Evolution of homologous recombination mechanisms

Henry M. Jackson Fdn For The Adv Mil/Med, Rockville MD

Investigators

Abstract

ABSTRACT Homologous recombination reshuffles genetic information between parental chromosomes generating genetic diversity and driving evolution. Recombination predominantly occurs at a set of genomic locations called recombination hotspots. In most mammals, including humans, hotspot locations are defined by the sequence- specific binding of the PRDM9 protein, which trimethylates lysine 4 of the histone H3 at the sites where recombination is later initiated. In Prdm9 knockout mice DSBs are targeted to gene promoters and enhancers, which also carry the H3K4 trimethylation mark. Therefore, PRDM9 directs recombination away from functional genomic elements. This role is important as data indicate mutagenic effects of recombination both on the local nucleotide level and in gross chromosomal rearrangements. Nevertheless, some species do not have the Prdm9 gene or have lost canonical Prdm9 through evolution. In most of such species, recombination hotspots still exist, but they form at the H3K4me3-marked gene promoters and other genomic regions with accessible DNA. In contrast, nematodes and dipterans do not have recombination hotspots. Why promoters are not targeted by the DSB machinery in such species is not understood. In this study we propose to answer this question with the example of the marsupial Monodelphis Domestica, the first vertebrate species that, according to our preliminary data, lacks recombination hotspots. In addition to the prominent role of homologous recombination in evolution, recombination per se is essential for proper segregation of homologous chromosomes during gametogenesis. Recombination defects are invariably associated with infertility, miscarriage and aneuploidy-related birth defects. Defining the mechanisms that control genetic recombination will eventually aid in detection, prevention and/or treatment of aneuploidy-related infertility and birth defects.