Biology subjects

Mullis, M.

Publications and source records attributed to Mullis, M..

7 recordsLinked to original sources

bioRxiv2026

A multiomic lifespan signature in genetically diverse, diet-restricted mice

Dietary restriction extends lifespan across model organisms, but the plasma molecular changes mediating this effect remain incompletely characterized. We present a longitudinal multiomic analysis of 2,234 plasma samples from 960 Diversity Outbred mice subjected to intermittent fasting or caloric restriction and followed to natural death. Using mass spectrometry, we quantified 1,512 metabolites, lipids, and proteins and mapped their associations with diet, age and longevity. DR-induced molecular changes scale with caloric intake and modulate inflammatory, lipid catabolism, and oxidative stress pathways. Aging showed a biphasic signature with sharp acceleration beyond 85% of lifespan, demarcating terminal decline. Mediation and survival modeling both identified superoxide dismutase (SODE) and vascular cell adhesion molecule (VCAM1) as top lifespan predictors. Genetic analysis revealed 9,599 QTL, nine of which coincided with previously identified lifespan QTLs, and were largely related to immune regulation. These findings provide a rich multiomic and genetic resource for the aging research community.

systems biology↗

bioRxiv2025

Automated Quantitative Assessment of Elastic Fibers in Verhoeff-Van Gieson-Stained Mouse Aorta Histological Images

The mechanical resilience of the aortic wall hinges on the organisation of its concentric elastic laminae, yet histological evaluation of these fibers remains largely qualitative and observer-dependent. We present a fully automated, stain-aware pipeline that transforms Verhoeff-Van Gieson (VVG) whole-slide images of mouse aortae into reproducible, quantitative maps of elastic-fiber architecture. Leveraging optical-density deconvolution to disentangle elastin from collagen, the workflow couples multi-resolution processing with graph-based skeletonisation to preserve gigapixel detail while scaling efficiently. It returns pixel-level measurements of fiber thickness, tortuosity, lamina count and network complexity, together with validation snapshots for transparent quality control. By eliminating observer bias and delivering high-throughput morphometry, our framework enables powered genotype-phenotype screens in genetically diverse mouse populations and provides objective read-outs for interventions aimed at preserving matrix integrity. The modular codebase is open-source, readily extendable to other elastin-rich tissues or stains, and forms a bridge between qualitative microscopy and biomechanical phenotyping--setting the stage for large-scale, data-driven exploration of vascular structure-function relationships.

pathology↗

bioRxiv2024

A global atlas of subsurface microbiomes reveals phylogenetic novelty, large scale biodiversity gradients, and a marine-terrestrial divide

Subsurface environments constitute one of Earths largest habitats for microbial life, yet differences between surface and subsurface microbiomes and between marine and terrestrial microbiomes remain unclear. We analyzed 478 archaeal and 1054 bacterial amplicon sequence datasets and 147 metagenomes from diverse and globally distributed surface and subsurface environments. Taxonomic analyses show that archaeal and bacterial diversity is similar in marine and terrestrial microbiomes at local to global scales. However, community composition greatly differs between marine and terrestrial microbiomes, suggesting a horizontal phylogenetic divide between sea and land that mirrors patterns in plant and animal diversity. In contrast, community composition overlapped from surface to subsurface environments indicating vertical diversity continua rather than a discrete subsurface biosphere. Diversity of terrestrial microbiomes decreases from surface to subsurface environments. Marine subsurface diversity and phylogenetic novelty rivaled (bacteria) or even exceeded (archaea) that of surface environments, suggesting that the marine subsurface holds a considerable and underestimated fraction of Earths archaeal and bacterial diversity. TeaserSubsurface ecosystems within Earths crust and seafloor harbor diverse and distinct microbiomes featuring many unknown lineages.

microbiology↗

bioRxiv2023

Interactions between the gut microbiome, dietary restriction, and aging in genetically diverse mice

The intestinal microbiome changes with age, but the causes and consequences of microbiome aging remain unclear. Furthermore, the gut microbiome has been proposed to mediate the benefit of lifespan- extending interventions such as dietary restriction, but this hypothesis warrants further exploration. Here, by analyzing 2997 metagenomes collected longitudinally from 913 deeply phenotyped, genetically diverse mice, we provide new insights into the interplay between the microbiome, aging, dietary restriction, host genetics, and a wide range of health parameters. First, we find that microbiome uniqueness increases with age across datasets and species. Moreover, age-associated changes are better explained by cumulative exposure to stochastic events (neutral theory) than by the influence of an aging host (selection theory). Second, we unexpectedly find that the majority of microbiome features are significantly heritable and that the amount of variation explained by host genetics is as large as that of aging and dietary restriction. Third, we find that the intensity of dietary restriction parallels the extent of microbiome changes and that dietary restriction does not rejuvenate the microbiome. Lastly, we find that the microbiome is significantly associated with multiple health parameters -- including body composition, immune parameters, and frailty -- but not with lifespan. In summary, this large and multifaceted study sheds light on the factors influencing the microbiome and aspects of host physiology modulated by the microbiome.

microbiology↗

bioRxiv2023

Regulators of health and lifespan extension in genetically diverse mice on dietary restriction

Caloric restriction (CR) delays aging and extends healthy lifespan in multiple species. Alternative forms of dietary restriction (DR) such as intermittent fasting (IF) have drawn significant interest as a more sustainable regimen, but the landscape of longevity-promoting dietary interventions remains largely unexplored. Identifying the most robust, efficacious, and experimentally tractable modes of DR is key to better understanding and implementing effective longevity interventions for human healthspan. To that end, we have performed an extensive assessment of DR interventions, investigating the effects of graded levels of CR (20% and 40%) and IF (1 day and 2 days of fasting per week) on the health and survival of 960 genetically diverse female mice. All interventions extended lifespan, although only CR significantly reduced the mortality doubling time. Notably, IF did not extend lifespan in mice with high pre-intervention bodyweight. We carried out extensive phenotyping to determine the health effects of long-term DR and to better understand the mechanisms driving within-diet heterogeneity in lifespan. The top within-diet predictor of lifespan was the ability of mice to maintain bodyweight through periods of handling, an indicator of stress resilience. Additional predictors of long lifespan include specific changes in immune cells, red blood cell distribution width (RDW), and retention of adiposity in late life. We found that lifespan is heritable (h2 = 0.24), and that genetic background has a larger influence on lifespan than dietary interventions. We identified a significant association for lifespan and RDW on chromosome 18 that explained 4.3% of the diet-adjusted variation in lifespan. Diet-induced changes on metabolic traits, although beneficial, were relatively poor predictors of lifespan, arguing against the long-standing notion that DR works by counteracting the negative effects of obesity. These findings indicate that improving health and extending lifespan are not synonymous and that metabolic parameters may be inappropriate endpoints for evaluating aging interventions in preclinical models and clinical trials.

genetics↗

bioRxiv2023

Genome-scale analysis of interactions between genetic perturbations and natural variation

Interactions between genetic perturbations and segregating loci can cause perturbations to show different phenotypic effects across genetically distinct individuals. To study these interactions on a genome scale in many individuals, we used combinatorial DNA barcode sequencing to measure the fitness effects of 7,700 CRISPRi perturbations targeting 1,712 distinct genes in 169 yeast cross progeny (or segregants). We identified 460 genes whose perturbation has different effects across segregants. Several factors caused perturbations to show variable effects, including baseline segregant fitness, the mean effect of a perturbation across segregants, and interacting loci. We mapped 234 interacting loci and found four hub loci that interact with many different perturbations. Perturbations that interact with a given hub exhibit similar epistatic relationships with the hub and show enrichment for cellular processes that may mediate these interactions. These results suggest that an individuals response to perturbations is shaped by a network of perturbation-locus interactions that cannot be measured by approaches that examine perturbations or natural variation alone.

genetics↗

bioRxiv2021

The interplay of additivity, dominance, and epistasis in a diploid yeast cross

We used a double barcoding system to generate and phenotype a panel of ~200,000 diploid yeast segregants that can be partitioned into hundreds of interrelated families. This experimental design enabled the detection of thousands of genetic interactions and many loci whose effects vary across families. Traits were largely specified by a small number of hub loci with major additive and dominance effects, and pervasive epistasis. Genetic background commonly influenced both the additive and dominance effects of loci, with multiple modifiers typically involved. The most prominent dominance modifier was the mating locus, which had no effect on its own. Our findings show that the interplay between additivity, dominance, and epistasis underlies a complex genotype-to-phenotype map in diploids. One sentence summaryIn diploids, epistasis frequently modifies both additivity and dominance.

genetics↗