Experimental assay of a fitness landscape on a macroevolutionary scale

Characterization of the fitness landscape, a representation of fitness for a large set of genotypes, is key to understanding how genetic information is interpreted to create functional organisms. Here, we reconstruct the evolutionarily-relevant segment of the fitness landscape of His3, a gene coding for an enzyme in the histidine synthesis pathway, focusing on combinations of amino acid states found at orthologous sites of extant species. We find that the His3 fitness landscape is dominated by synergistic epistasis, such that the cumulative effect of amino acid substitutions causes a dramatic decline in fitness. Furthermore, in 63% of sites substitutions were strongly positive in one genetic background and strongly negative in another, with 41% of sites showing reciprocal sign epistasis. This sign epistasis, present in proportionally few genotypes, was caused by simultaneous interaction of multiple sites with demonstrating a complex multidimensional nature of the His3 fitness landscape.对适应度景观（fitness landscape）——即针对海量基因型的适应度进行表征的量化形式——进行刻画，是解析遗传信息如何被解读以构建功能性有机体的核心关键。本研究重构了组氨酸合成通路中编码酶的基因His3的适应度景观中与进化相关的片段，研究聚焦于现存物种同源位点上存在的氨基酸状态组合。研究发现，His3的适应度景观以协同上位性（synergistic epistasis）为主导，氨基酸替换的累积效应会导致适应度出现显著下降。此外，在63%的位点中，某一遗传背景下的氨基酸替换呈现强正向适应度效应，而在另一遗传背景下则呈现强负向适应度效应；其中41%的位点表现为互反符号上位性（reciprocal sign epistasis）。这种仅在少数基因型中存在的符号上位性，由多位点的同时相互作用所引发，这也彰显出His3适应度景观具有复杂的多维本质。