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The secret about human evolution found in spit

Genetic detectives discover surprising findings about our evolution by studying saliva.

|SOURCE| What does a protein in our spit called MUC7 that all of us have – but most of us have never heard of – have to do with human history? A surprising amount, as a recent paper by Xu et al. has discovered. Despite being a rather obscure protein to most of us, MUC7 is actually quite important – it helps get rid of bacteria and other junk in our oral tracts.

One of the most interesting features of the gene that encodes MUC7 is that it contains a series of repeated DNA sequences (called the “PTS repeat region” for the amino acids these sequences encode: proline, threonine, and serine). Repeated structural elements are a fairly common feature of the genome, and these regions tend to be where many interesting evolutionary events occur.

In the case of MUC7, there has been some suggestion that variation in the repeat number may be associated with variation in the composition of oral microorganisms; that is, differences in the proteins in your spit might influence the kinds of microorganisms that live in your mouth (although this has only been investigated and demonstrated so far in populations with European ancestry, there isn’t any reason to believe that it won’t be true of all humans).

Xu and colleagues wanted to investigate whether there was a relationship between PTS repeat number and ancestry in populations. This might give insights into how this gene has evolved in human history, and sets the stage for a deeper investigation of how the composition of proteins in our saliva might have co-evolved with human oral microbes.

To do this, they obtained sequences of the entire MUC7 gene from individuals in a set of populations from different regions worldwide, and classified them into haplogroups, clusters of similar genetic lineages present in individuals who share a recent common ancestor. They found that all people tested fell within one of eight different haplogroups. Next, they characterized the number of PTS repeats in each individual, finding that all individuals have either 5 or 6 repeats. They then looked for evolutionary patterns, such as a correlation between the number of repeats and haplogroup membership. They found that all but two of the haplogroups (G and E) were associated with 6 PTS repeats; G and E had just 5.

In constructing their gene trees, which reflect evolutionary relationships, the authors noticed something odd about haplogroup E, which was found only in sub-Saharan African populations: it was extremely divergent (on a long branch by itself) from the rest of the MUC7 haplogroups. In fact, by using the molecular clock (under the assumption that the rate of mutation in this gene was regular in all lineages), they were able to date the last time haplogroup E shared a common ancestor with the other haplogroups. The result was surprising to say the least: the species to which the gene belongs dates to about 1.5-2 million years ago. That is extremely old: for context, it long predates the separation of Homo sapiens and Neanderthal populations (260-765 thousand years before present).

What could account for this strange result? The authors went through a series of rather elegant simulation tests to investigate different possibilities (which I don’t have room here to describe in detail, but I encourage everyone to read about in the original paper). They found that the most likely explanation was that it entered human populations via introgression (a fancy genetics term for gene flow) from an archaic hominin population. This population would not have been Neandertal or Denisovan (who weren’t around), but instead is a never-before-genetically-characterized archaic hominin group in Africa. These uncharacterized ancestors are sometimes referred to as “ghost” species, as we can’t definitively tie them to any known hominin at this point. The ancestors of present-day Sub-Saharan Africans likely interbred with this “ghost” species sometime prior to 150,000 years ago.

This finding is important, because although we know that archaic introgression has occurred in African populations throughout their evolution, up until now the majority of research studying archaic introgression has focused on much more recent hominins (Neanderthals and Denisovans) interacting with non-African populations. This is also the oldest documented instance of archaic introgression that I’m aware of. It gives us a remarkable glimpse of the genetic diversity present in our ancestors in a way that isn’t possible by any other means. I would imagine that as we learn more about our genetic histories, we will find more and more of these odd legacies from our distant kin.

One final aspect of this research interests me: the fact that while those of us belonging to haplogroup E appear to have received the version with 5 PTS repeats from an archaic hominin, others of us (belonging to haplogroup G) independently evolved a different 5 repeat version. We know this occurred independently, because MUC7 has a different DNA sequence in these individuals, even though the number of repeats are the same. This finding of two separate haplogroups containing the same number of repeats, suggested that recurrent evolution, or the repeated evolution of a certain trait (in this case a specific number of repeated genetic elements) might have occurred in different human populations. Positive selection would likely have maintained the introgressed 5 repeat version of MUC7 in sub-Saharan African populations up until the present day, suggesting that it might convey some kind of evolutionary advantage to the people who carry it. Similarly, the 5 repeat version of MUC 7 found in haplogroup G populations (found in Eurasia) might also reflect the presence of a selective advantage, perhaps associated with variation in oral microbiome composition, as discussed at the beginning of this article and supported by an association of a single nucleotide variant with the presence of particular microorganisms in the oral cavity. I’m looking forward to the authors’ future work on this particular question.

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