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Remarkable selective constraints on exonic dinucleotide repeats.

ABSTRACT: Long dinucleotide repeats found in exons present a substantial mutational hazard: mutations at these loci occur often and generate frameshifts. Here, we provide clear and compelling evidence that exonic dinucleotides experience strong selective constraint. In humans, only 18 exonic dinucleotides have repeat lengths greater than six, which contrasts sharply with the genome-wide distribution of dinucleotides. We genotyped each of these dinucleotides in 200 humans from eight 1000 Genomes Project populations and found a near-absence of polymorphism. More remarkably, divergence data demonstrate that repeat lengths have been conserved across the primate phylogeny in spite of what is likely considerable mutational pressure. Coalescent simulations show that even a very low mutation rate at these loci fails to explain the anomalous patterns of polymorphism and divergence. Our data support two related selective constraints on the evolution of exonic dinucleotides: a short-term intolerance for any change to repeat length and a long-term prevention of increases to repeat length. In general, our results implicate purifying selection as the force that eliminates new, deleterious mutants at exonic dinucleotides. We briefly discuss the evolution of the longest exonic dinucleotide in the human genome--a 10 x CA repeat in fibroblast growth factor receptor-like 1 (FGFRL1)--that should possess a considerably greater mutation rate than any other exonic dinucleotide and therefore generate a large number of deleterious variants.

SUBMITTER: Haasl RJ

PROVIDER: S-EPMC4550590 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Remarkable selective constraints on exonic dinucleotide repeats.

Haasl Ryan J RJ Payseur Bret A BA

Evolution; international journal of organic evolution 20140709 9

Long dinucleotide repeats found in exons present a substantial mutational hazard: mutations at these loci occur often and generate frameshifts. Here, we provide clear and compelling evidence that exonic dinucleotides experience strong selective constraint. In humans, only 18 exonic dinucleotides have repeat lengths greater than six, which contrasts sharply with the genome-wide distribution of dinucleotides. We genotyped each of these dinucleotides in 200 humans from eight 1000 Genomes Project po ...[more]

PMID: 24899386

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Project description:Changes in gene regulation may be important in evolution. However, the evolutionary properties of regulatory mutations are currently poorly understood. This is partly the result of an incomplete annotation of functional regulatory DNA in many species. For example, transcription factor binding sites (TFBSs), a major component of eukaryotic regulatory architecture, are typically short, degenerate, and therefore difficult to differentiate from randomly occurring, nonfunctional sequences. Furthermore, although sites such as TFBSs can be computationally predicted using evolutionary conservation as a criterion, estimates of the true level of selective constraint (defined as the fraction of strongly deleterious mutations occurring at a locus) in regulatory regions will, by definition, be upwardly biased in datasets that are a priori evolutionarily conserved. Here we investigate the fitness effects of regulatory mutations using two complementary datasets of human TFBSs that are likely to be relatively free of ascertainment bias with respect to evolutionary conservation but, importantly, are supported by experimental data. The first is a collection of almost >2,100 human TFBSs drawn from the literature in the TRANSFAC database, and the second is derived from several recent high-throughput chromatin immunoprecipitation coupled with genomic microarray (ChIP-chip) analyses. We also define a set of putative cis-regulatory modules (pCRMs) by spatially clustering multiple TFBSs that regulate the same gene. We find that a relatively high proportion ( approximately 37%) of mutations at TFBSs are strongly deleterious, similar to that at a 2-fold degenerate protein-coding site. However, constraint is significantly reduced in human and chimpanzee pCRMS and ChIP-chip sequences, relative to macaques. We estimate that the fraction of regulatory mutations that have been driven to fixation by positive selection in humans is not significantly different from zero. We also find that the level of selective constraint in our TFBSs, pCRMs, and ChIP-chip sequences is negatively correlated with the expression breadth of the regulated gene, whereas the opposite relationship holds at that gene's nonsynonymous and synonymous sites. Finally, we find that the rate of protein evolution in a transcription factor appears to be positively correlated with the breadth of expression of the gene it regulates. Our study suggests that strongly deleterious regulatory mutations are considerably more likely (1.6-fold) to occur in tissue-specific than in housekeeping genes, implying that there is a fitness cost to increasing "complexity" of gene expression.

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Remarkable selective constraints on exonic dinucleotide repeats.

Publications

Remarkable selective constraints on exonic dinucleotide repeats.

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