Diverse genetic architectures lead to the same cryptic phenotype in a yeast cross

Abstract

Cryptic genetic variants that do not typically influence traits can interact epistatically with each other and mutations to cause unexpected phenotypes. To improve understanding of the genetic architectures and molecular mechanisms that underlie these interactions, we comprehensively dissected the genetic bases of 17 independent instances of the same cryptic colony phenotype in a yeast cross. In eight cases, the phenotype resulted from a genetic interaction between a de novo mutation and one or more cryptic variants. The number and identities of detected cryptic variants depended on the mutated gene. In the nine remaining cases, the phenotype arose without a de novo mutation due to two different classes of higher-order genetic interactions that only involve cryptic variants. Our results may be relevant to other species and disease, as most of the mutations and cryptic variants identified in our study reside in components of a partially conserved and oncogenic signalling pathway.

Modifiers of the Genotype–Phenotype Map: Hsp90 and Beyond

“…Perturbation of Hsp90 was thus thought to uncover cryptic polymorphisms that do not typically show effects, thereby expanding the amount of heritable phenotypic variation in a population [1,2,4–7] (Fig 1A). Because of its role in buffering, Hsp90 began to be regarded as a capacitor that facilitates the accumulation of cryptic genetic variation [1–3,8–12].…”

Genetic suppression: Extending our knowledge from lab experiments to natural populations

“…However, revertants recovered from these screens typically carry multiple mutations and which mutation is the suppressor is not always clear-cut [12, 16]. A straightforward strategy to distinguish a mutation with a phenotypic effect from its co-occurring ‘passenger’ mutations is by using crosses in combination with whole genome sequencing [12, 21]. Recently, such an approach was used to identify more than 200 mutation-suppressor pairs in a single study [12].…”

“…Supporting this view, crossing experiments in budding yeast indicate that most conditional essentialities are mediated by two or more genetic variants [19, 66]. More generally, work on other cases in which a mutation shows different effects across genetic backgrounds has shown that response to mutations can be mediated by higher-order sets of variants that interact not only with a mutation, but also with each other [21, 64, 67–70] and potentially even the environment [68]. However, only a small number of examples of this phenomenon have been comprehensively teased apart at the genetic level [55], leaving open the possibility that other genetic architectures, such as those in which a mutation acts as a hub of pairwise genetic interactions with many different variants [7, 8], could also be important.…”

“…Naturally occurring suppression might involve a number of variants with small effects on molecular function, which may individually alter the structures of mRNAs and peptides, enzymatic activities, or transcript and protein levels in subtle ways (e.g. [21]). Some of these variants may influence individual genes, whereas others may have more global effects, in some cases influencing the expression of a large fraction of the genome.…”

“…For example, recent studies in yeast [19–21] and humans [22, 23] have shown that the ability to suppress particular large effect and Mendelian mutations can segregate within populations. At present, the extent to which lab studies on suppression relate to these cases of naturally occurring suppression is unclear.…”