Those of us that work in ART know the frustrating experience of telling a woman that all her embryos are aneuploid, and not viable for transfer. Aneuploidy, i.e. the presence in the blastomeres of an embryo with an unbalanced chromosome complement, is extremely common in human embryos, and its frequency is associated with maternal age, although it is present at high rates even in young fertile women. Aneuploidy rates in human are, in fact, much higher than other monotocic mammals such as cows or horses, for instance, higher than all mammals analyzed so far actually.
Why is that? A new study published last week in the journal Science is bringing some understanding to this question, and what it finds is fascinating. The authors re-analyzed more than 40.000 DNA samples, taken in the course of ART cycles from embryos biopsies at day 3, at day 5, and from progenitors. Their aim was to identify the origin and frequency of DNA errors, and understand at least partially the embryo selection process that goes on between day 3 and day 5 embryos. Because of new techniques to analyze DNA at the genomic level, it is possible to detect which paternal homolog is the source of the aneuploidy, i.e. it is possible to know whether the aneuploidy is of paternal or maternal origin.
The authors found that, as expected, there was a background of meiosis derived aneuploidy which was maternal age related. However and importantly, they also found a significant amount of mitotic derived errors, which in turn did not show any association with maternal age. Aneuploidy in human embryo is visible at Day 3 of development, when the embryo development is still under the influence of proteins and mRNAs accumulated in the oocytes, and we can say that its biology is almost completely maternally driven. The authors reasoned that there might be a maternal effect in the high rate of mitotic, non age-associated aneuploidy rate they found.
To test this hypothesis they looked at all blastomeres with an alteration of paternal origin. Since meiotic alteration on the paternal side are very rare, comprising about 1% of trisomies detected, it is logical to consider that paternally derived alterations are of mitotic origin. With this in mind, they looked at associations between mitotic alterations and specific area od the genome of both the father and the mother, and they found a peak on chromosome 4. In this region, one allele was highly related to mitotic errors. This is a very relevant findings, because the allele linked to mitotic errors in the embryos is not, as we might think, a rare aberration. This allele is very common in all human populations across the globe, and 20 to 45% of individuals carry it. Moreover, the researchers found that the presence of this allele diminishes going from day3 to day 5 embryos, indicating that there might be a selection in the embryos against it. In other words, there is a genetic variant which is common in the human species, and which is associated to an embryo being aneuploid. The frequency of this variant in a population of biopsied embryos is lower at day 5 than day 3, indicating a culling of carrier embryos.
So, what genes can we found in this region of chromosome 4? There are a few, but one specifically catches the eye: polo like kinase 4 (PLK4). PLK4 is a well-known protein to those interested in chromosome segregation. It is a protein involved in mitosis and can cause alterations in the fidelity of chromosome segregation when it is altered or nonfunctioning.
The authors went further in their quest for understanding of this variant, and compared the locus they found to the partial annotation of the genome from the Neandretal, and they have found, very surprisingly, that the allele seems to have been under strong selective pressure during the evolution of the human race.
So, why is a variant that is linked to strong fecundity alteration so frequent in humans, and why does it appear to be selected for during evolution? An intriguing theory, proposed by the authors, suggests that the allele may provide a selective advantage by obscuring paternity. The human species already possesses a number of traits which obscure paternity, such as concealed ovulation and constant receptivity for intercourse, and it is speculated that this allele would further increase the paternal investment in offspring by increasing the natural time to pregnancy. It is also possible that genetically spacing childbirths would offer a competitive advantage to the mother, by allowing for more time of focused investment in a previous offspring.
Whatever the evolutionary significance of the allele, it is an exciting new find in reproductive medicine, one that has been possible because of the technical advances genomewide DNA testing and data analysis, and by the thousands of human embryos that have been tested in the course of assisted reproduction cycles. The identification of this new genetic variant, so strongly associated with embryo aneuploidy, is likely to help couple counselling and aneuploidy risk assessment, improving diagnosis and prognosis.
Scientific Director, Clinica EUGIN