Rare Variants in Hypermutable Genes Underlie Common Morphology and Growth Traits in WildSaccharomyces paradoxus

Abstract

Understanding the molecular basis of common traits is a primary challenge of modern genetics. One model holds that rare mutations in many genetic backgrounds may often phenocopy one another, together explaining the prevalence of the resulting trait in the population. For the vast majority of phenotypes, the role of rare variants and the evolutionary forces that underlie them are unknown. In this work, we use a population of Saccharomyces paradoxus yeast as a model system for the study of common trait variation. We observed an unusual, flocculation and invasive-growth phenotype in one-third of S. paradoxus strains, which were otherwise unrelated. In crosses with each strain in turn, these morphologies segregated as a recessive Mendelian phenotype, mapping either to IRA1 or to IRA2, yeast homologs of the hypermutable human neurofibromatosis gene NF1. The causal IRA1 and IRA2 haplotypes were of distinct evolutionary origin and, in addition to their morphological effects, associated with hundreds of stressresistance and growth traits, both beneficial and disadvantageous, across S. paradoxus. Single-gene molecular genetic analyses confirmed variant IRA1 and IRA2 haplotypes as causal for these growth characteristics, many of which were independent of morphology. Our data make clear that common growth and morphology traits in yeast result from a suite of variants in master regulators, which function as a mutation-driven switch between phenotypic states.A primary goal of modern genetics is to understand the molecular basis of traits that segregate at high frequency in populations. Toward this end, hundreds of studies have sought to map causal genes, using tests for allele sharing among affected but unrelated individuals. Against a backdrop of recent successes in fruit fly and plant populations (Atwell et al. 2010;Brachi et al. 2010;Chan et al. 2011;Filiault and Maloof 2012;Mackay et al. 2012;Magwire et al. 2012;Weber et al. 2012;Dunn et al. 2013), association mapping in many systems has yielded loci that explain only a small part of the variation in a given trait across individuals (McCarthy et al. 2008). The latter challenges have motivated the proposal that the bulk of common phenotypic variation may be attributable to rare, highly penetrant mutations (Dickson et al. 2010;McClellan and King 2010; Veltman and Brunner 2012), including recurrent variation at hypermutable loci (Shen et al. 1996;Chan et al. 2010;Michaelson et al. 2012). As yet, the genetic architecture of most common traits remains unknown, and experimental systems in which to investigate the principles of common trait variation have been at a premium in the literature.Saccharomyces yeasts have long been a workhorse of the molecular-genetic research community, with resources now becoming available for analyses of population-level variation (Liti et al. 2009). Among the most well-studied phenotypes in the classic yeast literature are cell-clumping and filamentation-like behaviors in certain laboratory strains, which serve as models for fungal pa...

Mapping the architecture of regulatory variation provides insights into the evolution of complex traits

“…We found that most activators in this pathway are expressed at higher levels in S. paradoxus, while inhibitors expression is higher in S. cerevisiae ( Fig 5D). Variants of one such inhibitor, Ira2, was previously reported to be involved in morphological variation in wild S. paradoxus isolates [21], supporting the notion that these expression variations could have a large phenotypic effect.…”

“…Still, evolutionary related species that express the same set of proteins differ in complex phenotypes, allowing non-motile cells to forage for nutrients [17][18][19]. By contrast, S. paradoxus (CBS432), a close relative of S. cerevisiae, becomes filamentous even in rich media [20,21]. Therefore, the two species activate distinct differentiation programs when presented with the same condition, providing a model for evolutionary recruitment.…”

Polygenic analysis of very high acetic acid tolerance in the yeast Saccharomyces cerevisiae reveals a complex genetic background and several new causative alleles

“…The IRA2 allele of MS164 has an insertion of eight nucleotides at position 820 of 9248 nucleotides, creating a stop codon at position 880, and thus likely encoding a strongly truncated inactive protein. Although IRA2 likely constitutes the causative allele in the gene block 3 in view of the frameshift mutation and the previous reports linking IRA2 polymorphisms to differences in stress tolerance [42,[63][64][65][66][67][68], its involvement appears more complex with possible interaction with one or more neighboring genetic elements.…”

The Valley-of-Death: Reciprocal sign epistasis constrains adaptive trajectories in a constant, nutrient limiting environment

“…Significantly, we have shown previously that IRA1/2 and MTH1 mutations can arise in the same background, and attain high frequency [46]. It is noteworthy that allelic variation at IRA1 and IRA2, which are homologs of the hypermutable human neurofibromatosis gene NF1 , results in diverse morphological and growth phenotypes in Saccharomyces paradoxus [50]. …”