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.

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.

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

In diploid species, genetic loci can show additive, dominance, and epistatic effects. To characterize the contributions of these different types of genetic effects to heritable traits, we use a double barcoding system to generate and phenotype a panel of ~200,000 diploid yeast strains that can be partitioned into hundreds of interrelated families. This experiment enables the detection of thousands of epistatic loci, many whose effects vary across families.

Genetic basis of a spontaneous mutation's expressivity.

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.

The complex underpinnings of genetic background effects.

Genetic interactions between mutations and standing polymorphisms can cause mutations to show distinct phenotypic effects in different individuals. To characterize the genetic architecture of these so-called background effects, we genotype 1411 wild-type and mutant yeast cross progeny and measure their growth in 10 environments. Using these data, we map 1086 interactions between segregating loci and 7 different gene knockouts.