Theses Doctoral

Understanding the Evolution of Recombination Rate Variation and PRDM9

Baker, Zachary

Meiotic recombination is a fundamental genetic process in all sexually reproducing eukaryotes, ultimately responsible for the generation of new combinations of alleles upon which natural selection can act. It begins with the formation of programmed double stranded breaks along the genome, and ends with their repair as non-crossover or crossover recombination events. The localization of such events along the genome has important evolutionary consequences for genome structure, base composition, patterns of genetic diversity, linkage disequilibrium and introgression, along the genome, as well as in the evolution of post-zygotic hybrid sterility and speciation. Understanding how meiotic recombination events are localized is thus crucial to the proper interpretation of observed genetic variation, and to the field of population genetics as a whole. However, little is known about how most species localize recombination events. While some species localize meiotic recombination events fairly evenly along the genome (e.g., Caenorhabditis elegans or Drosophila), most species studied to date, including all yeasts, plants and vertebrates, localize the vast majority of meiotic recombination events to narrow intervals of the genome known as recombination hotspots. Within such species, there appear to be at least two general mechanisms underlying the localization of hotspots. First, in many species, including baker’s yeast, canids, birds, and plants, the vast majority of hotspots are found in close proximity with promoter-like features of the genome, such as transcriptional start sites and CpG-islands. Recombination landscapes in these species tend to be highly conserved between closely related species. Second, in mice, primates and cattle, the vast majority of hotspots are found away from promoter-like features of the genome, and at sites bound by the PRDM9 protein, which has a rapidly evolving DNA-binding specificity. Concordantly, the recombination landscapes in these species tends to be rapidly evolving. The aim of Chapter 2 of this dissertation is to characterize the distribution of mechanisms across vertebrates indirectly, by leveraging what is known about their genetic and molecular underpinnings. In particular, I consider what is known about the molecular mechanisms and evolutionary consequences of using PRDM9 to localize recombination events, and attempt to infer which vertebrate species are or are not likely to be using PRDM9 in an analogous manner. I find that PRDM9 has been lost repeatedly within vertebrates, and, moreover, that many species carry partial PRDM9 orthologs lacking one or more feature believed to be important for its role in recombination. In Chapter 3, I demonstrate that swordtail fish, which have such a partial PRDM9 ortholog, do not use PRDM9 to localize recombination events. Instead, they use promoter-like features of the genome, similar to species lacking PRDM9 altogether. This work suggests that only species carrying complete PRDM9 orthologs are likely to use them to localize recombination events, and that upon the partial or complete loss of PRDM9, species typically default to the use of promoter-like features. Beyond more immediately practical insight, understanding the phylogenetic distribution of mechanisms by which meiotic recombination events are localized along the genome will shed light on why different species employ different mechanisms. The repeated losses of PRDM9-directed recombination across vertebrates suggests that selective pressures are not always strong enough to justify the evolutionary maintenance of PRDM9. Notably, theory suggests that PRDM9’s DNA-binding specificity has to be continually evolving in order for it to localize recombination events to hotspots. This is a consequence of gene conversion acting to remove PRDM9 binding sites from the population over time. Models have been proposed in which selection favors younger PRDM9 alleles because their binding sites have experienced less erosion due to gene conversion. Nonetheless, it has remained unclear how the loss of PRDM9 binding sites might cause a reduction in fitness, principally because it has remained unclear what the evolutionary benefit of having hotspots is more generally. Recently, however, a number of studies investigating the role of PRDM9 in mediating hybrid sterility in certain crosses of musculus subspecies have implicated the erosion of its binding sites in this process. In particular, the lineage specific erosion of PRDM9 binding sites causes, in the F1 generation, the PRDM9 alleles from each parental lineage to bind primarily to the non-parental genetic background, where its binding sites have not yet been eroded. These studies suggest that there is a benefit to the symmetric binding of PRDM9 across homologous chromosomes, and that fitness is reduced as a consequence of asymmetry in PRDM9 binding. In Chapter 4 of this dissertation I develop a population genetics based model of the co-evolution of PRDM9 and its binding sites taking into consideration these recent findings. In particular, I model competition between PRDM9 binding sites and define fitness as a function of PRDM9 binding symmetry. This model demonstrates that PRDM9 binding symmetry will decrease over time in randomly mating populations, and that selection for symmetric binding is sufficient to drive the rapid turnover of PRDM9 alleles. Importantly, the requirement for symmetry in this model shapes the recombination landscape by favoring highly skewed binding distributions. This model thus provides theoretical support for the hypothesis that a requirement for symmetry might underlie the evolutionary advantage of recombination hotspots.


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More About This Work

Academic Units
Cellular, Molecular and Biomedical Studies
Thesis Advisors
Przeworski, Molly F.
Ph.D., Columbia University
Published Here
January 16, 2020