| abstract |
In most mammals and likely throughout vertebrates, the gene PRDM9 specifies the locations of meiotic double strand breaks; in mice and humans at least, it also aids in their repair. For both roles, many of the molecular partners remain unknown. Here, we take a phylogenetic approach to identify genes that may be interacting with PRDM9, by leveraging the fact that PRDM9 arose before the origin of vertebrates, but was lost many times, either partially or entirely––and with it, its role in recombination. As a first step, we characterize PRDM9 domain composition across 379 vertebrate species, inferring at least eight independent losses. We then use the interdigitation of PRDM9 orthologs across vertebrates to test whether it co-evolved with any of 241 candidate genes co-expressed with PRDM9 in mice or associated with recombination phenotypes in mammals. Accounting for the phylogenetic relationship among species, we identify three genes whose presence and absence is unexpectedly coincident with that of PRDM9 : ZCWPW1 , which was recently shown to be recruited to sites of PRDM9 binding and to facilitate double strand break repair; TEX15 , which has also been suggested to play a role in repair; and ZCWPW2 , the paralog of ZCWPW1 . ZCWPW2 is expected to be recruited to sites of PRDM9 binding as well; its tight coevolution with PRDM9 across vertebrates suggests that it is a key interactor, with a role either in recruiting the recombination machinery or in double strand break repair. Author Summary Our understanding of meiotic recombination in mammals has seen great progress over the past 15 years, spurred in part by the convergence of lines of evidence from molecular biology, statistical genetics and evolutionary biology. We now know that in most mammals and likely in many vertebrates, the gene PRDM9 specifies the location of meiotic double strand breaks and that in mice and humans at least, it also aids in their repair. For both roles, however, many of the molecular partners remain unknown. To search for these, we take a phylogenetic approach, leveraging the fact that the complete PRDM9 has been lost at least eight times in vertebrates and thus that its presence is interdigitated across species. By this approach, we identify three genes whose presence or absence across vertebrates is significantly coupled to the presence or absence of PRDM9 : TEX15 , ZCWPW1 and the paralog of ZCWPW1 , ZCWPW2 . ZCWPW1 was recently shown to be recruited to sites of PRDM9 binding and to aid in the repair of double strand breaks. TEX15 has also been suggested to be involved in the repair process. ZCWPW2 is likely recruited to sites of PRDM9 binding; its tight coevolution with PRDM9 across vertebrates suggests that it plays an important role either in double strand break formation, potentially as the missing link that recruits the recombination machinery to sites of PRDM9 binding, or in double strand break repair. |
Gene
RNA