Pervasive cryptic epistasis in molecular evolution.
Pervasive cryptic epistasis in molecular evolution.
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DOI：
10.1371/journal.pgen.1001162
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发表时间：
2010-10-21
期刊：
影响因子：
4.5
通讯作者：
Dean AM
中科院分区：
文献类型：
--
作者：
Lunzer M;Golding GB;Dean AM
The functional effects of most amino acid replacements accumulated during molecular evolution are unknown, because most are not observed naturally and the possible combinations are too numerous. We created 168 single mutations in wild-type Escherichia coli isopropymalate dehydrogenase (IMDH) that match the differences found in wild-type Pseudomonas aeruginosa IMDH. 104 mutant enzymes performed similarly to E. coli wild-type IMDH, one was functionally enhanced, and 63 were functionally compromised. The transition from E. coli IMDH, or an ancestral form, to the functional wild-type P. aeruginosa IMDH requires extensive epistasis to ameliorate the combined effects of the deleterious mutations. This result stands in marked contrast with a basic assumption of molecular phylogenetics, that sites in sequences evolve independently of each other. Residues that affect function are scattered haphazardly throughout the IMDH structure. We screened for compensatory mutations at three sites, all of which lie near the active site and all of which are among the least active mutants. No compensatory mutations were found at two sites indicating that a single site may engage in compound epistatic interactions. One complete and three partial compensatory mutations of the third site are remote and lie in a different domain. This demonstrates that epistatic interactions can occur between distant (>20Å) sites. Phylogenetic analysis shows that incompatible mutations were fixed in different lineages. Many bioinformatics and functional genomics predictions are derived from evolutionary patterns of amino acid replacement in protein sequence alignments. Most computational methods assume that replacements in one sequence will be tolerated in all related sequences. Here, we evaluate—by direct experiment—the functional impact of amino acid replacements accumulated during the course of evolution. Our initial results show that cryptic interactions among amino acid replacements are common and that most are deleterious. This result has implications not only for the evolution of function, recombination, sex, dominance, robustness, disease, and even speciation, but also for practical applications—in conservation biology (e.g. to decide which organisms to preserve) and in vaccine design (e.g. using consensus or reconstructed ancestral sequences). Analyzing one interaction in detail, we find that compensatory mutations need not lie in close proximity to the original mutation as generally supposed. This result suggests that unsuspected structure–function relationships can be revealed by analyzing patterns of site-to-site interactions among amino acid replacements in evolution.
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DOI：
10.1038/nrg2579
发表时间：
2009-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Cordell HJ
通讯作者：
Cordell HJ
影响因子：
5.6
作者：
Bershtein, Shimon;Goldin, Korina;Tawfik, Dan S.
通讯作者：
Tawfik, Dan S.
影响因子：
10.7
作者：
Dutheil, J;Pupko, T;Galtier, N
通讯作者：
Galtier, N
影响因子：
10.7
作者：
Field, Steven F.;Matz, Mikhail V.
通讯作者：
Matz, Mikhail V.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y