Recent changes to the human accelerated region

ResearchBlogging.orgSome genes have undergone very little evolution and so are highly conserved between species, being almost identical in animals which are far from similar. Such conservation is typically due to the fact that these conserved genes are fundamental for survival and so any mutations are fatal. This strong purifying selection puts a handbrake on evolution, keeping these genes the same for millions of years.

For example, some genes responsible for the production of helicase are highly conserved, being very similar in both bacteria and mice. Helicase is important as it separates the DNA double helix, allowing for the strands of DNA to be copied. Any changes to this enzyme would essentially mean a cell could no longer create proteins or even reproduce, explaining its conservation.

However, there are some anomalies, such as the human accelerated region (HAR). The HAR consists of genes which are typically highly conserved yet have undergone significant evolution in humans. Whilst these genes might be almost identical in both chimps and chickens, there are numerous differences between chimps and humans.

In the world of journalistic hyperbole the HAR genes are often held up as “what makes us human.” Whilst this is an obvious exaggeration (plenty of non-conserved genes have changed too) the HAR is nonetheless an important part of what separates Homo sapiens from Pan troglodytes and the rest of the animal kingdom. But what about the rest of the genus Homo? How different were they?

This is a reconstruction of a neanderthal. If he had a haircut and a shower could you spot him in a line-up?

Wind the clock back only 100,000 years (a blink of an eye in geologic time) and there were 5 different species of Homo living on planet earth. There was Homo sapiens in Africa, Homo neanderthalensis in Europe, Homo erectus in Asia, Homo floresiensis in Indonesia and the Denisovans in Siberia. The freaky Chinese hominin that was recently found may have been a sixth species living in China. Whilst these species were anatomically different, how different was their behaviour? Their intelligence? Were they fundamentally different to us?

Recently a team of scientists have attempted to utilise the HAR to shed light on these deep questions, comparing our genome to that of the neanderthals and Denisovans. The idea being to identify which segments of the human accelerated region are truly human and which bits are shared by all of these species, showing just how unique we are.

For some background, the Denisovan lineage diverged from our own around 900,000 years ago and eventually wound up in Siberia. There appears to have been some more recent interbreeding between the Denisovans and modern humans passing through Siberia en-route to Malaysia and Australia. As such modern aboriginal Australians and Malaysians have a small proportion of Denisovans DNA

The neanderthals diverged from us only 600,000-400,000 years ago and wound up in Europe and the Middle East. As humans travelled through the Middle East out of Africa we also interbred with them (humans are randy) and so now all non-African humans have a small percentage of neanderthal DNA.

Anyhoo, back to the research. After running all their fancy analyses on their DNA samples they discovered that 12% of changes to the human genome are unique to humans, not being shared with either neanderthals are Denisovans. As such they must have appeared within the last 400,000 years. However they found that only 8.3% of changes to the HAR region occurred in that time frame, less than expected based on overall genome rates of change.

Recent changes to the HAR

The percentage of changes to different types of DNA that are unique to modern humans. Note how HARs are below the average (red line)

Not only are there fewer of these changes but they also appear to have occurred within a relatively short space of time. Statistical analysis revealed that if you had one recent HAR mutation you were 2.3 times more likely than average to have a second, suggesting that they occurred relatively close together (in time).

Recently fixed HARs

The red box indicates how many recent HAR changes have been fixed whilst the black line indicates how many changes to other parts of the genome have been fixed

Despite the fact that there had been fewer recent HAR mutations, more of them had become “fixed” in the population (fixation is simply when a mutation spreads until it is present in every member of a group). 16% of recent HAR changes were fixed whilst only 8% of non-HAR changes had become fixed. The fact HAR changes were spreading so quickly might suggest that they were favourable so natural selection quickly spread them throughout humanity.

Alternatively the rapid fixation of HAR mutations may have something to do with what caused them. They found that a lot of these new changes were A/T to C/G substitutions (i.e. when A or T is replaced by C or G), more than would be expected by chance. Such a bias could be the result of “biased gene conversion” during recombination.

Recombination occurs during meiosis (the production of sex cells) and involves a bit of the chromosome being swapped for a bit on another chromosome. This can produce duplications, with a chromosome having a bit it already has added to it again. As the cells repair any damage this causes they’re biased towards fixing C/G base pairs, acting as an “artificial” selection pressure for such substitutions.


Whilst this process couldn’t account for all of the HAR fixation it may explain the differences between the HARs and non-HARs. There are more C/G substitutions in HARs because HAR mutations are the product of recombination and they’re more likely to rise to fixation than non-HARs because biased gene conversion favours those substitutions. If this is the case then it might indicate these HARs are no more beneficial than other mutations. However, the research does not reveal if this is actually the case, only hints at it.

So where does that leave us? Well we now know that 8% of changes to HARs are unique to humans and happened close together in time. These HARs are also more likely to rise to fixation. If this increased fixation rate is due to natural selection then it might indicate we are quite different to our neanderthal and Denisovan cousins, possessing a suite of derived beneficial genes they do not have.

However, if the increased fixation rate is actually the result of the biased conversion then it would suggest that there aren’t as many adaptive changes between humans and our non-human cousins as we once thought.

Burbano HA, Green RE, Maricic T, Lalueza-Fox C, de la Rasilla M, Rosas A, Kelso J, Pollard KS, Lachmann M, & Pääbo S (2012). Analysis of human accelerated DNA regions using archaic hominin genomes. PloS one, 7 (3) PMID: 22412940

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