Wednesday, December 22, 2010

A new broom sweeps gene?

Today we write about a story that isn't hot off the press, but was published in Nature a few months ago, and  happens to be one of those findings that we think more people should know about:.  The issue is the genetic signature of selection, something that has become the focus of much anthropological and population genetic research with the advent of whole genome sequencing data.

What the authors did was to follow populations of fruit flies over 600 generations and comb the entire genome of 260 of them for variation after applying intense artificial selection on the measurable, and malleable, traits of accelerated development and early fertility.  They bred a population in which development was about 20% faster than in unselected populations.  The question was whether a single gene or multiple genes would be responsible for the change.

They compared the genomes of the selected and control populations with the reference fruit fly genome, and found hundreds of thousands of SNPs, or single nucleotide polymorphisms, differences between the populations.  Of these, they found tens of thousands of amino acid-changing SNPs, about 200 segregating stop codons and 118 segregating splice variants -- that is, variants that could be responsible for the phenotypic changes they had selected for.  They further narrowed down these candidate loci to 662 SNPs in 506 genes that they considered to be potential candidates "for encoding the causative differences between the ACO and CO populations, to the extent that those differences are due to structural as opposed to regulatory variants."
For the biological processes, there is an apparent excess of genes important in development; for example, the top ten categories are imaginal disc development, smoothened signalling pathway, larval development, wing disc development, larval development (sensu Amphibia), metamorphosis, organ morphogenesis, imaginal disc morphogenesis, organ development and regionalization. This is not an unexpected result, given the ACO [accelerated development population] selection treatment for short development time, but it indicates an important role for amino-acid polymorphisms in short-term phenotypic evolution.
Actually the idea that adaptive change was brought about by gene-impeding mutations (premature stop codons and splice variants, for example) is interesting.  It means that adaptive change under selection doesn't just improve function, but it may also destroy function--to pave the way to the change, one might surmise.

They went on to do a 'sliding window' comparison of regions of the genome that diverged significantly between the selected and control populations, and identified 'a large number'. is apparent that allele frequencies in a large portion of the genome have been affected following selection on development time, suggesting a highly multigenic adaptive response.
The authors interpreted this work in terms of the 'soft' or 'hard' sweep idea that is often used to explain reduced gene frequencies ( a 'hard sweep' being when a single mutation quickly becomes fixed in a population, and a 'soft sweep' being when multiple genes influence a trait).  They suggest two explanations for their 'failure to observe the signature of a classic sweep in these populations, despite strong selection' (not enough time for the causative gene to reach fixation in the population, or that selection acts on standing, not new mutations).

RA Fisher
But, it wouldn't be a surprise to RA Fisher (this is a link to his Facebook page, by the way -- go friend him, he only has 6!) that the observed changes are due to polygenes.  But it is nice to see an experimental confirmation, and to note the implications it has for understanding complex traits.

Many biologists have been lured into single-gene thinking by the research paradigm and model set up initially by Mendel.  For decades single-gene traits formed the core of what we would call the evolving molecular genetics including Morgan's work on chromosomal arrangement of genes, many human geneticists' work on 'Mendelian' disease, the work leading to the idea that genes code for proteins, and much else.

Besides these examples of causal genetics, we had selection examples such as sickle cell anemia, that seemed to reflect evolutionary genetics and were due to single protein changes.  But we always knew (or those who cared to understand genetics should have known and could have) that traits were more complex than that as a rule.  Sewall Wright and others knew this clearly in the early 20th century.  'Quantitative genetics' going back basically to Darwin (or at least his 2d cousin Francis Galton) recognized the idea of quantitative inheritance and Fisher's influential but largely impenetrable (to mere mortals) 1918 paper was a flagship that reflected formally the growing recognition that complex traits could be reconciled with Mendelian genetics if many genes contributed to complex traits.

The idea that strong directional or 'positive' selection favored a single gene grew out of the Mendelian thread, but nobody in quantitative genetics (such as agricultural breeders or many working in population genetics theory) and those who understood gene networks, should have known that most of the time, especially given the typical weakness of selection, selection would not just find and fix a single allele in a single gene.

We had reason to know, and certainly know now that when a trait's effects are spread across many variable and contributing genes, the net selective difference on most if not all of them will be very small. The response to selection will be just what the fly experiments, and many others likewise, found.

In the television attention-seeking era we need melodramatic terms, and that is just what ideas like selective 'sweeps' are.  The circumstances under which a single allele will 'sweep' (watch out, here comes that broom sweeping clean!) would occur across an entire species' habitat replacing all other alleles that affect a trait are likely to be very restrictive.  We don't need terms like hard and soft sweeps, and should not be over-dramatizing what we find.  Even a hard 'sweep' at the phenotype level is typically 'soft' at the specific gene level, and usually also softly leaves phenotypic variation in the population after it's over.

At the same time, these experiments are giving us great detailed knowledge about how evolution works, when there is, and when there is not strong selection.  This supports long-standing theory and is no kind of 'paradigm shif', it's true, but it is new understanding of the details and genetic mechanisms by which Nature gets from here to there--whether it does that in a hurry or not.

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