R2d2 takes unfair advantage of females
February 14, 2015 7:59 AM   Subscribe

R2d2 takes unfair advantage of females
Our group at the University of North Carolina has just published a paper (open access) on an exciting new female meiotic drive system that we call R2d2. There is also a nice accompanying perspective article (also open access) from researchers at the Fred Hutchinson Cancer Institute in Seattle. Read on for a short description of meiotic drive and the findings of the paper.

There aren't many scientific concepts that are considered so certain that they've been elevated to the status of "law," but Gregor Mendel has two to his name. Essentially, these laws tell us why sexual reproduction is important - because it randomizes the combinations of genes inherited by each person to create genetic and phenotypic variability.

However, there are some exceptions to Mendel's laws. One of the most interesting and least well understood is meiotic drive. Meiotic drive occurs because, when females produce eggs (the processes called oogenesis) the cell divisions that occur are asymmetric - that is, only one of the two cells that are produced is viable. In biology, asymmetry is disfavored because, when one thing is better than another, either compensating mechanisms evolve to erase the difference, or something evolves to take unfair advantage of that difference. Asymmetric female meiosis has survived out of necessity, because the female sex cell needs to prepare to become a new life - it needs to take all of the material that it can from the parent cell to kickstart development following conception. Therefore, as you might expect, parasitic (or "selfish") genetic elements have evolved to take advantage of that asymmetry in order to promote their preferential inclusion in the viable cell (the egg, or ova).

It is quite rare to observe meiotic drive. In the 50+ years that it has been studied (beginning with the seminal work from Sandler and Novitski in 1957), only a handful of systems have been described. One important example that is known to occur in humans is the non-random transmission of Robertsonian (Rb) translocations. Rb translocations are fusions that occur between some chromosomes, most notably chromosomes 14 and 21 in humans. In about 5% of cases, Downs syndrome (trisomy of chromosome 21) is caused by the transmission of an Rb translocation of chromosome 21. For an unknown reason, Rb translocations are preferentially transmitted to the egg at a rate of about 60% in humans. Interestingly, that trend is reversed in mice.

Another interesting case of non-random transmission occurs on mouse chromosome 2, although until now it has never been linked to meiotic drive. For 30+ years, mouse geneticists have noticed that in some of their experimental crosses (breeding experiments between two different strains of mice), after two or more generations there is a significant overrepresentation of the chromosome 2 from one parental strain compared to the other. Our lab at the University of North Carolina (and our collaborators at The Jackson Laboratory in Bar Harbor, ME) has been developing for the past 10 years a new mouse population that is set to revolutionize the way we do genetics. Called the Collaborative Cross (CC), it is an eight-way combination of very diverse strains. The most high-profile success of the CC so far has been the modeling of response to Ebola virus, something not previously possible in an experimental organism. Several years ago, we found that Chromosome 2 in the CC also exhibited this strange pattern of inheritance, and we linked it back to a single strain, WSB/EiJ. WSB/EiJ is what is called a "wild-derived" strain because it was initiated from mice that were caught in the wild (as opposed to the normal "classical" strains used in the lab, which originated from pet mice). The mice that initiated the WSB/EiJ strain were trapped on the eastern shore of Maryland, near Centreville.

After more than a year of performing breeding experiments, genetic assays and computational analysis, we were able to map the non-random segregation of Chromosome 2 to a small region located roughly in the middle of the chromosome. Even better, we identified a chunk of DNA (called R2d) that exists as one copy in mice that have normal Chromosome 2 segregation, but which exists in a much higher number (around 30) in mice that have unfair segregation. Furthermore, the additional copies occur at a different place in the genome (R2d2) than does the single copy found in all mice (R2d1). Although we are not yet certain of the mechanism that enables R2d2 to give an unfair advantage, we hypothesize that is is acting as a "neocentromere." The centromere is the region of the chromosome that attaches to the molecular machinery (the "spindle") during meiotic cell division that pulls chromosomes apart so that each of the two new cells get an equal number of chromosomes. The molecular basis of Mendel's laws is that the attachment of chromosomes to the two ends of the meiotic spindle is supposed to be random. However, a neocentromere can give a chromosome an unfair advantage by being able to attach to the spindle that is oriented toward the egg. While it is clear how this process of selecting the "winning" cell happens in plants, the process in mammals is not understood.

There are many additional aspects of this system that make it biologically interesting and potentially applicable to biotech uses and to human health. If anyone is interested in making a front page post about this, I'm happy to provide additional details and explanation.
Role: I am the lead author on the paper
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