Biology subjects

Lynch, V. J.

Publications and source records attributed to Lynch, V. J..

5 recordsLinked to original sources

bioRxiv2018

Relaxed constraint and thermal desensitization of the cold-sensing ion channel TRPM8 in mammoths

Unlike the living elephants, which live in warm tropical and subtropical habitats, mammoths lived in extreme cold environments where average winter temperatures ranged from -30{degrees} to -50{degrees}C. Like other cold adapted and artic species, mammoths evolved of suite of morphological and molecular adaptations that facilitated life in the cold. Here we reanalyze mammoth genomes and find that genes with mammoth-specific amino acid substitutions are enriched in functions related to temperature sensation. Among the genes with mammoth-specific amino acid substitutions is TRPM8, which mediates sensitivity to nonnoxious cool temperatures from 25- 28{degrees}C and cooling sensations induced by the chemical agonists menthol and icilin. We find that TRPM8 evolved rapidly in the mammoth stem-lineage, likely because of an episode of relaxed purifying selection. Functional characterization of resurrected mammoth and ancestral TRPM8 indicates that the mammoth TRPM8 is desensitized to cold but maintains sensitivity to menthol and icilin. These data suggest that as mammoths evolved into a cold tolerant species they lost the need for a cold-sensitive TRPM8.

evolutionary biology↗

bioRxiv2018

An ancient fecundability-associated polymorphism creates a new GATA2 binding site in a distal enhancer of HLA-F

Variation in female reproductive traits such as fertility, fecundity, and fecundability are heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits has been challenging. Here we explore the functional significance and evolutionary history of a G/A polymorphism of SNP rs2523393, which we have previously shown is an eQTL for the HLA-F gene and significantly associated with fecundability (time to pregnancy). We replicated the association between rs2523393 genotype and HLA-F expression using GTEx data and demonstrate that HLA-F is up-regulated in the endometrium during the window of implantation and by progesterone in decidual stromal cells. Next, we show that the rs2523393 A allele creates a new GATA2 binding site in a progesterone responsive distal enhancer that loops to the HLA-F promoter. Remarkably, we found that the A allele is derived in the human lineage, that G/A polymorphism arose before the divergence of modern and archaic humans, and is segregating at intermediate to high frequencies across human populations. Remarkably, the derived A is also has been identified in a GWAS as a risk allele for multiple sclerosis. These data suggests that the polymorphism is maintained by antagonistic pleiotropy and a reproduction-health tradeoff in human evolution.

genetics↗

bioRxiv2017

A zombie LIF gene in elephants is up-regulated by TP53 to induce apoptosis in response to DNA damage

Large bodied organisms have more cells that can potentially turn cancerous than smallbodied organisms with fewer cells, imposing an increased risk of developing cancer. This expectation predicts a positive correlation between body size and cancer risk, however, there is no correlation between body size and cancer risk across species ( Petos Paradox). Here we show that elephants and their extinct relatives (Proboscideans) may have resolved Petos Paradox in part through re-functionalizing a leukemia inhibitory factor pseudogene (LIF6) with pro-apoptotic functions. The LIF6 gene is transcriptionally up-regulated by TP53 in response to DNA damage, and translocates to the mitochondria where it induces apoptosis. Phylogenetic analyses of living and extinct Proboscidean LIF6 genes indicates its TP53 response element evolved coincident with the evolution of large body sizes in the Proboscidean stem-lineage. These results suggest that re-functionalizing of a pro-apoptotic LIF pseudogene may have been permissive (though not sufficient) for the evolution of large body sizes in Proboscideans.

evolutionary biology↗

bioRxiv2017

Accumulation And Functional Architecture Of Deleterious Genetic Variants During The Extinction Of Wrangel Island Mammoths

Woolly mammoths were among the most abundant cold adapted species during the Pleistocene. Their once large populations went extinct in two waves, an end-Pleistocene extinction of continental populations followed by the mid-Holocene extinction of relict populations on St. Paul Island ~5,600 years ago and Wrangel Island ~4,000 years ago. Wrangel Island mammoths experienced an episode of rapid demographic decline coincident with their isolation, leading to a small population, reduced genetic diversity, and the fixation of putatively deleterious alleles, but the functional consequences of these processes are unclear. Here we show that the Wrangel Island mammoth accumulated many putative deleterious mutations that are predicted to cause diverse behavioral and developmental defects. Resurrection and functional characterization of Wrangel Island mammoth genes carrying these substitutions identified both loss and gain of function mutations in genes associated with developmental defects (HYLS1), oligozoospermia and reduced male fertility (NKD1), diabetes (NEUROG3), and the ability to detect floral scents (OR5A1). These results suggest that Wrangel Island mammoths may have suffered adverse consequences from their reduced population sizes and isolation.

genetics↗

bioRxiv2016

Transposable element exaptation is the primary source of novelty in the primate gene regulatory landscape

Gene regulation plays a critical role in the evolution of phenotypic diversity. We investigated the evolution of liver promoters and enhancers in six primate species. We performed ChlP-seq for two histone modifications and RNA-seq to profile cis-regulatory element (CRE) activity and gene expression. The primate regulatory landscape is largely conserved across the lineage. Conserved CRE function is associated with sequence conservation, proximity to coding genes, cell type specificity of CRE function, and transcription factor binding. Newly evolved CREs are enriched in immune response and neurodevelopmental functions, while conserved CREs bind master regulators. Transposable elements (TEs) are the primary source of novelty in primate gene regulation. Newly evolved CREs are enriched in young TEs that affect gene expression. However, only 17% of conserved CREs overlap a TE, suggesting that target gene expression is under strong selection. Finally, we identified specific genomic features driving the functional recruitment of newly inserted TEs.

genomics↗