genetic architecture - senecio7の日記

Rockman MV 2012 The QTN program and the alleles that matter for evolution: all that's gold does not glitter. Evolution 66:1-17.

what is the question to which QTNs are the answer?
their pursuit is often invoked as a means of addressing the molecular basis of phenotypic evolution or of estimating the roles of evolutionary forces
the QTNs that are accessible to experimentalists, QTNs of relatively large effect, may be uninformative about these issues
20th century evolutionary biology generally viewed large-effect variants as atypical
the field has recently undergone a quiet realignment toward a view of readily discoverable large-effect alleles as the primary molecular substrates for evolution
neither theory nor data justify this realignment
evolution often acts via large numbers of small-effect polygenes, individually undetectable
these small-effect variants are different in kind, at the molecular level, from the large-effect alleles accessible to experimentalists
discoverable QTNs address some fundamental evolutionary questions
they are essentially misleading about many others

in fields from evo-devo to population genetics, the hope is that the identities of the functional variants will reveal the position of nature in the parameter space defined by the extremes of our models
additivity versus pervasive epistasis
pleiotropy versus modularity, oligogenic versus polygenic adaptation
micro- versus macromutation
common versus rare alleles
protein coding versus cis-regulatory
balancing selection versus mutation-selection balance

if only we could put our hands on the actual causal variants, the quantitative trait nucleotides (QTNs), maybe we could put these tired old debates to bed
this is the QTN program
its admirable commitment to empiricism so dominates research in molecular evolutionary genetics that its premises are rarely questioned

for the QTN program to succeed, the allelic variants it discovers must be representative examples of the underlying pool of QTNs
this condition is rarely met
perhaps, cannot be met

what is the phenotypic effect-size distribution of evolutionarily relevant mutations?

what we can measure is by definition uninteresting and what we are interested in is by definition unmeasurable

this micromutationist perspective, with its dismissal of large-effect alleles, was hardly unique to Lewontin
the critical model underlying this synthesis is the infinitesimal, derived from Fisher's polygenic model of inheritance
cracks appeared in the micromutationist synthesis around 20 years ago (Orr and Coyne 1992)
the now-standard history of adaptation genetics (Orr 2005a) begins with Fisher's geometric model
the conclusion that the infinitesimal model does not always hold has been taken to mean that the geometric model always does
Orr's version of the geometric model ... deals with a very specific genetic scenario:
a single bout of adaptive evolution to a fixed optimum with no standing variation
even in that limited case, its claims about the effect-size distribution say little about absolute effect sizes

QTNs mapped to date are effectively Mendelian, not simply samples from an exponential distribution
I describe biases that undermine the utility of QTL data for characterizing the effect-size distribution
small-effect alleles are different in kind from large-effect alleles at the molecular level, underscoring the challenge of using QTN data to understand the relationship between molecular function and phenotype evolution

the path from QTL to QTN typically requires functional assays
in most species the perturbations induced by experimental manipulations are likely to dwarf the effects of all but the largest effect QTNs
even if we embrace the geometric model's prediction of exponential effect-size distribution, our QTN successes have only sampled the most extreme outliers in the distribution's tail

we tend to study traits that exhibit dramatic and discrete differences between populations or species
we invest in genetic studies when we have some reason to think the genetics will be tractable
we publish our results when we have identified QTLs

the estimated QTL effect-size distribution is expected to be L shaped even when the underlying loci have identical effect sizes
the same is true for any underlying effect-size distribution

chance spatial clustering of infinitesimals with effects in the same direction will appear to be a large-effect locus

despite two decades of intensive effort, we have fallen short of our long-term goal of explaining genetic variation for quantitative traits in terms of the underlying genes, the effects of segregating alleles in different genetic backgrounds and in a range of ecologically relevant environments as well as on other traits, the molecular basis of functional allelic effects and the population frequency of causal variants
QTL alleles with large effects are rare
the bulk of genetic variation for quantitative traits is due to many loci with effects that were individually or in aggregate (owing to tight linkage of QTLs with opposite effects) too small to detect because previous studies were underpowered

recent models of the genetics of adaptive evolution have tended to focus on new-mutation models, which treat evolution as a series of sequential selective sweeps dependent on the appearance of new beneficial mutations
fixed differences among human populations are exceptionally rare, despite sufficient time for new mutations to have fixed
cryptic variation is enriched for potentially beneficial alleles relative to new mutations, because the alleles are definitively not unconditionally deleterious

most diseases represent the tails of continuous phenotypic distributions
many of the alleles that contribute to disease may be ancestral, suggesting that loci shaping disease risk are exactly those that contribute to ongoing adaptation to modern conditions

most Mendelian mutations alter protein sequences
fewer than 1% were regulatory mutations
59% were missense or nonsense point mutations
based on the present catalog of more than 85,000 mutations, these numbers are 1.6% and 66%, respectively

the nearly exclusive occurrence of protein-coding variants among Mendelian point mutations in humans and worms implies one of two things
protein-coding variants represent the vast majority of all functional sites
noncoding variants tend not to have Mendelian effects
comparative genomics data refute the first possibility

in humans, there are several times as many conserved noncoding sites as coding
in C. elegans 45% of conserved sites are noncoding
roughly half the functional noncoding elements in humans exhibit no detectable evolutionary constraint across mammals