Reading an agressively-stated scientific opinion is an acquired taste-- in published work, academics prefer to subtly hint that their colleague is ass, rather than just saying it directly like we do here on the internets. But when one is used to the dry writing of the scientific research articles, those subtle (or sometimes not so subtle) digs come to be rather enjoyable.

Which is why I enjoyed this piece by Michael Lynch [pdf], just published in PNAS. Dr. Lynch has long been an advocate for taking population genetics forces into account when studying genome evolution and innovation, and here he makes his case:

Although the basic theoretical foundation for understanding the mechanisms of evolution, the field of population genetics, has long been in place, the central significance of this framework is still occasionally questioned, as exemplified in this quote from Carroll (4), "Since the Modern Synthesis, most expositions of the evolutionary process have focused on microevolutionary mechanisms. Millions of biology students have been taught the view (from population genetics) that 'evolution is change in gene frequencies.' Isn't that an inspiring theme? This view forces the explanation toward mathematics and abstract descriptions of genes, and away from butterflies and zebras. . . The evolution of form is the main drama of life's story, both as found in the fossil record and in the diversity of living species. So, let's teach that story. Instead of 'change in gene frequencies,' let's try 'evolution of form is change in development'." Even ignoring the fact that most species are unicellular and differentiated mainly by metabolic features, this statement illustrates two fundamental misunderstandings. Evolutionary biology is not a story-telling exercise, and the goal of population genetics is not to be inspiring, but to be explanatory.

His argument is that many of the features of the eukaryotic cell, often assumed to be products of adaptations, may be largely the result of deleterious fixations due to a much smaller eukaryotic effective population size. It remains unclear how these features-- introns, large genomes, some aspects of gene regulation-- came to arise given their apparent costs. According to Lynch, population genetics provides a simple framework for testing neutral versus adaptive hypothesis on this subject (he favors neutral explanations). This has been largely ignored due to, well, the fact that math is hard:

The field of population genetics is technically demanding, and it is well known that most biologists abhor all things mathematical. However, the details do matter in the field of evolutionary biology.

Overall, he presents a sort of neutral theory of genome evolution, or at least the beginnings of one. And I must admit I'm intrigued by this possibility that "a long-term synergism may exist between nonadaptive evolution at the DNA level and adaptive evolution on the phenotypic level".

Some possibile examples of this: one of the current roles of the nuclear membrane is to segregate the actions of transcription from those of translation so that introns can be spliced out before a protein is made. It's an interesting hypothesis, then, that the nuclear membrane itself (one of the defining hallmarks of a eukaryotic cell) evolved in response to the existence of introns. Lynch cites another paper arguing that the nonsense-mediated decay pathway could also have evolved to prevent the translation of transcripts resulting from splicing errors. Finally, I've also heard much speculation that many of the regulatory mechanisms we take for granted-- methylation, histone modifications, etc.-- could have evolved to silence selfish DNA elements before taking on the broader roles they play today.

Sewall Wright put much emphasis on the role of genetic drift in allowing the evolutionary process to cross regions of low fitess to find other adaptive peaks. Maybe early population geneticists really did discover everything worth knowing about evolution.

Labels: Evolution, Population genetics

A recent paper on the relative number of genes that have undergone positive selection in chimps and humans recieved quite a bit of press (see Razib's comments here, here, and here). The title is quite provocative ("More genes underwent positive selection in chimpanzee evolution than in human evolution"), so I finally gave it a read. Frankly, if you haven't read it already, don't waste your time.

Let's grant the authors their starting position-- that there is a "common belief" that more genes have undergone positive selection in the human lineage than in the chimpanzee lineage (I would argue that this belief isn't all that widespead, though ultimately the reasons for the intiation of the study are irrelevant). In theory, addressing the veracity of this claim is easy-- make a list of the genes that have undergone positive selection along the human lineage, make a list of the genes that have undergone positive selection along the chimp lineage, and start counting. The devil, of course, is in the details.

Due to the fact that not every selected gene will leave a detectable signature, the major assumption of the authors' analysis, then, is that the fraction of detected selected genes along the human lineage is the same as the fraction of detected selected genes along the chimp lineage. That is, if the number of genes that have undergone positive selection in both lineages is the same, but 75% are detected in chimps and only 50% are detected in humans, one might erroneously conclude that more genes have undergone selection in chimps than in humans, while in truth the number of selected genes is the same. This, I will argue, is precisely the mistake made in this paper.

Let's take a look at how the authors identified genes that have undergone positive selection. The basis of the test is essentially the ratio of non-synonymous to synonymous changes in a given gene along a given lineage (non-synonymous changes alter the amino acid sequence of a protein and are presumed to be functional, while synonymous changes do not changes the sequence of a protein and provide a sort of background substitution rate). So if there is an excess of non-synonymous changes (a ratio > 1), one might conclude that the gene has been subject to positive selection. The power of this test to dectect selection is contingent on finding an excess of amino acid-changing substitutions in a lineage.

So what could alter said power? First, it's clear that a single selected site will alter the ratio only slightly, two selected sites will alter it a little more, three even more, etc. So the more selective fixations that occur in a gene, the more power the test will have to conclude for selection. On the other hand, take the number of synonymous substitutions-- if there are more of these, the levels of "noise" are elevated relative the levels of "signal", and there is lower power to conclude for selection.

There is a major difference between historical human and chimpanzee populations that alters the power of the test in the two lineages; indeed, the authors mention this difference without really grasping why it discounts their conclusions. That difference is population size. Humans have historically had a smaller effective population size than chimpanzees and, as the authors note, natural selection is more efficient in a larger population. Thus, advantageous alleles can be pushed to fixation with greater probability, while neutral or deleterious alleles are fixed at a lower rate. So smaller populations should have overall higher levels of substitution (assuming positively selected changes are a minority of all fixations). This is exactly what is seen in the data-- humans have 30,083 synonymous fixations and 19,000 non-synonymous fixations, while the numbers for chimp are 29,644 and 17,701, respectively.

These changes in the rates of allele fixations should lead to a weaker signal of selection in humans, and thus less power to detect it. It's no surprise, then, that the authors find less selected genes in humans than in chimps. Even if the number of selected genes were exactly the same, the relatively stronger signal of selection in chimps should produce exactly the same result. Perhaps the authors want to argue that fewer amino acid changes have been fixed by positive selection in humans than in chimps; this is what population genetics theory predicts, and may be true. However, to extrapolate from a number of amino acid changes to a number of genes is problematic; a single adaptive change in a gene could have major phenotypic consequences without being detected with the sorts of tests employed in this study.

Labels: Evolution, Genetics, Population genetics

When we talk about genetic variation between populations, most of the time we're referring to SNPs or other "simple" polymorphisms, mostly because that's what we have data on. Detailed population genetics studies of copy number variants are just starting to appear; this paper is one of them. It's an anlysis of the frequency of a deletion of the gene APOBEC3B, involved in immunity to retroviral infection. As you can see in the map below, the gene is present in most people of European and African descent, but is missing in a significant fraction of Asian and Native American populations. Nothing revolutionary here, but expect more studies of this sort in the future.

ADDENDUM: I hasten to add, lest RPM read this post, that when I say these studies are starting to appear, I'm speaking about these sorts of studies in humans. In Drosophila, large deletions and inversions are the classic genetic polymorphisms used in population genetic analyses (due to their easy visibility in polytene chromosomes).

Labels: Population genetics