Diminishing returns epistasis among beneficial mutations decelerates adaptation

Abstract

Epistasis has substantial impacts on evolution, in particular, the rate of adaptation. We generated combinations of beneficial mutations that arose in a lineage during rapid adaptation of a bacterium whose growth depended on a newly introduced metabolic pathway. The proportional selective benefit for three of the four loci consistently decreased when they were introduced onto more fit backgrounds. These three alleles all reduced morphological defects caused by expression of the foreign pathway. A simple theoretical model segregating the apparent contribution of individual alleles to benefits and costs effectively predicted the interactions between them. These results provide the first evidence that patterns of epistasis may differ for within- and between-gene interactions during adaptation and that diminishing returns epistasis contributes to the consistent observation of decelerating fitness gains during adaptation.

Figure 1

Mutational network and distinct patterns of epistasis for mutations between and within genes. (A) Each node displays the allelic composition (fghA, pntAB, gshA, GB) of a given genotype (bold) and its fitness. Ancestral and evolved alleles are indicated by 0 and 1, respectively, leading from the ancestral EM strain (0000) to the evolved EVO isolate (1111). Each edge indicates an allelic replacement (fghA, orange; pntAB, blue; gshA, green; GB, red) and the corresponding selective coefficient. Variation in relative selective effect (normalized to max s_i) of each allele as a function of the fitness of the background was introduced into for: (B) between-gene epistasis in Methylobacterium (background fitness normalized from EM = 0 to max =1; colors as in A); or (C) within-gene epistasis for E. coli beta lactamase (background fitness normalized to max MIC = 1; log scale for visualization; squares indicate deleterious effects), data from (5).

Figure 2

Morphological aberrations caused by expression of the foreign pathway. Distinct cellular morphologies of (B) WT, or EM ancestor showing (C) curved, (D) branched, or (E) elongated cells. (F) Mean cell length and proportion of elongated (black), branched (white), and curved (grey) cells for various strains. Plasmid pCM410 expresses the foreign pathway while pCM160 is an empty control plasmid.

Figure 3

Antagonistic trend of epistasis detected from the data captured by the benefit-cost model. (A–D) Plots of measured (open circles) and predicted (solid triangles) selective coefficients s for each of the four evolved alleles, respectively, versus the fitness of the background onto which the allele was introduced. Dashed lines indicate selective advantages for each allele on the ancestral background (i.e., expectation for no epistasis: W_ij = λ_iλ_jW_o).