Human signatures of balancing selection, one form and source of genomic variation.
We generally think of selection as an inexorable force towards greater fitness, eliminating mutations and less fit forms in favor of those more successful. But there is a lot else going on. For one thing, much mutation is meaningless, or "neutral". For another, our lives and traits are so complicated that interactions can lead to hilly adaptive landscapes where many successful solutions exist, rather than just one best solution. One form of adaptive and genetic complexity is balancing selection, which happens when two alleles (i.e. mutants or variants) of one gene have distinct roles in the whole organism or ecological setting, each significant, and thus each is maintained over time.
A quick example is color in moths. Dark colors work well as camouflage in dirty urban environments, while lighter colors work better in the countryside. Since both conditions exist, and moths move around between them, both color schemes are selected for, resulting in a population that is persistently mixed for this trait. Indeed, the capacity of predators to learn these colors may also lead to an automatic advantage for the less frequent color, another form of balancing selection. Heterozygotes may also have an intrinsic advantage, as is so clearly the case for the sickle cell mutation in hemoglobin, against malaria. These are all classic examples. But to bring it home, a society has only so much capacity for people like Donald Trump. Insofar as sociopathy is genetic, there will necessarily be a frequency-dependent limit, where this trait (and other antisocial traits) may be highly successful at (extremely) low frequency, but terminally destructive at high frequencies.
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| Schematic selective landscapes. Sometimes selection just optimizes an existing trait by intensifying it (1), or moving it along trait space to a new optimum (2). But other times, multiple forms (i.e. variants, or mutations) of a given locus each have some useful / beneficial characteristic, and may be selected either discretely for particular effects (3), or generally for their diversity (4). |
One laborious method to find such sites of balancing selection in a genome is to compare it to genomes of other species. If the same variants exist in each species over long periods of divergence, that argues that such conserved sites of diversity are maintained by balancing selection. Studies of humans and chimpanzees have found some such sites, but not many. But these methods are known to be very conservative, missing out on what is likely to be most cases.
A recent paper offered a slighly more sensitive way to find signs of balancing selection in the human genome, and found quite a lot of them. (Some background here.) It is based, as many investigations of selection are, on a special property of protein-coding genes, due to the degeneracy of the genetic code, that some mutations are "synonymous" and lead to no change in the coded protein, and others are "non-synonymous" and do change the protein. The latter would be assumed to be visible to selection, and sometimes give significant signals of conservation (i.e. low rates of change between species and populations, and few variations maintained in a population). This embedded signal/control pairing of information helps to insulate against many problems in analysis, and can tell us pretty directly how severe selection is on such sites.
It is worth adding that each basepair in the human genome has its own selective constraints. One position may code for the active site of some enzyme and be extremely well conserved, while the next may be a "synonymous" that has very few or no selective constraints, and another lies in junk DNA that doesn't code for anything or regulate anything, is effectively neutral, and can be changed with no effect. The system is in this sense massively parallel, and able to experience evolution individually at each site concurrently. On the other hand, selection on one site affects the frequencies at nearby sites, since selective "sweeps" through that area of the genome drag the nearby regions of DNA (and whatever variants they may harbor) along, whether positively if the site is increasing in frequency, or negatively if it is deleterious and causing death of its bearers. The reach of this "linkage" effect depends on the recombination frequency, which is relatively low, leading the moderate stability (and linkage) of relatively large "haplotypes" in our genomes.
At any rate, as the methods for detecting selection improve, more selection is detected, which is the lesson of this paper. These authors claim that while their method still significantly under-estimates balancing selection, they find evidnce for the existence of hundreds of sites in humans, when comparing genomes between different geographic regions of the world. A couple hundred of these sites are in the MHC regions- the immunological areas of the genome that code for antibodies and related proteins. These are well-known to be hotspots both for diversity and for the ongoing selective arms race vs pathogens (as we have recently experienced vs Covid). Seeing a lot of balancing selection there makes complete sense, naturally.
The authors note that their focus on coding regions of the genome, and other technical limitations such as the need to find these sites through population comparisons, argues strongly that their estimate is a severe undercount. Thus one can assume that there will be at least several thousand sites of balanced selection in humans. This is quite apart from the many more sites of ongoing unidirectional selection, mostly purifying against problem mutations, but also towards positive characteristics. An accounting that is only starting to get going, over the vast amounts of variation we harbor. So we live in a dynamic world, inside and out.
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