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

Abstract

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. Here, we show traits are largely specified by a small number of hub loci with major additive and dominance effects, and pervasive epistasis. Genetic background commonly influences both the additive and dominance effects of loci, with multiple modifiers typically involved. The most prominent dominance modifier in our data is the mating locus, which has 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.

Sex-specific Associations in the Hybrid Mouse Diversity Panel help define genetic architecture

“…However, the additive component was always the largest component of total heritability. The contribution of non-additive or dominance factors to total heritability is consistent with many prior studies, as is the smaller contribution relative to additive effects 12,[15][16][17][18] . However, it remains possible that a portion of the additive effects are in fact due to their underlying effect in interactions 19,20 .…”

“…Integration of this omnigenic model may lead to more accurate genetic models for complex traits, for which current models fail to accurately account for most heritability and similarly fail to accurately predict trait outcomes based on polygenic risk scored in distinct and diverse populations [15][16][17][29][30][31] . These studies were made possible by performing sex-stratified analyses, instead of adjusting for sex as is typically done in most GWAS models.…”

Dominance is common in mammals and is associated with trans-acting gene expression and alternative splicing

“…We have demonstrated here that understanding the prevalence, causes and consequences of genetic dominance not only clarifies the genetic architecture of complex traits [47,51,81] but also improves the power to detect associations. Our work complements earlier studies that have improved genomic prediction in theoretical simulation studies [82,83] and in practical breeding applications for animals [84,85] and plants [86,87].…”

Automated quantitative trait locus analysis (AutoQTL)

“…In future experiments, we aim to model features that have strong main effects and are also involved in epistatic interactions with other loci. It has been observed that loci with strong main effects are also epistatic hubs, involved in many 2- and 3-way epistatic interactions in the genome [ 3 ]. We hope to discover these epistatic hubs as well as epistatic loci without large main effects in future experiments using AutoQTL.…”

“…A recent large-scale study in Saccharomyces cerevisiae identified that of the 61% broad-sense heritability detected, 21% was due to non-additive effects (dominance deviations and epistasis) [ 3 ]. In a related previous study, also in S. cerevisiae , of the 91.7% of the phenotypic variance attributed to genetic sources, non-additive effects accounted for 18.7% [ 4 ] Furthermore, non-additive QTL outnumbered additive QTL 3:1.…”