Biology subjects

Keeble, S.

Publications and source records attributed to Keeble, S..

4 recordsLinked to original sources

bioRxiv2023

Different complex regulatory phenotypes underlie hybrid male sterility in divergent rodent crosses

Hybrid incompatibilities are a critical component of species barriers and may arise due to negative interactions between divergent regulatory elements in parental species. We used a comparative approach to identify common themes in the regulatory phenotypes associated with hybrid male sterility in two divergent rodent crosses, dwarf hamsters and house mice. We investigated three potential characteristic gene expression phenotypes in hybrids including the propensity of transgressive differentially expressed genes towards over or underexpression, the influence of developmental stage on patterns of misexpression, and the role of the sex chromosomes on misexpression phenotypes. In contrast to near pervasive overexpression in hybrid house mice, we found that misexpression in hybrid dwarf hamsters was dependent on developmental stage. In both house mouse and dwarf hamster hybrids, however, misexpression increased with the progression of spermatogenesis, although to varying extents and with potentially different consequences. In both systems, we detected sex-chromosome specific overexpression in stages of spermatogenesis where inactivated X chromosome expression was expected, but the hybrid overexpression phenotypes were fundamentally different. Importantly, misexpression phenotypes support the presence of multiple developmental blocks to spermatogenesis in dwarf hamster hybrids, including a potential role of meiotic stalling or breakdown early in spermatogenesis. Collectively, we demonstrate that while there are some similarities in hybrid expression phenotypes of house mice and dwarf hamsters, there are also clear differences that point towards unique mechanisms underlying hybrid male sterility. Our results highlight the potential of comparative approaches in helping to understand the causes and consequences of disrupted gene expression in speciation.

evolutionary biology↗

bioRxiv2021

Stage-specific disruption of X chromosome expression during spermatogenesis in sterile house mouse hybrids

Hybrid sterility is a complex phenotype that can result from the breakdown of spermatogenesis at multiple developmental stages. Here, we disentangle two proposed hybrid male sterility mechanisms in the house mice, Mus musculus domesticus and M. m. musculus, by comparing patterns of gene expression in sterile F1 hybrids from a reciprocal cross. We found that hybrid males from both cross directions showed disrupted X chromosome expression during prophase of meiosis I consistent with a loss of Meiotic Sex Chromosome Inactivation (MSCI) and Prdm9-associated sterility, but that the degree of disruption was greater in mice with an M. m. musculus X chromosome consistent with previous studies. During postmeiotic development, gene expression on the X chromosome was only disrupted in one cross direction, suggesting that misexpression at this later stage was genotype-specific and not a simple downstream consequence of MSCI disruption which was observed in both reciprocal crosses. Instead, disrupted postmeiotic expression may depend on the magnitude of earlier disrupted MSCI, or the disruption of particular X-linked genes or gene networks. Alternatively, only hybrids with a potential deficit of Sly copies, a Y-linked ampliconic gene family, showed overexpression in postmeiotic cells, consistent with a previously proposed model of antagonistic coevolution between the X and Y-linked ampliconic genes contributing to disrupted expression late in spermatogenesis. The relative contributions of these two regulatory mechanisms and their impact on sterility phenotypes awaits further study. Our results further support the hypothesis that X-linked hybrid sterility in house mice has a variable genetic basis, and that genotype-specific disruption of gene regulation contributes to overexpression of the X chromosome at different stages of development. Overall, these findings underscore the critical role of epigenetic regulation of the X chromosome during spermatogenesis and suggest that these processes are prone to disruption in hybrids.

evolutionary biology↗

bioRxiv2021

Molecular Evolution across Mouse Spermatogenesis

Genes involved in spermatogenesis tend to evolve rapidly, but we still lack a clear understanding of how different components of molecular evolution vary across this complex developmental process. We used fluorescence activated cell sorting (FACS) to generate expression data for both early (meiotic) and late (postmeiotic) cell types across thirteen inbred strains of mice (Mus) spanning ~7 million years of evolution. We used these comparative developmental data to investigate the evolution of lineage-specific expression, protein-coding sequences, and expression levels. We found increased lineage specificity and more rapid protein-coding and expression divergence during late spermatogenesis, suggesting that signatures of rapid testis molecular evolution are punctuated across sperm development. Despite strong overall developmental parallels in these components of molecular evolution, protein and expression divergences were only weakly correlated across genes. We detected more rapid protein evolution on the X chromosome relative to the autosomes, while X-linked gene expression tended to be relatively more conserved likely reflecting chromosome-wide regulatory constraints. Using allele-specific FACS expression data from crosses between four strains, we found that the relative contributions of different regulatory mechanisms also differed between cell-types. Genes showing cis-regulatory changes were more common late in spermatogenesis, and tended to be associated with larger differences in expression levels and greater expression divergence between species. In contrast, genes with trans-acting changes were more common early and tended to be more conserved across species. Our findings advance understanding of gene evolution across spermatogenesis and underscore the fundamental importance of developmental context in molecular evolutionary studies.

evolutionary biology↗

bioRxiv2018

The choice of tree prior and molecular clock does not substantially affect phylogenetic inferences of diversification rates

Comparative methods allow researchers to make inferences about evolutionary processes and patterns from phylogenetic trees. In Bayesian phylogenetics, estimating a phylogeny requires specifying priors on parameters characterizing the branching process and rates of substitution among lineages, in addition to others. However, the effect that the selection of these priors has on the inference of comparative parameters has not been thoroughly investigated. Such uncertainty may systematically bias phylogenetic reconstruction and, subsequently, parameter estimation. Here, we focus on the impact of priors in Bayesian phylogenetic inference and evaluate how they affect the estimation of parameters in macroevolutionary models of lineage diversification. Specifically, we use BEAST to simulate trees under combinations of tree priors and molecular clocks, simulate sequence data, estimate trees, and estimate diversification parameters (e.g., speciation rates and extinction rates) from these trees. When substitution rate heterogeneity is large, parameter estimates deviate substantially from those estimated under the simulation conditions when not captured by an appropriate choice of relaxed molecular clock. However, in general, we find that the choice of tree prior and molecular clock has relatively little impact on the estimation of diversification rates insofar as the sequence data are sufficiently informative and substitution rate heterogeneity among lineages is low-to-moderate.

evolutionary biology↗