The findings of this theme are not very surprising, but it is gracious to see them formally expressed and tested.
The determination 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 cast or selection: drift is behind and good in small populations, whereas selection is faster, depending on the comparative advantage of the new allele.
Polymorphism in the human genome can be retained 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.
Common variants are normally not functional; this makes sense as alleles that differ functionally from their competitors at a given locus are probably to win/lose in the evolutionary game and either become fixed, disappear, or be retained at an exceedingly low frequency (and therefore not be common).
The determination 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 cast or selection: drift is behind and good in small populations, whereas selection is faster, depending on the comparative advantage of the new allele.
Polymorphism in the human genome can be retained 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 report suggests is that:
- Most common variants are not functional
- Common derived variants that are functional attain a high frequency and get the major alleles
- Rare variants are more potential to be functional than green ones
- Selection operates mostly by the constant culling of new alleles, sometimes by favoring new derived alleles, but, not so often 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 belief that most of our alleles are commodity"building blocks"; if they are brought together harmoneously, they create positive results. The occasional allele may cause a big effect, and some alleles fit better together than others. Yet, most of the winner or loser of a construction depends on how the components fit together, and not what they are.
This Lego-block paradigm is based on the belief that most of our alleles are commodity"building blocks"; if they are brought together harmoneously, they create positive results. The occasional allele may cause a big effect, and some alleles fit better together than others. Yet, most of the winner or loser 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 debasement of use by rare mutations that run in families or small populations, and part of it is due to the fortuitous combination of commodity alleles that birth no long-term evolutionary advantage/disadvantage (function), but are co-inherited in the short-term from parents to offspring.
The authors make this to say:
Our analyses indicate that most of the functional variation carried by man is probably to be rare genetic variant that is at least moderately deleterious and held to low frequency by selection.43,44 These analyses therefore offer a potential explanation for the comparatively limited use of common genetic mutation in almost human diseases identified by genome-wide association studies.1,3
From the press release:
"The more common a form is, the less likely it is to be ground in a functional part 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 work is the most comprehensive attempt to date using annotations of the functional regions of the human genome and fully sequenced genomes."
Goldstein said that "the magnitude of the event is striking and is uniform across all frequencies of variants we looked at." He too said he was surprised by the notable consistency of the finding. "It's not exactly that the most rare variants are different from the most common, it's that at every gain in frequency, a form is less and less likely to be base in a functional part of the DNA," Goldstein said. "This analysis is uniform with what appears to be a growing consensus that common variants are less significant in common diseases than many had earlier thought."
"The more common a form is, the less likely it is to be ground in a functional part 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 work is the most comprehensive attempt to date using annotations of the functional regions of the human genome and fully sequenced genomes."
Goldstein said that "the magnitude of the event is striking and is uniform across all frequencies of variants we looked at." He too said he was surprised by the notable consistency of the finding. "It's not exactly that the most rare variants are different from the most common, it's that at every gain in frequency, a form is less and less likely to be base in a functional part of the DNA," Goldstein said. "This analysis is uniform with what appears to be a growing consensus that common variants are less significant in common diseases than many had earlier 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
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 form of inherited mutation that is principally responsible for phenotypic variation in species. Here, we address this question for humans specifically from the position of population allele frequency of variants across the complete genome, including both cryptography and noncoding regions. We establish simple criteria to measure the likelihood that variants are functional based on their genomic locations and so use whole-genome sequence information from 29 subjects of European ancestry to assess the relationship between the functional properties of variants and their population allele frequencies. We see that for all criteria used to evaluate the likelihood that a form is functional, the rarer variants are significantly more probably to be functional than the more common variants. Strikingly, these patterns disappear when we concentrate on just those variants in which the major alleles are derived. These analyses suggest that the bulk of the genetic variance in price of phenotypic consequence may ensue from a mutation-selection balance, as opposed to balancing selection, and induce direct relevance to the subject of human disease.
Link
Abstract
One of the longest running debates in evolutionary biology concerns the form of inherited mutation that is principally responsible for phenotypic variation in species. Here, we address this question for humans specifically from the position of population allele frequency of variants across the complete genome, including both cryptography and noncoding regions. We establish simple criteria to measure the likelihood that variants are functional based on their genomic locations and so use whole-genome sequence information from 29 subjects of European ancestry to assess the relationship between the functional properties of variants and their population allele frequencies. We see that for all criteria used to evaluate the likelihood that a form is functional, the rarer variants are significantly more probably to be functional than the more common variants. Strikingly, these patterns disappear when we concentrate on just those variants in which the major alleles are derived. These analyses suggest that the bulk of the genetic variance in price of phenotypic consequence may ensue from a mutation-selection balance, as opposed to balancing selection, and induce direct relevance to the subject of human disease.
Link
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