Population-level survey of loss-of-function mutations revealed that background dependent fitness genes are rare and functionally related in yeast

Abstract

In natural populations, the same mutation can lead to different phenotypic outcomes due to the genetic variation that exists among individuals. Such genetic background effects are commonly observed, including in the context of many human diseases. However, systematic characterization of these effects at the species level is still lacking to date. Here, we sought to comprehensively survey background-dependent traits associated with gene loss-of-function (LoF) mutations in 39 natural isolates of Saccharomyces cerevisiae using a transposon saturation strategy. By analyzing the modeled fitness variability of a total of 4,469 genes, we found that 15% of them, when impacted by a LoF mutation, exhibited a significant gain- or loss-of-fitness phenotype in certain natural isolates compared to the reference strain S288C. Out of these 632 genetic background-dependent fitness genes identified, a total of 2/3 show a continuous variation across the population while 1/3 are specific to a single genetic background. Genes related to mitochondrial function are significantly overrepresented in the set of genes showing a continuous variation and display a potential functional rewiring with other genes involved in transcription and chromatin remodeling as well as in nuclear-cytoplasmic transport. Such rewiring effects are likely modulated by both the genetic background and the environment. While background-specific cases are rare and span diverse cellular processes, they can be functionally related at the individual level. All background-dependent fitness genes tend to have an intermediate connectivity in the global genetic interaction network and have shown relaxed selection pressure at the population level, highlighting their potential evolutionary characteristics.

Heme Oxygenase-1 (HMX1) Loss of Function Increases the In-Host Fitness of the Saccharomyces ‘boulardii’ Probiotic Yeast in a Mouse Fungemia Model

“…These results are reminiscent of the virulence data presented by McCullough et al [ 73 ], who showed, using two batches of the same product, that virulence (defined as growth in the host) may be variable. Such differences in the genetic backgrounds may explain the different outcomes of the iron starvation experiments and the mice infection in this study, detailed below, similarly to how a recent large-scale study showed that variations in S. cerevisiae genetic backgrounds substantially affect gain- or loss-of-fitness effects of loss-of-function mutations [ 74 ].…”

Evolutionary trajectories are contingent on mitonuclear interactions

“…In these cells, despite a strongly deleterious effect on organismal fitness, copies of the mitochondrial genome deleted at loci essential for respiration may outcompete healthy copies thanks to their higher replication origin density (de Zamaroczy et al 1981; Mangin et al 1983; Bernardi 2005). Furthermore, deletion screens in yeasts have also repeatedly identified signals of frequent essentiality switching among genes involved in mitochondrial functions, both across (Kim et al 2010) and within species (Caudal et al 2022; Chen et al 2022), suggesting enhanced evolvability at these loci. In summary, because of unique characteristics and selection pressures, the rate of evolution tends to be higher in the mitochondrial genome than in the nuclear genome, with a critical influence on genetic divergence, speciation, reproductive strategies, and morphology (Hill 2015).…”