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How Often Do Protein Genes Navigate Valleys of Low Fitness?

ABSTRACT: To escape from local fitness peaks, a population must navigate across valleys of low fitness. How these transitions occur, and what role they play in adaptation, have been subjects of active interest in evolutionary genetics for almost a century. However, to our knowledge, this problem has never been addressed directly by considering the evolution of a gene, or group of genes, as a whole, including the complex effects of fitness interactions among multiple loci. Here, we use a precise model of protein fitness to compute the probability P ( s , Δ t ) that an allele, randomly sampled from a population at time t, has crossed a fitness valley of depth s during an interval t - Δ t , t in the immediate past. We study populations of model genes evolving under equilibrium conditions consistent with those in mammalian mitochondria. From this data, we estimate that genes encoding small protein motifs navigate fitness valleys of depth 2 N s ≳ 30 with probability P ≳ 0 . 1 on a time scale of human evolution, where N is the (mitochondrial) effective population size. The results are consistent with recent findings for Watson⁻Crick switching in mammalian mitochondrial tRNA molecules.

SUBMITTER: Nelson ED

PROVIDER: S-EPMC6523826 | biostudies-other | 2019 Apr

REPOSITORIES: biostudies-other

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How Often Do Protein Genes Navigate Valleys of Low Fitness?

Nelson Erik D ED Grishin Nick V NV

Genes 20190408 4

To escape from local fitness peaks, a population must navigate across valleys of low fitness. How these transitions occur, and what role they play in adaptation, have been subjects of active interest in evolutionary genetics for almost a century. However, to our knowledge, this problem has never been addressed directly by considering the evolution of a gene, or group of genes, as a whole, including the complex effects of fitness interactions among multiple loci. Here, we use a precise model of p ...[more]

PMID: 30965625

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Project description:BackgroundSingle nucleotide substitutions in protein-coding genes can be divided into synonymous (S), with little fitness effect, and non-synonymous (N) ones that alter amino acids and thus generally have a greater effect. Most of the N substitutions are affected by purifying selection that eliminates them from evolving populations. However, additional mutations of nearby bases potentially could alleviate the deleterious effect of single substitutions, making them subject to positive selection. To elucidate the effects of selection on double substitutions in all codons, it is critical to differentiate selection from mutational biases.ResultsWe addressed the evolutionary regimes of within-codon double substitutions in 37 groups of closely related prokaryotic genomes from diverse phyla by comparing the fractions of double substitutions within codons to those of the equivalent double S substitutions in adjacent codons. Under the assumption that substitutions occur one at a time, all within-codon double substitutions can be represented as "ancestral-intermediate-final" sequences (where "intermediate" refers to the first single substitution and "final" refers to the second substitution) and can be partitioned into four classes: (1) SS, S intermediate-S final; (2) SN, S intermediate-N final; (3) NS, N intermediate-S final; and (4) NN, N intermediate-N final. We found that the selective pressure on the second substitution markedly differs among these classes of double substitutions. Analogous to single S (synonymous) substitutions, SS double substitutions evolve neutrally, whereas analogous to single N (non-synonymous) substitutions, SN double substitutions are subject to purifying selection. In contrast, NS show positive selection on the second step because the original amino acid is recovered. The NN double substitutions are heterogeneous and can be subject to either purifying or positive selection, or evolve neutrally, depending on the amino acid similarity between the final or intermediate and the ancestral states.ConclusionsThe results of the present, comprehensive analysis of the evolutionary landscape of within-codon double substitutions reaffirm the largely conservative regime of protein evolution. However, the second step of a double substitution can be subject to positive selection when the first step is deleterious. Such positive selection can result in frequent crossing of valleys on the fitness landscape.

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How Often Do Protein Genes Navigate Valleys of Low Fitness?

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How Often Do Protein Genes Navigate Valleys of Low Fitness?

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