missing heritability - senecio7の日記

Hemani G, Knott S & Haley C 2013 An evolutionary perspective on epistasis and the missing heritability. PLoS Genet 9:e1003295.

one reason that the problem of the "missing heritability" arises is because the additive genetic variation that is estimated to be contributing to the variance of a trait will most likely be an artefact of the non-additive variance that can be maintained over evolutionary time
even a small reduction in linkage disequilibrium between causal variants and observed SNPs rapidly erodes estimates of epistatic variance, leading to an inflation in the perceived importance of additive effects
the perception of independent additive effects comprising the majority of the genetic architecture of complex traits is biased upwards
the search for causal variants in complex traits under selection is potentially underpowered by parameterising for additive effects alone
the detection of causal variants through genome-wide association studies may be improved by searching for epistatic effects explicitly

epistatic interactions can allow deleterious mutations to persist under selection
these interactions can abate the depletion of additive genetic variation
a much larger element of non-additive genetic variance is maintained
the heritability estimated from family studies could be a mixture of both additive and non-additive components
searching directly for epistatic effects greatly improves the discovery of variants under selection, despite the multiple testing penalty being much larger
common practices in genome-wide association studies could lead to both an ascertainment bias in detecting additive effects and a confirmation bias in perceiving that most of the genetic variance is additive

traits under selection often evolve more slowly than expected
contrary to expectation, genetic variation is maintained under selection
this problem is known as 'stasis'
it is particularly evident in fitness-related traits where the genetic variation tends to be highest
yet there is commonly no observed response to selection at all

by definition epistasis will form a part of the 'unknown heritability'
epistatic interactions could also contribute to h² estimates
this could arise through two possible mechanisms
firstly by generating real additive variation as marginal effects from higher order genetic interactions
secondly by creating a statistical illusion of additive variance through confounding between non-additive and common environment effects in twin study based estimates

at the intermediate, within-population level there is a distinct lack of evidence for any widespread importance of epistasis arising from natural variation
most genetic variation appears to be additive

for many of the patterns of epistasis that we assayed, deleterious effects can be maintained at intermediate frequencies over long evolutionary time periods
a small amount of additive variation is maintained by epistasis but most genetic variation is non-additive
there is a strong bias in GWA studies that lead to an overestimation of additive effects at QTLs
perhaps counterintuitively, the most powerful way to uncover additive variation under selection is to parameterise the search to include epistatic effects using dense genotype information

because additive variance decays linearly with LD [46], at low LD they remain detectable leading to an ascertainment bias for additive vs non-additive effects

even in the best case scenario, where G-P maps were generated to maximise additive variance, total genetic variance was mostly composed of non-additive components
this finding is in disagreement with a recent study [28], which showed that for various two-locus epistatic models, the deterministic partitions of genetic variance calculated across different frequency distributions were largely comprised of the additive component
those allele frequencies at which additive variance is high (a large proportion of the frequency spectrum), are evolutionarily unstable
should epistatic variants be affecting fitness traits then the majority of the variance will be non-additive