When a baby does not make it to term, an irregular number of chromosomes in the embryo is often the root cause. The phenomenon, known as aneuploidy, is surprisingly common: it can be detected in roughly three-quarters of human embryos by the third day following fertilization.
Now scientists have identified a mutation linked to aneuploidy that is common in modern humans but was, based on a genome analysis, nonexistent in Neanderthals or Denisovans. The researchers also found evidence that evolution actually favored the presence of this mutation in the modern human genome despite its obvious negative effects on fertility. The findings are detailed in the April 10 issue of the journal Science.
Evolutionary biologists Rajiv McCoy and Dmitri Petrov at Stanford University and their collaborators at San Carlos, Calif.-based genetic testing company Natera sought genetic factors that might play a role in aneuploidy. The researchers analyzed the genomes of single cells from day-3 embryos that were generated during in vitro fertilization. Before embryos generated via IVF are implanted, cells are often taken from these embryos for genetic analysis to gauge their health.
When the scientists compared the genomes of these embryos with those of their parents, they discovered a mutation on chromosome 4 of the maternal genome that was strongly linked to aneuploidy arising after fertilization. This mutation is a single nucleotide polymorphism (SNP), or change to a single base in a person’s genome. The aneuploidy that results is so early and catastrophic that it likely causes the loss of embryos before the pregnancies are even detectable.
Consistent with this idea, the researchers found that women attempting to have children via IVF who possess this mutation had significantly fewer day-5 embryos. This suggests this mutation reduces fertility.
“Finding any genetic variation that influences aneuploidy is surprising, because of the well-established link between aneuploidy and pregnancy loss,” McCoy said. “One would assume that natural selection would remove that kind of variation from the population.”
The region where this mutation is found contains eight genes. The scientists noted these genes include PLK4, which is the master regulatory gene behind the duplication of the centriole, a key structure in cell division in humans and other animals. Prior research suggests that both under-expression and over-expression of this gene can lead to chromosome instability. However, it remains uncertain, says McCoy, whether this mutation leads to under-expression or over-expression of PLK4, or if it causes a change in the resulting protein’s structure — or if it even affects PLK4 at all.
The scientists discovered this mutation lurks in a wide range of modern human populations at startlingly high frequencies of 20 to 45 percent. Moreover, this widespread mutation is absent in the genomes of both Neanderthals and Denisovans, the closest known extinct relatives of modern humans, suggesting it arose in the past 100,000 to 400,000 years.
Furthermore, by contrasting genetic variation found in the Neanderthal genome with that present in modern humans, the researchers found that the region containing the mutation has apparently experienced strong positive selection during evolution. In other words, either this mutation has some kind of benefit, or it hitchhiked with a different gene that does.
“Our work does not imply that there is a benefit to miscarriage,” McCoy said. “Instead, the findings potentially imply that there may be evolutionary tradeoffs involved with this genetic variant.”
One possibility, Petrov speculates, is that the gene, by allowing for frequent pregnancy loss, obscured paternity, and hence increased the chances that a male would help care for offspring that were not his own – a tendency among primitive humans that could have benefited the group.
Another possibility is that reducing fertility lengthens the intervals between pregnancies, which could in turn mean that more resources were spent on older children, hence improving their rates of survival. Petrov notes, though, a flaw in this explanation: the mutation would probably increase the intervals between offspring in a haphazard manner, meaning in some cases they would be very close together, and in others quite far apart.
Evolutionary ramifications aside, the findings could have important implications for hopeful future parents that face fertility issues, says bioinformatician Samuel Vohr at the University of California, Santa Cruz, who co-authored a commentary on this paper in Science.
“As infertility can be caused by many factors, understanding the specific mechanisms is important for developing diagnostic and therapeutic technologies later on,” Vohr says. “For couples faced with infertility, it could mean additional information to help guide their decisions and perhaps more personalized treatment options in the future.”