I do not write often about genetics—as well I shouldn’t, since this is a column for general audiences, and genetics is one of the most jargon-infested fields out there (that, and I am not sure if I have the necessary expertise to do so). But I’ll make an exception this week, since about a fortnight ago I attended a two-part seminar by Dr. Evan Eichler, the content of which I had been assigned to summarize—the result, due in no small part to strict (and strictly impossible) word limits, looked somewhat like a Porsche that had been through a car crusher, and I was not too pleased about writing a hypercompressed summary of what rightfully deserved a full-length piece of its own (I also lost the phrase “evolutionary double-edged blade,” which I was quite fond of, to the editing process—I tend to keep grudges over this sort of thing, and I still regret not getting that polygenic disorder/Lernaean hydra simile through on a similarly compressed story last year). Fortunately, this column is more than spacious enough to cover a seminar or two, so here you are—this week will be an adequate (I hope!) summary of Dr. Eichler’s talk, plus a couple of comments from my side.
Gene duplications are common in nature, and since two identical-looking genes can easily confuse the crossing-over process (which may cross the first gene with the second, instead of finding their proper counterparts on each chromosome), their very presence fosters the creation of new duplications in a rich-get-richer (or mutated-get-more-mutated) scheme. It is, however, important to keep in mind that these duplications are not necessarily evil, as having spare copies frees up the duplicates to diverge into their own niches. If you had a single copy of a vital gene, for example, and it decided to up and mutate, you’d likely wind up dead before you knew what hit you. But if you had a bunch of duplicates running around, then you could still soldier on with your backup copies—and in due time, the mutations could pile up until your initial gene and the duplicates had wholly different functions. Likewise, if you really needed to get extra mileage out of a specific gene product like, say, the starch-digesting enzyme amylase during that critical period when humans discovered agriculture and started switching to a starch-heavy diet, a couple of well-placed duplications could get you extra copies of (and extra production from) the relevant gene (and populations with starch-heavy diets evidently do have additional copies of the salivary amylase gene). The flip side of this coin is that duplication events also tend to wipe entire genes (or gene clusters) off the face of the genome, which obviously doesn’t bode well for those affected.
Humans, as it turns out, have a surprisingly extensive list of duplications, and some of these are notable in that they’re both long-range (most duplications are right next to each other, but ours apparently like jumping all over the place, both within and between chromosomes) and closely clustered together in what are called core duplicons. We share this abundance of duplication-attracting hubs with chimpanzees, gorillas and just about nothing else—while the genomes of other animals do feature duplications, no other species studied so far has quite as many as us (and those that do exist are usually short-distance tandem duplications), with even orangutans falling short of the mark. Why this is so is unclear; the long lifespans, low effective reproducing populations and frequent bottlenecks characteristic of human evolution may have had a hand, though it is curious that elephants, which share similar traits, are relatively lacking in duplications. Likewise, the phenomenon might have been an adaptation to environmental changes, and especially the switch from arboreal to terrestrial life, but orangutans have experienced equally pronounced changes in environmental conditions (having invaded Southeast Asia from Africa) and yet don’t display as many duplications as we do (my personal take is that the rapid invasion of a new ecological niche, and the extensive morphological changes that it required, may have played a role—orangutans did travel quite a distance across their evolutionary adventures, but they, unlike humans and true to their name [orangutan means “forest person”], never truly abandoned their arboreal lifestyle).
Whatever the case may be, the consequences are dire: an inordinate fondness of duplications might have done us much good in our evolutionary history, but the side effects of rampant gene deletion may be a major cause of intellectual disorders. Duplicons, after all, are regions that are genetically unstable and highly prone to mishaps, despite being loaded with clusters of vital genes—which makes them ticking genetic time bombs, just waiting for something to go awry. They are also quite important for the evolution of intelligence, as some of the duplicate genes have gone on to assume new functions in neurogenesis—and their deletion, made all the easier by their presence within duplicons, is about as detrimental as you would expect. Dr. Eichler’s current research focuses primarily on the identification of these large, duplicon-associated deletion events, and the resulting variance in gene copy numbers, which may account for a considerable portion (although not the vast majority, the causes of which as yet remain unknown) of autism spectrum disorders. The characterization of each disease-causing event, be it an inherited condition, a de novo mutation or a combination of multiple factors that are individually harmless or only able to cause minor conditions, may allow the division of this poorly defined disease complex into distinct, easily diagnosable and potentially treatable syndromes, in much the same way that cancer is now considered to be a vast network of distantly related diseases with the shared symptom of uncontrolled cell division.
I am rather running out of space (well, the column might have been spacious enough for an average seminar, but the extent of the material covered in Dr. Eichler’s talk was something to behold), but one last bit of curious data is that women are more resistant to intellectual disability than men: all else being equal, it takes more severe deletions for mental disorders to manifest in women, and when disease does occur, the symptoms are usually less pronounced. I wonder if that would have anything to do with the honest advertisement hypothesis—human intelligence is sometimes taken to be an artifact of sexual selection, and it could be to the benefit of males if they were fully transparent in demonstrating whether their intelligence was an honest indicator of their lack of large genetic deletions.