Search for: All records

Abstract Genes involved in spermatogenesis tend to evolve rapidly, but we lack a clear understanding of how protein sequences and patterns of gene expression evolve across this complex developmental process. We used fluorescence-activated cell sorting (FACS) to generate expression data for early (meiotic) and late (postmeiotic) cell types across 13 inbred strains of mice (Mus) spanning ∼7 My 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, whereas X-linked gene expression tended to be relatively more conserved likely reflecting chromosome-specific 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. 

Abstract Background DNA methylation dynamics in the brain are associated with normal development and neuropsychiatric disease and differ across functionally distinct brain regions. Previous studies of genome-wide methylation differences among human brain regions focus on limited numbers of individuals and one to two brain regions. Results Using GTEx samples, we generate a resource of DNA methylation in purified neuronal nuclei from 8 brain regions as well as lung and thyroid tissues from 12 to 23 donors. We identify differentially methylated regions between brain regions among neuronal nuclei in both CpG (181,146) and non-CpG (264,868) contexts, few of which were unique to a single pairwise comparison. This significantly expands the knowledge of differential methylation across the brain by 10-fold. In addition, we present the first differential methylation analysis among neuronal nuclei from basal ganglia tissues and identify unique CpG differentially methylated regions, many associated with ion transport. We also identify 81,130 regions of variably CpG methylated regions, i.e., variable methylation among individuals in the same brain region, which are enriched in regulatory regions and in CpG differentially methylated regions. Many variably methylated regions are unique to a specific brain region, with only 202 common across all brain regions, as well as lung and thyroid. Variably methylated regions identified in the amygdala, anterior cingulate cortex, and hippocampus are enriched for heritability of schizophrenia. Conclusions These data suggest that epigenetic variation in these particular human brain regions could be associated with the risk for this neuropsychiatric disorder. 

Abstract Embryonic development in mammals is highly sensitive to changes in gene expression within the placenta. The placenta is also highly enriched for genes showing parent-of-origin or imprinted expression, which is predicted to evolve rapidly in response to parental conflict. However, little is known about the evolution of placental gene expression, or if divergence of placental gene expression plays an important role in mammalian speciation. We used crosses between two species of dwarf hamsters (Phodopus sungorus and Phodopus campbelli) to examine the genetic and regulatory underpinnings of severe placental overgrowth in their hybrids. Using quantitative genetic mapping and mitochondrial substitution lines, we show that overgrowth of hybrid placentas was primarily caused by genetic differences on the maternally inherited P. sungorus X chromosome. Mitochondrial interactions did not contribute to abnormal hybrid placental development, and there was only weak correspondence between placental disruption and embryonic growth. Genome-wide analyses of placental transcriptomes from the parental species and first- and second-generation hybrids revealed a central group of co-expressed X-linked and autosomal genes that were highly enriched for maternally biased expression. Expression of this gene network was strongly correlated with placental size and showed widespread misexpression dependent on epistatic interactions with X-linked hybrid incompatibilities. Collectively, our results indicate that the X chromosome is likely to play a prominent role in the evolution of placental gene expression and the accumulation of hybrid developmental barriers between mammalian species. 

Abstract Adaptive radiations are characterised by the diversification and ecological differentiation of species, and replicated cases of this process provide natural experiments for understanding the repeatability and pace of molecular evolution. During adaptive radiation, genes related to ecological specialisation may be subject to recurrent positive directional selection. However, it is not clear to what extent patterns of lineage-specific ecological specialisation (including phenotypic convergence) are correlated with shared signatures of molecular evolution. To test this, we sequenced whole exomes from a phylogenetically dispersed sample of 38 murine rodent species, a group characterised by multiple, nested adaptive radiations comprising extensive ecological and phenotypic diversity. We found that genes associated with immunity, reproduction, diet, digestion and taste have been subject to pervasive positive selection during the diversification of murine rodents. We also found a significant correlation between genome-wide positive selection and dietary specialisation, with a higher proportion of positively selected codon sites in derived dietary forms (i.e. carnivores and herbivores) than in ancestral forms (i.e. omnivores). Despite striking convergent evolution of skull morphology and dentition in two distantly related worm-eating specialists, we did not detect more genes with shared signatures of positive or relaxed selection than in a non-convergent species comparison. While a small number of the genes we detected can be incidentally linked to craniofacial morphology or diet, protein-coding regions are unlikely to be the primary genetic basis of this complex convergent phenotype. Our results suggest a link between positive selection and derived ecological phenotypes, and highlight specific genes and general functional categories that may have played an integral role in the extensive and rapid diversification of murine rodents. 

Abstract Hybridization may often be an important source of adaptive variation, but the extent and long-term impacts of introgression have seldom been evaluated in the phylogenetic context of a radiation. Hares (Lepus) represent a widespread mammalian radiation of 32 extant species characterized by striking ecological adaptations and recurrent admixture. To understand the relevance of introgressive hybridization during the diversification of Lepus, we analyzed whole exome sequences (61.7 Mb) from 15 species of hares (1–4 individuals per species), spanning the global distribution of the genus, and two outgroups. We used a coalescent framework to infer species relationships and divergence times, despite extensive genealogical discordance. We found high levels of allele sharing among species and show that this reflects extensive incomplete lineage sorting and temporally layered hybridization. Our results revealed recurrent introgression at all stages along the Lepus radiation, including recent gene flow between extant species since the last glacial maximum but also pervasive ancient introgression occurring since near the origin of the hare lineages. We show that ancient hybridization between northern hemisphere species has resulted in shared variation of potential adaptive relevance to highly seasonal environments, including genes involved in circadian rhythm regulation, pigmentation, and thermoregulation. Our results illustrate how the genetic legacy of ancestral hybridization may persist across a radiation, leaving a long-lasting signature of shared genetic variation that may contribute to adaptation. [Adaptation; ancient introgression; hybridization; Lepus; phylogenomics.] 

Abstract Hares (genus Lepus) provide clear examples of repeated and often massive introgressive hybridization and striking local adaptations. Genomic studies on this group have so far relied on comparisons to the European rabbit (Oryctolagus cuniculus) reference genome. Here, we report the first de novo draft reference genome for a hare species, the mountain hare (Lepus timidus), and evaluate the efficacy of whole-genome re-sequencing analyses using the new reference versus using the rabbit reference genome. The genome was assembled using the ALLPATHS-LG protocol with a combination of overlapping pair and mate-pair Illumina sequencing (77x coverage). The assembly contained 32,294 scaffolds with a total length of 2.7 Gb and a scaffold N50 of 3.4 Mb. Re-scaffolding based on the rabbit reference reduced the total number of scaffolds to 4,205 with a scaffold N50 of 194 Mb. A correspondence was found between 22 of these hare scaffolds and the rabbit chromosomes, based on gene content and direct alignment. We annotated 24,578 protein coding genes by combining ab-initio predictions, homology search, and transcriptome data, of which 683 were solely derived from hare-specific transcriptome data. The hare reference genome is therefore a new resource to discover and investigate hare-specific variation. Similar estimates of heterozygosity and inferred demographic history profiles were obtained when mapping hare whole-genome re-sequencing data to the new hare draft genome or to alternative references based on the rabbit genome. Our results validate previous reference-based strategies and suggest that the chromosome-scale hare draft genome should enable chromosome-wide analyses and genome scans on hares.