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Inferring details of past evolution from DNA is tricky

Last week I discussed one of many papers that use the ratio of protein-changing to "neutral" genetic changes, along the branches of an evolutionary tree, to infer past natural selection. This week's paper presents data calling that approach into question. This does not necessarily undermine the overall conclusions of last week's paper, which were based on a variety of methods, including testing the actual performance of mutant proteins.

"Hotspots of biased nuclear substitutions in human genes" was published in PLoS Biology by Jonas Berglund and colleagues. I am not a molecular biologist, so will just summarize their main points. The paper is open access.

Most of our DNA does not code for proteins. Some of the noncoding DNA is known to have important regulatory functions. But there is lots of DNA whose function, if any, is unknown, but which is nonetheless highly similar among species, as if any change was lethal. Except, when someone tried deleting this DNA, a bit at a time, most of the deletions were not lethal or even (as far as they could tell) harmful. I discussed this work earlier.

Anyway, much of this noncoding DNA that differs little among most species is different in humans. Could these differences be what makes us different from other apes? Quite possibly. But are all these human-vs.-chimp differences important? Maybe not. An unexpectedly high fraction of the changes from the ape ancestor we share with chimps involved a change from A bound to T (a weak bond) to G bound to C (a strong bond). Unless noncoding DNA with stronger bonds is consistently better somehow (and only in humans!), this suggests that these changes are caused by some DNA-specific process and not by natural selection. In other words, these changes occurred whether or not they were beneficial, just as mutations do. Could similar AT=>GC changes have changed protein-coding sections of DNA?

The researchers compared 10,238 genes in humans, chimps, and macaques...

They focussed on those where DNA changes led to protein changes, often thought to indicate natural selection. Like the apparently-important noncoding regions of DNA, these protein-coding regions had more AT => GC changes than expected. Apparently, this can be caused by high rates of recombination, where stretches of DNA come from both parents.

So maybe recombination led to AT => GC changes which resulted in more protein-changing DNA changes than expected, which gave a possibly false signature of past natural selection. If so, then identifying which genes are actually key to uniquely human traits will be more difficult. I'm sure this will not be the last word on this subject.

This study does not cast any doubt on the common ancestry of humans and other apes. In fact, their specific conclusions depend on this common ancestry.


Comments

So maybe recombination led to AT => GC changes which resulted in more protein-changing DNA changes than expected, which gave a possibly false signature of past natural selection. If so, then identifying which genes are actually key to uniquely human traits will be more difficult. I'm sure this will not be the last word on this subject.

I think this is an important point. We are learning more and more about how the structure of DNA and its chemical properties can influence what kinds of mutations can occur (think mutational 'hotspots', and things like slipped-strand mispairing in microsatellite sequences). It's becoming clear that a significant percentage of changes are structurally determined. Of course, that does not affect how natural selection looks at them--they still have to meet the minimum requirements for the environment if they are to remain in the population for any length of time. But, as you point out, they may not be as indicative of positive selection as we once thought, at least in terms of defining us from other ape species.

I love this blog for bringing these kinds of papers up for consideration. Thanks.

Dave,

You're right, if a AT=>GC change affects survival and reproduction, natural selection will still operate.

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