Biology subjects

Mullis, M. N.

Publications and source records attributed to Mullis, M. N..

4 recordsLinked to original sources

bioRxiv2025

Genetic correlation-guided mega-analysis of DO mice provides mechanistic insight and candidate genes for age-related pathologies

Diversity Outbred (DO) mice are a powerful model system for mapping complex traits due to their high genetic diversity and mapping resolution. However, while there are extensive tools available for standard genetic analysis in DO mice, fewer techniques have been implemented to facilitate integrated, cross-study analysis. Here, we implement Haseman-Elston regression to estimate genetic correlations among 7,233 phenotypes measured across eleven independent DO mouse studies. We used this network of genetic correlations to cluster phenotypes according to shared genetics, which enhanced the power to detect quantitative trait loci (QTL). This approach empowered the detection of 884 QTL for 383 meta-phenotypes, explaining an average of 40.36% of the total genetic variance per mega-analysis. We leveraged this network for insights into specific areas of biology, including lifespan, frailty, immune composition, histological and functional lung phenotypes, and histological phenotypes of the aorta. We found the genetics of lifespan to share limited correlation with the genetics of frailty but stronger correlation with the genetics of immune cell composition. Additionally, mega-analyses driven by genetic correlations identified candidate genes (e.g. Cdkn2b) associated with degraded extracellular matrix in the aorta. Finally, an ensemble of genetic analyses implicated pulmonary neuroendocrine cell signaling and/or differentiation as a key driver of multiple lung pathophenotypes.

genetics↗

bioRxiv2024

Analysis of lifespan across Diversity Outbred mouse studies identifies multiple longevity-associated loci

Lifespan is an integrative phenotype whose genetic architecture is likely to highlight multiple processes with high impact on health and aging. Here, we conduct a genetic meta-analysis of longevity in Diversity Outbred (DO) mice that includes 2,444 animals from three independently conducted lifespan studies. We identify six loci that contribute significantly to lifespan independently of diet and drug treatment, one of which also influences lifespan in a sex-dependent manner, as well as an additional locus with a diet-specific effect on lifespan. Collectively, these loci explain over half of the estimated heritable variation in lifespan across these studies and provide insight into the genetic architecture of lifespan in DO mice.

genetics↗

bioRxiv2022

Complex genetics cause and constrain fungal persistence in different parts of the mammalian body

Determining how genetic polymorphisms enable certain fungi to persist in mammalian hosts can improve understanding of opportunistic fungal pathogenesis, a source of substantial human morbidity and mortality. We examined the genetic basis of fungal persistence in mice using a cross between a clinical isolate and the lab reference strain of the budding yeast Saccharomyces cerevisiae. Employing chromosomally-encoded barcodes, we tracked the relative abundances of 822 genotyped, haploid segregants in multiple organs over time and performed linkage mapping of their persistence in hosts. Detected loci showed a mix of general and antagonistically pleiotropic effects across organs. General loci showed similar effects across all organs, while antagonistically pleiotropic loci showed contrasting effects in the brain and the kidneys, liver, and spleen. Persistence in an organ required both generally beneficial alleles and organ-appropriate pleiotropic alleles. This genetic architecture resulted in many segregants persisting in the brain or in non-brain organs, but few segregants persisting in all organs. These results show complex combinations of genetic polymorphisms collectively cause and constrain fungal persistence in different parts of the mammalian body.

genetics↗

bioRxiv2020

Genetic architecture of a mutation's expressivity and penetrance

Genetic background often influences the phenotypic consequences of mutations, resulting in variable expressivity. How standing genetic variants collectively cause this phenomenon is not fully understood. Here, we comprehensively identify loci in a budding yeast cross that impact the growth of individuals carrying a spontaneous missense mutation in the nuclear-encoded mitochondrial ribosomal gene MRP20. Initial results suggested that a single large effect locus influences the mutations expressivity, with one allele causing inviability in mutants. However, further experiments revealed this simplicity was an illusion. In fact, many additional loci shape the mutations expressivity, collectively leading to a wide spectrum of mutational responses. These results exemplify how complex combinations of alleles can produce a diversity of qualitative and quantitative responses to the same mutation.

genetics↗