Here we present a draft genome sequence of the common chimpanzee (Pan troglodytes). Through comparison with the human genome, we have generated a largely complete catalogue of the genetic differenc ...

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Initial sequence of the chimpanzee genome and comparison with the human genome

The genetic basis of inbreeding depression and of the related phenomenon, heterosis, has been a puzzle for many decades. Based on recent studies in many species, the authors argue that both phenomena are predominantly caused by the presence of recessive deleterious mutations in populations. Inbreeding depression — the reduced survival and fertility of offspring of related individuals — occurs in wild animal and plant populations as well as in humans, indicating that genetic variation in fitness traits exists in natural populations. Inbreeding depression is important in the evolution of outcrossing mating systems and, because intercrossing inbred strains improves yield (heterosis), which is important in crop breeding, the genetic basis of these effects has been debated since the early twentieth century. Classical genetic studies and modern molecular evolutionary approaches now suggest that inbreeding depression and heterosis are predominantly caused by the presence of recessive deleterious mutations in populations.

The genetics of inbreeding depression.

Despite their name, synonymous mutations have significant consequences for cellular processes in all taxa. As a result, an understanding of codon bias is central to fields as diverse as molecular evolution and biotechnology. Although recent advances in sequencing and synthetic biology have helped to resolve longstanding questions about codon bias, they have also uncovered striking patterns that suggest new hypotheses about protein synthesis. Ongoing work to quantify the dynamics of initiation and elongation is as important for understanding natural synonymous variation as it is for designing transgenes in applied contexts.

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Synonymous but not the same: the causes and consequences of codon bias.

Synonymous mutations — sometimes called 'silent' mutations — are now widely acknowledged to be able to cause changes in protein expression, conformation and function. The recent increase in knowledge about the association of genetic variants with disease, particularly through genome-wide association studies, has revealed a substantial contribution of synonymous SNPs to human disease risk and other complex traits. Here we review current understanding of the extent to which synonymous mutations influence disease, the various molecular mechanisms that underlie these effects and the implications for future research and biomedical applications.

Understanding the contribution of synonymous mutations to human disease.

Although the assumption of the neutral theory of molecular evolution - that some classes of mutation have too small an effect on fitness to be affected by natural selection - seems intuitively reasonable, over the past few decades the theory has been in retreat. At least in species with large populations, even synonymous mutations in exons are not neutral. By contrast, in mammals, neutrality of these mutations is still commonly assumed. However, new evidence indicates that even some synonymous mutations are subject to constraint, often because they affect splicing and/or mRNA stability. This has implications for understanding disease, optimizing transgene design, detecting positive selection and estimating the mutation rate.

Hearing silence: non-neutral evolution at synonymous sites in mammals

Background: In mammals, contrary to what is usually assumed, recent evidence suggests that synonymous mutations may not be selectively neutral. This position has proven contentious, not least because of the absence of a viable mechanism. Here we test whether synonymous mutations might be under selection owing to their effects on the thermodynamic stability of mRNA, mediated by changes in secondary structure. Results: We provide numerous lines of evidence that are all consistent with the above hypothesis. Most notably, by simulating evolution and reallocating the substitutions observed in the mouse lineage, we show that the location of synonymous mutations is non-random with respect to stability. Importantly, the preference for cytosine at 4-fold degenerate sites, diagnostic of selection, can be explained by its effect on mRNA stability. Likewise, by interchanging synonymous codons, we find naturally occurring mRNAs to be more stable than simulant transcripts. Housekeeping genes, whose proteins are under strong purifying selection, are also under the greatest pressure to maintain stability. Conclusion: Taken together, our results provide evidence that, in mammals, synonymous sites do not evolve neutrally, at least in part owing to selection on mRNA stability. This has implications for the application of synonymous divergence in estimating the mutation rate.

/pdf/evidence-for-selection-on-synonymous-mutations-affecting-1e4yeg5ay8.pdf

Evidence for selection on synonymous mutations affecting stability of mRNA secondary structure in mammals

Silent sites in mammals have classically been assumed to be free from selective pressures Consequently, the synonymous substitution rate (Ks) is often used as a proxy for the mutation rate Although accumulating evidence demonstrates that the assumption is not valid, the mechanism by which selection acts remain unclear Recent work has revealed that the presence of exonic splicing enhancers (ESEs) in coding sequence might influence synonymous evolution ESEs are predominantly located near intron-exon junctions, which may explain the reduced single-nucleotide polymorphism (SNP) density in these regions Here we show that synonymous sites in putative ESEs evolve more slowly than the remaining exonic sequence Differential mutabilities of ESEs do not appear to explain this difference We observe that substitution frequency at fourfold synonymous sites decreases as one approaches the ends of exons, consistent with the existing SNP data This gradient is at least in part explained by ESEs being more abundant near junctions Between-gene variation in Ks is hence partly explained by the proportion of the gene that acts as an ESE Given the relative abundance of ESEs and the reduced rates of synonymous divergence within them, we estimate that constraints on synonymous evolution within ESEs causes the true mutation rate to be underestimated by not more than approximately 8% We also find that Ks outside of ESEs is much lower in alternatively spliced exons than in constitutive exons, implying that other causes of selection on synonymous mutations exist Additionally, selection on ESEs appears to affect nonsynonymous sites and may explain why amino acid usage near intron-exon junctions is nonrandom

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Evidence for Purifying Selection Against Synonymous Mutations in Mammalian Exonic Splicing Enhancers

In mammals divergence at fourfold degenerate sites in codons (K(4)) and intronic sequence (K(i)) are both used to estimate the mutation rate, under the supposition that both evolve neutrally. Does it matter which of these we use? Using either class of sequence can be defended because (1) K(4) is the same as K(i) (at least in rodents) and (2) there is no selectively driven codon usage (hence no systematic selection on third sites). Here we re-examine these findings using 560 introns (for 136 genes) in the mouse-rat comparison, aligned by eye and using a new maximum likelihood protocol. We find that the rate of evolution at fourfold sites and at intronic sites is similar in magnitude, but only after eliminating putatively constrained sites from introns (first introns and sites flanking intron-exon junctions). Any approximate congruence between the two rates is not, however, owing to an underlying similarity in the mode of sequence evolution. Some dinucleotides are hypermutable and differently abundant in exons and introns (e.g., CpGs). More importantly, after controlling for relative abundance, all dinucleotides starting with A or T are more prevalent in mismatches in exons than in introns, whereas C-starting dinucleotides (except CG) are more common in introns. Although C content at intronic sites is lower than at flanking fourfold sites, G content is similar, demonstrating that there exists a strong strand-specific preference for C nucleotides that is unique to exons. Transcription-coupled mutational processes and biased gene conversion cannot explain this, as they should affect introns and flanking exons equally. Therefore, by elimination, we propose this to be strong evidence for selectively driven codon usage in mammals.

/pdf/similar-rates-but-different-modes-of-sequence-evolution-in-2cwswlndp1.pdf

Similar Rates but Different Modes of Sequence Evolution in Introns and at Exonic Silent Sites in Rodents: Evidence for Selectively Driven Codon Usage

This article discusses research indicating that small changes in DNA can sometimes result in significant changes in an organism. Research in nucleotide sequencing that discovered a connection between a silent genetic mutation and health problems such as Marfan syndrome, Hirschsprung disease, and phenylketonuria is described. The effect of these mutations was found by examining mistranslation by messenger RNA in the protein production process. INSETS: BROKEN SILENCE;SILENCE IN THE CODE;SPLICING CUES ALTERED;Biased Vaccine

The price of silent mutations.

https://www.cell.com/trends/genetics/pdf/S0168-9525(05)00061-2.pdf

Jean-Vincent Chamary

Papers

Evidence for selection on synonymous mutations affecting stability of mRNA secondary structure in mammals

Evidence for Purifying Selection Against Synonymous Mutations in Mammalian Exonic Splicing Enhancers

Similar Rates but Different Modes of Sequence Evolution in Introns and at Exonic Silent Sites in Rodents: Evidence for Selectively Driven Codon Usage

The price of silent mutations.

Biased codon usage near intron-exon junctions: selection on splicing enhancers, splice-site recognition or something else?