Project description:Understanding how polygenic traits evolve and respond to selection is a major unsolved problem, because challenges exist for identifying genes underlying a complex trait and understanding how multi-locus selection operates in the genome. Here we used artificial selection experiments to study polygenic response to selection. Inbred strains from seven independent long-term selection experiments in mice for extreme bodyweight (“High” lines weigh 77-42g vs. 40-16g in “Controls” lines), were genotyped at 527,572 SNPs to identify genetic variants controlling bodyweight. We identified 67 high-resolution parallel selected regions (PSRs) where multiple High lines share variants rarely found among the Controls. By comparing allele frequencies in one selection experiment against its unselected control, we found classical selective sweep signatures centered on the PSRs. Multiple lines of evidence support two G protein-coupled receptors GPR133 and Prlhr, as positional candidate genes controlling bodyweight. Artificial selection may mimic natural selection in the wild: compared to control loci, we detected reduced heterozygosity in PSRs in wild populations of unusually large mice on islands. Many PSRs overlap loci associated with human height variation, possibly through evolutionary conservation of functional pathways. Our data suggest that parallel selection on complex traits may evoke parallel responses at many genes involved in diverse but relevant pathways. These samples were used to test the enrichment of certain gene functional categories. Genomic DNA SNP comparison between artificially selected high lines (BEH, DAHi, DUH, MUH, EDH, RAHi, Du6/G154 and Du6i/G80) and unselected control lines.
Project description:Using whole-genome bisulfite sequencing (WGBS), we profiled 18 DNA methylomes of cattle sperms that were collected from 18 representative age-matched Holstein bulls with high reliable phenotypes on many complex traits, including sire-conception rate (SCR), gestation length (GL), sire calving ease (SCE), cow conception rate (CCR) and body depth (BDE). Through comparison with human sperm methylome, we observed that genomic regions with differetial DNA methylation levels were enriched for GWAS signals and had important evolutionary impact. By comparing animals with extreme SCR, we showed that differentially methylated regions (DMR) associated with SCR and aging were significantly and selectively enriched for GWAS signals of male fertility traits in cattle. In addition, we detected ans compared DMRs assocaited with GL, CCR, SCE and BDE. We integrated GWAS signals of 37 complex traits with DMRs associated with GL to provide insights into genetic basis of GL.
Project description:Tardigrades are microscopic invertebrates renowned for their ability to survive extreme environmental stress such as radiation, extreme temperatures, and desiccation. Yet, the biochemical mechanisms they utilize to survive these extremes are poorly understood. Herein, we implement proteomics to investigate the biomolecular underpinnings of tardigrade osmobiosis – a survival state in response to osmotic pressure. Using two solutes, the non-ionic sucrose and the ionic NaCl, we reveal that de novo gene expression is not required for osmobiosis induction. While sucrose and NaCl induce slightly different proteomic effects, both solutes lead to an increased abundance or oxidation of proteins involved in ER or mitochondrial activity. Further, we investigate the role of mitochondria in tardigrade osmobiosis and demonstrate that inhibition of the alternative oxidase (AOX) within the mitochondrial respiratory chain (MRC) increases the rate of osmobiosis formation across both sucrose and NaCl. Subsequent electron paramagnetic resonance (EPR) spectroscopy reveals an increased rate of reactive oxygen species (ROS) formation in osmobiotes with AOX inhibited, suggesting a regulation of osmobiosis through MRC-derived ROS. In sum, this work suggests mitochondrial-ROS signaling is necessary for tardigrade osmobiosis and further clarifies the biochemical mechanisms contributing to tardigrade extremotolerance.
Project description:Extreme metabolic adaptations can elucidate genetic programs governing mammalian metabolism. Here we used convergent evolutionary changes in hibernating lineages to define conserved cis-regulatory elements (CREs) and metabolic programs. We characterized mouse hypothalamus gene expression and chromatin dynamics across fed, fasted, and refed states, then used comparative genomics of hibernating versus non-hibernating lineages to identify cis-elements with convergent changes in hibernators. Multi-omics approaches pinpointed CREs, hub genes, regulatory programs, and cell types underlying lineage divergence. Hibernators accumulated loss-of-function effects for CREs regulating hypothalamic responses, and the refeeding period after fasting served as a key phase for molecular processes with convergent evolutionary changes. This work provides a genetic framework for harnessing hibernator adaptations to understand human metabolic control.
Project description:Extreme metabolic adaptations can elucidate genetic programs governing mammalian metabolism. Here we used convergent evolutionary changes in hibernating lineages to define conserved cis-regulatory elements (CREs) and metabolic programs. We characterized mouse hypothalamus gene expression and chromatin dynamics across fed, fasted, and refed states, then used comparative genomics of hibernating versus non-hibernating lineages to identify cis-elements with convergent changes in hibernators. Multi-omics approaches pinpointed CREs, hub genes, regulatory programs, and cell types underlying lineage divergence. Hibernators accumulated loss-of-function effects for CREs regulating hypothalamic responses, and the refeeding period after fasting served as a key phase for molecular processes with convergent evolutionary changes. This work provides a genetic framework for harnessing hibernator adaptations to understand human metabolic control.
Project description:Extreme metabolic adaptations can elucidate genetic programs governing mammalian metabolism. Here we used convergent evolutionary changes in hibernating lineages to define conserved cis-regulatory elements (CREs) and metabolic programs. We characterized mouse hypothalamus gene expression and chromatin dynamics across fed, fasted, and refed states, then used comparative genomics of hibernating versus non-hibernating lineages to identify cis-elements with convergent changes in hibernators. Multi-omics approaches pinpointed CREs, hub genes, regulatory programs, and cell types underlying lineage divergence. Hibernators accumulated loss-of-function effects for CREs regulating hypothalamic responses, and the refeeding period after fasting served as a key phase for molecular processes with convergent evolutionary changes. This work provides a genetic framework for harnessing hibernator adaptations to understand human metabolic control.
Project description:Extreme metabolic adaptations can elucidate genetic programs governing mammalian metabolism. Here we used convergent evolutionary changes in hibernating lineages to define conserved cis-regulatory elements (CREs) and metabolic programs. We characterized mouse hypothalamus gene expression and chromatin dynamics across fed, fasted, and refed states, then used comparative genomics of hibernating versus non-hibernating lineages to identify cis-elements with convergent changes in hibernators. Multi-omics approaches pinpointed CREs, hub genes, regulatory programs, and cell types underlying lineage divergence. Hibernators accumulated loss-of-function effects for CREs regulating hypothalamic responses, and the refeeding period after fasting served as a key phase for molecular processes with convergent evolutionary changes. This work provides a genetic framework for harnessing hibernator adaptations to understand human metabolic control.