper suggests is that:

1. Most common variants are not functional
2. Common derived variants that are functional attain a high frequency and become the major alleles
3. Rare variants are more likely to be functional than common ones
4. Selection operates mostly by the constant culling of new alleles, sometimes by favoring new derived alleles, but, not so much by a tug-of-war between competing alleles

I'd say that this is quite consistent with my lego-block paradigm:

This Lego-block paradigm is based on the notion that most of our alleles are commodity"building blocks"; if they are brought together harmoneously, they produce positive results. The occasional allele may have a large effect, and some alleles fit better together than others. Yet, most of the success or failure of a construction depends on how the components fit together, and not what they are.

That, in my opinion, is where the "hidden heritability" mostly hides: part of it is due to the degradation of function by rare mutations that run in families or small populations, and part of it is due to the fortuitous combination of commodity alleles that have no long-term evolutionary advantage/disadvantage (function), but are co-inherited in the short-term from parents to offspring.

The authors have this to say:

Our analyses suggest that most of the functional variation carried by humans is likely to be rare genetic variation that is at least moderately deleterious and held to low frequency by selection.43,44 These analyses therefore provide a possible explanation for the relatively limited role of common genetic variation in most human diseases identified by genome-wide association studies.1,3

From the press release:

"The more common a variant is, the less likely it is to be found in a functional region of the genome," said senior author David Goldstein, Ph.D., director of the Duke Center for Human Genome Variation. "Scientists have reported this observation before, but this study is the most comprehensive effort to date using annotations of the functional regions of the human genome and fully sequenced genomes."

Goldstein said that "the magnitude of the effect is dramatic and is consistent across all frequencies of variants we looked at." He also said he was surprised by the notable consistency of the finding. "It's not just that the most rare variants are different from the most common, it's that at every increase in frequency, a variant is less and less likely to be found in a functional region of the DNA," Goldstein said. "This analysis is consistent with what appears to be a growing consensus that common variants are less important in common diseases than many had originally thought."

The American Journal of Human Genetics, 31 March 2011

doi:10.1016/j.ajhg.2011.03.008

A Genome-wide Comparison of the Functional Properties of Rare and Common Genetic Variants in Humans

Qianqian Zhu et al.

Abstract
One of the longest running debates in evolutionary biology concerns the kind of genetic variation that is primarily responsible for phenotypic variation in species. Here, we address this question for humans specifically from the perspective of population allele frequency of variants across the complete genome, including both coding and noncoding regions. We establish simple criteria to assess the likelihood that variants are functional based on their genomic locations and then use whole-genome sequence data from 29 subjects of European origin to assess the relationship between the functional properties of variants and their population allele frequencies. We find that for all criteria used to assess the likelihood that a variant is functional, the rarer variants are significantly more likely to be functional than the more common variants. Strikingly, these patterns disappear when we focus on only those variants in which the major alleles are derived. These analyses indicate that the majority of the genetic variation in terms of phenotypic consequence may result from a mutation-selection balance, as opposed to balancing selection, and have direct relevance to the study of human disease.

Link