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Natural selection of protein structural and functional properties: a single nucleotide polymorphism perspective.

ABSTRACT: BACKGROUND: The rates of molecular evolution for protein-coding genes depend on the stringency of functional or structural constraints. The Ka/Ks ratio has been commonly used as an indicator of selective constraints and is typically calculated from interspecies alignments. Recent accumulation of single nucleotide polymorphism (SNP) data has enabled the derivation of Ka/Ks ratios for polymorphism (SNP A/S ratios). RESULTS: Using data from the dbSNP database, we conducted the first large-scale survey of SNP A/S ratios for different structural and functional properties. We confirmed that the SNP A/S ratio is largely correlated with Ka/Ks for divergence. We observed stronger selective constraints for proteins that have high mRNA expression levels or broad expression patterns, have no paralogs, arose earlier in evolution, have natively disordered regions, are located in cytoplasm and nucleus, or are related to human diseases. On the residue level, we found higher degrees of variation for residues that are exposed to solvent, are in a loop conformation, natively disordered regions or low complexity regions, or are in the signal peptides of secreted proteins. Our analysis also revealed that histones and protein kinases are among the protein families that are under the strongest selective constraints, whereas olfactory and taste receptors are among the most variable groups. CONCLUSION: Our study suggests that the SNP A/S ratio is a robust measure for selective constraints. The correlations between SNP A/S ratios and other variables provide valuable insights into the natural selection of various structural or functional properties, particularly for human-specific genes and constraints within the human lineage.

SUBMITTER: Liu J

PROVIDER: S-EPMC2643940 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Natural selection of protein structural and functional properties: a single nucleotide polymorphism perspective.

Liu Jinfeng J Zhang Yan Y Lei Xingye X Zhang Zemin Z

Genome biology 20080408 4

<h4>Background</h4>The rates of molecular evolution for protein-coding genes depend on the stringency of functional or structural constraints. The Ka/Ks ratio has been commonly used as an indicator of selective constraints and is typically calculated from interspecies alignments. Recent accumulation of single nucleotide polymorphism (SNP) data has enabled the derivation of Ka/Ks ratios for polymorphism (SNP A/S ratios).<h4>Results</h4>Using data from the dbSNP database, we conducted the first la ...[more]

PMID: 18397526

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Project description:The combined actions of natural selection, mutation, and recombination forge the landscape of genetic variation across genomes. One frequently observed manifestation of these processes is a positive association between neutral genetic variation and local recombination rates. Two selective mechanisms and/or recombination-associated mutation (RAM) could generate this pattern, and the relative importance of these alternative possibilities remains unresolved generally. Here we quantify nucleotide differences within populations, between populations, and between species to test for genome-wide effects of selection and RAM in the partially selfing nematode Caenorhabditis briggsae. We find that nearly half of genome-wide variation in nucleotide polymorphism is explained by differences in local recombination rates. By quantifying divergence between several reproductively isolated lineages, we demonstrate that ancestral polymorphism generates a spurious signal of RAM for closely related lineages, with implications for analyses of humans and primates; RAM is, at most, a minor factor in C. briggsae. We conclude that the positive relation between nucleotide polymorphism and the rate of crossover represents the footprint of natural selection across the C. briggsae genome and demonstrate that background selection against deleterious mutations is sufficient to explain this pattern. Hill-Robertson interference also leaves a signature of more effective purifying selection in high-recombination regions of the genome. Finally, we identify an emerging contrast between widespread adaptive hitchhiking effects in species with large outcrossing populations (e.g., Drosophila) versus pervasive background selection effects on the genomes of organisms with self-fertilizing lifestyles and/or small population sizes (e.g., Caenorhabditis elegans, C. briggsae, Arabidopsis thaliana, Lycopersicon, human). These results illustrate how recombination, mutation, selection, and population history interact in important ways to shape molecular heterogeneity within and between genomes.

Project description:BackgroundTo characterize the genetic basis of phenotypic evolution, numerous studies have identified individual genes that have likely evolved under natural selection. However, phenotypic changes may represent the cumulative effect of similar evolutionary forces acting on functionally related groups of genes. Phylogenetic analyses of divergent yeast species have identified functional groups of genes that have evolved at significantly different rates, suggestive of differential selection on the functional properties. However, due to environmental heterogeneity over long evolutionary timescales, selection operating within a single lineage may be dramatically different, and it is not detectable via interspecific comparisons alone. Moreover, interspecific studies typically quantify selection on protein-coding regions using the D(n)/D(s) ratio, which cannot be extended easily to study selection on noncoding regions or synonymous sites. The population genetic-based analysis of selection operating within a single lineage ameliorates these limitations.FindingsWe investigated selection on several properties associated with genes, promoters, or polymorphic sites, by analyzing the derived allele frequency spectrum of single nucleotide polymorphisms (SNPs) in 28 strains of Saccharomyces paradoxus. We found evidence for significant differential selection between many functionally relevant categories of SNPs, underscoring the utility of function-centric approaches for discovering signatures of natural selection. When comparable, our findings are largely consistent with previous studies based on interspecific comparisons, with one notable exception: our study finds that mutations from an ancient amino acid to a relatively new amino acid are selectively disfavored, whereas interspecific comparisons have found selection against ancient amino acids. Several of our findings have not been addressed through prior interspecific studies: we find that synonymous mutations from preferred to unpreferred codons are selected against and that synonymous SNPs in the linker regions of proteins are relatively less constrained than those within protein domains.ConclusionsWe present the first global survey of selection acting on various functional properties in S. paradoxus. We found that selection pressures previously detected over long evolutionary timescales have also shaped the evolution of S. paradoxus. Importantly, we also make novel discoveries untenable via conventional interspecific analyses.

Dataset Information

Natural selection of protein structural and functional properties: a single nucleotide polymorphism perspective.

Publications

Natural selection of protein structural and functional properties: a single nucleotide polymorphism perspective.

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