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Yam, P.

Publications and source records attributed to Yam, P..

2 recordsLinked to original sources
bioRxiv2026

Primary-Level Meta-Analysis of Diversity Outbred Mice Identifies a Fasting Plasma Trimethylamine N-Oxide (TMAO) Locus Modified by Sex and Diet

Trimethylamine n-oxide (TMAO) is a plasma metabolite linked to adverse cardiometabolic health with complex regulation involving diet, sex, and host genetics. We explored the role of these factors in the genetic regulation of TMAO by performing a primary-level meta-analysis in 1,482 female and male Diversity Outbred (DO) mice from five distinct studies conducted in various regions of the United States. We identified a quantitative trait locus (QTL) associated with TMAO concentration at [~]86 megabase pairs on mouse chromosome 12 with a highly significant LOD score of 67.67. Alleles at the chromosome 12 QTL inherited from the Cast/EiJ (CAST) and PWK/PhJ (PWK) mouse strains primarily drove the association with reduced TMAO concentrations. The chromosome 12 QTL remained significant in sex-stratified analyses and the mode of inheritance appeared additive; furthermore, the QTL was regulated by sex-by-genotype and sex-by-diet interactions. Using a CAST/EiJ X C57BL/6J F2 cross, positional candidates were prioritized by eQTL analysis. Further analysis in a study utilizing the eight DO founding strains identified that Acyp1 was differentially expressed in hepatic tissue from CAST mice, prompting investigation into its genetic regulation. Acyp1 demonstrated relevant cis- and trans-regulation and was significantly correlated with TMAO and hepatic Fmo3. However, no significant relationships between Acyp1 and TMAO were identified in mice inactivated for Acyp1 or with AAV overexpression of Acyp1 in the liver. Genes within the chromosome 12 QTL have synteny with humans and may translate to the genetic regulation of human plasma TMAO concentrations and atherosclerosis. Author SummaryWe explored the roles of diet, sex, and genetics on the regulation of fasting plasma trimethylamine n-oxide (TMAO) concentration by performing a meta-analysis in 1,482 female and male Diversity Outbred (DO) mice from five unique studies. We identified a QTL associated with TMAO concentration on chromosome 12 at [~]86 mega base pair (Mb) with a highly significant LOD score of 67.67. The locus is modified by both sex and diet.

genetics↗
bioRxiv2019

A New Role for Telomerase in Promoting Meiotic Homolog Pairing Fidelity

We report a role for telomerase, beyond its known function of telomeric DNA end extension, in maintaining normal chromosome dynamics during meiosis in Saccharomyces cerevisiae. When telomerase at telomeres was reduced by various genetic means, increased frequencies of crossover and noncrossover recombination events occurred. To investigate the mechanism of this increased meiotic recombination, we examined the kinetics of meiosis events, and tracked the movement of chromosomes in live cells during meiotic prophase. Cytoskeletal forces acting on telomeres during meiosis have been shown to promote active chromosome motion needed to pair homologous chromosomes. Here we show that changes in telomerase interaction with telomeres using a tlc1-11 mutant result in altered meiotic motion. Specifically, reduction in telomerase at telomeres leads to a decreased frequency of high velocity chromosome pulls. In the tlc1-11 mutant, we see earlier synapsis and increased genome-wide recombination for the majority of the cells and lower gamete viability. Notably, homologous pairing is not delayed unlike other telomere binding mutants. Although synapsis initiates earlier, the overall timing of synapsis remains the same, except for a subset of cells that do not exit meiosis I. Together, these results suggest that the strong pulling component of the active chromosome motion promotes homolog pairing fidelity, likely by pulling apart improperly associated regions. Our combined observations are consistent with a model in which telomerase-mediated telomeric anchoring to the nuclear envelope helps engage and properly transmit cytoskeletal forces to chromosomes. Thus, telomerase contributes to efficient chromosome movements leading to normal gamete viability.

cell biology↗