Caveman genes — what our shared history with Denisovans means

A recent article in Nature determines, fairly conclusively, that a certain variant of a certain gene which allows Tibetans to thrive at high altitudes comes directly from interbreeding with Denisovans — from an extinct cousin of Homo Sapiens Sapiens.

The gene — EPAS1 — is a regulator which pumps more hemoglobin and more red blood cells into your body if there isn’t enough oxygen. Tibetans — and Denisovans, presumably — have a copy that isn’t very efficient at higher altitudes. That means that while people with “sea level” variants fill up their circulatory systems to bursting with more oxygen-depleted blood, Tibetans’ circulatory systems remain at a more relaxed state. In consequence, they don’t get the high blood pressure and other dangerous effects of altitude sickness that other people tend to get.

Many Tibetans (almost 90% of them) share a “high altitude” variant allele of EPAS1, while most Han Chinese (more than 90% of them) share a “sea level” variant. What’s more, the “high-altitude” variant is so similar to the variant sequenced from a Denisovan bone fragment — and so different from the “sea level” variant — that it is exceptionally unlikely to come from anywhere except Denisovans.

What does this mean for human evolution?

What it doesn’t mean is that Tibetans are “more Denisovan” than are Han Chinese. In fact, neither of these populations shares large portions of their genome with Denisovans in general. Of the populations examined, only Melanesians share significant portions of their DNA (around 5%) with Denisovan man. This one gene is part of perhaps 0.1% of the genome of mainland Asian or other non-African humans that is shared with Denisovans. And this allele is present in both populations, just at very different levels (10% versus 90%).

Practically, this means that a tiny portion of the human genome, as people migrated east out of Africa, came from interbreeding with the Denisovan lineage. That’s true for the ancestor of Han Chinese as well as Tibetans (in fact, it’s the same ancestor).

The difference between the populations arises because one allele of one gene (the “high altitude” variant of EPAS1) became very advantageous when these humans started living in the Tibetan plateau, where the air has only about 60% as much oxygen as you’d find at sea level. In particular, the “high altitude” variant of EPAS1 protects pregnant mothers and developing fetuses: Tibetan populations have significantly lower rates of preterm birth and other diseases of pregnancy than Han Chinese living in Tibet. And since it provides protection at childbearing ages and at birth, this is exactly the kind of variation that would be subject to strong selective pressures.

What it suggests, which hasn’t been known definitively before, is that although we can’t find much Denisovan in non-Melanesian populations, interbreeding with the Denisovan (as well as Neanderthal) lineage was definitely a part of human history.

A new token example for evolution in humans

This is yet another example in human evolution of a low-frequency allele rapidly expanding in frequency because it confers a strong selective advantage. In that way, it’s like variants promoting lactose tolerance, or like amylase duplications making starches more digestible, or variants that provide protection against malaria. But to my mind this may become the new go-to example of human evolution and selection in human populations for several reasons: it’s a distinct variant, with unambiguous selection, and a very fast rise to prominence.

It’s a distinct variant because it was inherited whole-cloth from Denisovans. A small number of hybrid families led to some hybrid offspring led to a population with this allele at a low rate. So far it has been inherited as a unit, which simplifies the evolutionary story.

It’s a case of unambiguous selection because its major effect is that it promotes survival at high altitudes. There’s no predisposition to sickle cell anemia or beta thalassemia as there is with alleles providing malaria resistance. And it has a big effect on pregnancy and infant mortality — its effect on the number of offspring someone could have, in addition to the number of years that person could live, is obvious.

And it’s a very fast rise to prominence. Han Chinese and Tibetan populations have a recent common ancestor, and they have probably had interbreeding throughout history. The fact that this allele provides such selective pressure that it could rise to 90% prominence in such a short time is absolutely striking.

Genetic opportunists and the advantage of a big family

One of the big biological truisms that gets thrown around a lot but isn’t necessarily well understood is the idea that, to a certain extent, “evolvability” gets selected for. Which is to say that a certain level of diversity in a species is a huge advantage, because it means you can expand to new niches (like the high altitude Tibetan plateau) and the variants that allow you to succeed in that niche will already be present in the population.

It’s very easy to see this principle in work in bacteria; when stressed, bacteria often will mutate or disable their DNA damage protection machinery, promoting more mutations and rapidly gaining a huge number of variants. But that doesn’t happen in animals; with a bigger genome and more cells the pressure against cancer is greater than the pressure towards variation.

Pretty much the only thing that animals have to work on there — the only place you can observe this — is (1) large populations and (2) sexual reproduction.

Large populations act in animals just like they would in bacteria: more individuals means more individual variants means more sampling of the possible space of genetic variants. Sexual reproduction makes it easier for those variants to recombine and mix and (hopefully) find a fruitful combination.

In that light, subspecies like Neanderthal and Densiova were a crucial genetic resource for early humans, providing variation that allowed humans to survive in a wide variety of environments all over the world.