Abstract
Meiotic recombination generates new genetic variation and assures the proper segregation of chromosomes in gametes. PRDM9, a zinc finger protein with histone methyltransferase activity, initiates meiotic recombination by binding DNA at recombination hotspots and directing the position of DNA double-strand breaks (DSB). The DSB repair mechanism suggests that hotspots should eventually self-destruct, yet genome-wide recombination levels remain constant, a conundrum known as the hotspot paradox. To test if PRDM9 drives this evolutionary erosion, we measured activity of the Prdm9 Cst allele in two Mus musculus subspecies, M.m. castaneus, in which Prdm9Cst arose, and M.m. domesticus, into which Prdm9Cst was introduced experimentally. Comparing these two strains, we find that haplotype differences at hotspots lead to qualitative and quantitative changes in PRDM9 binding and activity. Using Mus spretus as an outlier, we found most variants affecting PRDM9Cst binding arose and were fixed in M.m. castaneus, suppressing hotspot activity. Furthermore, M.m. castaneus×M.m. domesticus F1 hybrids exhibit novel hotspots, with large haplotype biases in both PRDM9 binding and chromatin modification. These novel hotspots represent sites of historic evolutionary erosion that become activated in hybrids due to crosstalk between one parent's Prdm9 allele and the opposite parent's chromosome. Together these data support a model where haplotype-specific PRDM9 binding directs biased gene conversion at hotspots, ultimately leading to hotspot erosion.
Highlights
Genetic recombination increases variability by facilitating selection for new, favorable combinations of alleles and against deleterious mutations
A hallmark of meiosis is the process of recombination, in which pieces of maternal and paternal genetic material are exchanged, creating new combinations that are inherited by their progeny
We have used the power of mouse genetics and large scale measurements of PRDM9 location and activity to show that this cycle of hotspot loss and recovery does occur over the course of hundreds of thousands of years, and is directed by PRDM9
Summary
Genetic recombination increases variability by facilitating selection for new, favorable combinations of alleles and against deleterious mutations. DNA double-strand breaks (DSBs) are subsequently introduced by the conserved enzyme SPO11 (MGI:1349669) near the NDR [8,9,10]. These programmed DSBs are repaired by one of two distinct pathways resulting in either cross-overs (COs), which result in the exchange of flanking DNA, or noncross-overs (NCOs) which do not [10]. Both COs and NCOs can create small gene conversion tracks where the DNA sequence of the activating chromatid is repaired using the homologous partner chromatid as the template [11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
