The Genomic Architecture of Interactions Between Natural Genetic Polymorphisms and Environments in Yeast Growth

Abstract

Gene-environment interaction (G×E) refers to the phenomenon that the same mutation has different phenotypic effects in different environments. Although quantitative trait loci (QTLs) exhibiting G×E have been reported, little is known about the general properties of G×E, and those of its underlying QTLs. Here, we use the genotypes of 1005 segregants from a cross between two Saccharomyces cerevisiae strains, and the growth rates of these segregants in 47 environments, to identify growth rate QTLs (gQTLs) in each environment, and QTLs that have different growth effects in each pair of environments (g×eQTLs) . The average number of g×eQTLs identified between two environments is 0.58 times the number of unique gQTLs identified in these environments, revealing a high abundance of G×E. Eighty-seven percent of g×eQTLs belong to gQTLs, supporting the practice of identifying g×eQTLs from gQTLs. Most g×eQTLs identified from gQTLs have concordant effects between environments, but, as the effect size of a mutation in one environment enlarges, the probability of antagonism in the other environment increases. Antagonistic g×eQTLs are enriched in dissimilar environments. Relative to gQTLs, g×eQTLs tend to occur at intronic and synonymous sites. The gene ontology (GO) distributions of gQTLs and g×eQTLs are significantly different, as are those of antagonistic and concordant g×eQTLs. Simulations based on the yeast data showed that ignoring G×E causes substantial missing heritability. Together, our findings reveal the genomic architecture of G×E in yeast growth, and demonstrate the importance of G×E in explaining phenotypic variation and missing heritability.

Keywords: QTL mapping; Saccharomyces cerevisiae; antagonism; missing heritability; pleiotropy.

Figure 1

Examples of gQTLs and g×eQTLs. (A) Genomic distributions of detected gQTLs in HydPer and IndAci, and g×eQTLs between the two environments. The effect size of a gQTL under the environment where it is identified is shown on the Y-axis, while its genomic position is shown on the X-axis. A class I g×eQTL is circled at the triangle if it is a gQTL only in HydPer, and circled at the star if it is a gQTL only in IndAci, but is circled on the X-axis if it is a gQTL in both environments. Observed class II g×eQTLs are indicated on the X-axis. (B–F) Mean growth rates of segregants carrying the two alternative alleles at various gQTLs or g×eQTLs. SE are too small to see. (B) A class I antagonistic g×eQTL that is a gQTL (SNP: 24637) in both 5FluUra and CalChl. (C) A class I concordant g×eQTL (SNP: 24651) that is a gQTL in both 5FluUra and Xylose. (D) A class I g×eQTL that is a gQTL (SNP: 4821) in LitChl but not 5FluUra. (E) A gQTL (SNP: 2277) in 5FluUra that does not show significant G×E. (F) A class II antagonistic g×eQTL (SNP: 3512), which is a gQTL in neither 5FluCyt nor HydPer.

Figure 2

Genomic distributions of (A) gQTLs, (B) class I g×eQTLs, and (C) observed class II g×eQTLs. The genome is divided into 7500-nucleotide bins. The total number of gQTLs from all 47 environments, the total number of class I g×eQTLs from all 1081 pairs of environments, and the total number of observed class II g×eQTLs from all 1081 pairs of environments are plotted for each bin. The 16 chromosomes are colored differently. Three genes referred to in the main text are marked according to their genomic locations.

Figure 3

Relative numbers of g×eQTLs and gQTLs from all pairs of environments. (A) Frequency distribution of the fraction of unique gQTLs identified from two individual environments that are class I g×eQTLs for the pair of environments. (B) Frequency distribution of the fraction of all g×eQTLs (i.e., class I + extrapolated class II) that are class I. (C) Frequency distribution of the ratio between the number of all g×eQTLs for a pair of environments and the total number of unique gQTLs identified in the two environments.

Figure 4

Patterns of antagonistic G×E. (A) Frequency distribution of the fraction of class I g×eQTLs that are antagonistic. (B) gQTLs with large effects in the environments where they are identified are more likely than small-effect gQTLs to have antagonistic effects in another environment. Error bars indicate one SE. The rank correlation ρ and associated P-value are based on the unbinned data. (C) Environments that are under-represented with antagonistic g×eQTLs with other environments. The X-axis shows the number of environments with which an environment listed on the Y-axis has no antagonistic class I g×eQTL. (D) Environments that are enriched with antagonistic g×eQTLs with other environments. The X-axis shows the number of environments with which an environment listed on the Y-axis has >50% of class I g×eQTLs being antagonistic.

Figure 5

Ignoring G×E causes missing heritability. (A) The genomic distributions of gQTLs identified from phenotypes measured in one environment and those measured in two environments (50% segregants from each environment), respectively. Y-axis shows the fraction of phenotypic variance explained by the identified gQTLs under each mapping scheme. E effect, environmental effect. Without controlling E effect means that neither environmental effect nor G×E is considered in mapping. Controlling E effect means environmental effect but not G×E is considered in mapping. (B) Average faction of phenotypic variance explained by gQTLs (r²) decreases as the phenotypic data used originate from more environments. The average narrow-sense heritability is 0.55. 2E, phenotypic data are from a mixture of two environments; 5E, phenotypic data are from a mixture of five environments; 10E, phenotypic data are from a mixture of 10 environments. Results are summarized from 100 random sets of 2, 5, and 10 environments, respectively. (C) Frequency distribution of the distance between gQTLs identified using mixed phenotypes from two environments and those identified using phenotypes from individual environments. The results are summarized from 100 random pairs of environments.