Biology subjects

Baker, Z.

Publications and source records attributed to Baker, Z..

5 recordsLinked to original sources

bioRxiv2023

Patterns of recombination in snakes reveal a tug of war between PRDM9 and promoter-like features

In vertebrates, there are two known mechanisms by which meiotic recombination is directed to the genome: in humans, mice, and other mammals, recombination occurs almost exclusively where the protein PRDM9 binds, while in species lacking an intact PRDM9, such as birds and canids, recombination rates are elevated near promoter-like features. To test if PRDM9 also directs recombination in non-mammalian vertebrates, we focused on an exemplar species, the corn snake (Pantherophis guttatus). Unlike birds, this species possesses a single, intact PRDM9 ortholog. By inferring historical recombination rates along the genome from patterns of linkage disequilibrium and identifying crossovers in pedigrees, we found that PRDM9 specifies the location of recombination events outside of mammals. However, we also detected an independent effect of promoter-like features on recombination, which is more pronounced on macrothan microchromosomes. Thus, our findings reveal that the uses of PRDM9 and promoter-like features are not mutually-exclusive, and instead reflect a tug of war, which varies in strength along the genome and is more lopsided in some species than others. One sentence summaryWhile the localization of meiotic recombination in vertebrates was previously thought to occur using one of two distinct mechanisms, our analysis of recombination in corn snakes reveals that they and likely other vertebrates use both of these mechanisms.

evolutionary biology↗

bioRxiv2022

Down the Penrose stairs: How selection for fewer recombination hotspots maintains their existence

In many species, meiotic recombination events tend to occur in narrow intervals of the genome, known as hotspots. In humans and mice, double strand break (DSB) hotspot locations are determined by the DNA-binding specificity of the zinc finger array of the PRDM9 protein, which is rapidly evolving at residues in contact with DNA. Previous models explained this rapid evolution in terms of the need to restore PRDM9 binding sites lost to gene conversion over time, under the assumption that more PRDM9 binding always leads to more DSBs. In recent experimental work, however, it has become apparent that PRDM9 binding on both homologs facilitates DSB repair, and moreover that, in the absence of enough symmetric binding, meiosis no longer progresses reliably. We therefore consider the possibility that the benefit of PRDM9 stems from its role in coupling DSB formation and efficient repair. To this end, we model the evolution of PRDM9 from first principles: from its binding dynamics to the population processes that govern the evolution of the zinc finger array and its binding sites in the genome. As we show, the loss of a small number of strong binding sites leads to the use of a greater number of weaker ones, resulting in a sharp reduction in symmetric binding and favoring new PRDM9 alleles that restore the use of a smaller set of strong binding sites. This decrease in PRDM9 binding symmetry and in its ability to promote DSB repair drive the rapid zinc finger turnover. These results imply that the advantage of new PRDM9 alleles is in limiting the number of binding sites used effectively, rather than in increasing net PRDM9 binding, as previously believed. By extension, our model suggests that the evolutionary advantage of hotspots may have been to increase the efficiency of DSB repair and/or homolog pairing.

evolutionary biology↗

bioRxiv2021

PRDM9 losses in vertebrates are coupled to the loss of at least three other meiotic genes

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 446 vertebrate species, inferring at least thirteen 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 find two genes whose presence and absence is unexpectedly coincident with that of PRDM9: ZCWPW1, which was recently shown to facilitate double strand break repair, and its paralog ZCWPW2, as well as more tentative evidence for TEX15 and FBXO47. ZCWPW2 is expected to be recruited to sites of PRDM9 binding; 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 SummaryOur 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 thirteen times in vertebrates and thus that its presence is interdigitated across species. By this approach, we identify two genes whose presence or absence across vertebrates is coupled to the presence or absence of PRDM9, ZCWPW1 and ZCWPW2, as well as two genes for which the evidence is weaker, TEX15 and FBXO47. ZCWPW1 was recently shown to be recruited to sites of PRDM9 binding and to aid in the repair of double strand breaks. ZCWPW2 is likely recruited to sites of PRDM9 binding as well; 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.

evolutionary biology↗

bioRxiv2016

Repeated losses of PRDM9-directed recombination despite the conservation of PRDM9 across vertebrates

Studies of highly diverged species have revealed two mechanisms by which meiotic recombination is directed to the genome--through PRDM9 binding or by targeting promoter-like features--that lead to dramatically different evolutionary dynamics of hotspots. Here, we identify PRDM9 orthologs from genome and transcriptome data in 225 species. We find the complete PRDM9 ortholog across distantly related vertebrates but, despite this broad conservation, infer a minimum of six partial and three complete losses. Strikingly, taxa carrying the complete ortholog of PRDM9 are precisely those with rapid evolution of its predicted binding affinity, suggesting that all domains are necessary for directing recombination. Indeed, as we show, swordtail fish carrying only a partial but conserved ortholog share recombination properties with PRDM9 knock-outs.

evolutionary biology↗

bioRxiv2016

The population genetics of human disease: the case of recessive, lethal mutations

Do the frequencies of disease mutations in human populations reflect a simple balance between mutation and purifying selection? What other factors shape the prevalence of disease mutations? To begin to answer these questions, we focused on one of the simplest cases: recessive mutations that alone cause lethal diseases or complete sterility. To this end, we generated a hand-curated set of 417 Mendelian mutations in 32 genes, reported to cause a recessive, lethal Mendelian disease. We then considered analytic models of mutation-selection balance in infinite and finite populations of constant sizes and simulations of purifying selection in a more realistic demographic setting, and tested how well these models fit allele frequencies estimated from 33,370 individuals of European ancestry. In doing so, we distinguished between CpG transitions, which occur at a substantially elevated rate, and three other mutation types. The observed frequency for CpG transitions is slightly higher than expectation but close, whereas the frequencies observed for the three other mutation types are an order of magnitude higher than expected. This discrepancy is even larger when subtle fitness effects in heterozygotes or lethal compound heterozygotes are taken into account. In principle, higher than expected frequencies of disease mutations could be due to widespread errors in reporting causal variants, compensation by other mutations, or balancing selection. It is unclear why these factors would have a greater impact on variants with lower mutation rates, however. We argue instead that the unexpectedly high frequency of disease mutations and the relationship to the mutation rate likely reflect an ascertainment bias: of all the mutations that cause recessive lethal diseases, those that by chance have reached higher frequencies are more likely to have been identified and thus to have been included in this study. Beyond the specific application, this study highlights the parameters likely to be important in shaping the frequencies of Mendelian disease alleles.\n\nAuthor SummaryWhat determines the frequencies of disease mutations in human populations? To begin to answer this question, we focus on one of the simplest cases: mutations that cause completely recessive, lethal Mendelian diseases. We first review theory about what to expect from mutation and selection in a population of finite size and further generate predictions based on simulations using a realistic demographic scenario of human evolution. For a highly mutable type of mutations, such as transitions at CpG sites, we find that the predictions are close to the observed frequencies of recessive lethal disease mutations. For less mutable types, however, predictions substantially under-estimate the observed frequency. We discuss possible explanations for the discrepancy and point to a complication that, to our knowledge, is not widely appreciated: that there exists ascertainment bias in disease mutation discovery. Specifically, we suggest that alleles that have been identified to date are likely the ones that by chance have reached higher frequencies and are thus more likely to have been mapped. More generally, our study highlights the factors that influence the frequencies of Mendelian disease alleles.

genetics↗