Evidence that natural selection acts on silent mutation

Conrad, Michael; Friedlander, Carl; Goodman, Morris

doi:10.1016/0303-2647(83)90031-x

Cited by 11 publications

(6 citation statements)

References 15 publications

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“…Aside from the effects on splicing, silent mutations can disturb mRNA processing and transport (26,27). The widespread biases in codon usage can also cause non-neutrality of the silent mutations: if a silent mutation switches encoding to a codon with a low pool of corresponding tRNA, it can severely decrease the efficiency of translation and protein production (28,29). We found that the average relative selection coefficient against splice mutations was half that against nonsense mutations.…”

Section: Discussionmentioning

confidence: 84%

Strength of the purifying selection against different categories of the point mutations in the coding regions of the human genome

Gorlov¹,

Kimmel²,

Amos³

2006

Human Molecular Genetics

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Using available Information on the total absolute size of the coding region of the human genome, data on codon usage and pseudogene-derived mutation rates for different single nucleotide substitutions we have estimated, for the human genome, the potential numbers of mutation events capable to produce: (1) nonsense; (2) missense (radical and conservative); (3) silent; (4) splice; and (5) protein-elongating (those changing wild-type stop codon into an amino acid encoding codon) mutations. We used the NCBI dbSNP database to retrieve data on the observed number of polymorphisms of each category. The fraction of polymorphisms in each category among all potential events in the genome depends on the strength of selection: the higher the rate of polymorphism, the weaker the selection. We used nonsense mutations as a referent group. Compared with nonsense mutations, we found that the relative selection coefficient against protein-elongating mutations was 21%, and the relative selection was 12% against missense mutations. Radical missense mutations were found to be four times more deleterious compared to conservative ones. Surprisingly, we found that silent mutations on average are not neutral; with the average harmfulness of 3% of nonsense mutations. Silent mutations may be deleterious when they affect splicing by creating cryptic donor-acceptor sites or by disturbing exonic splicing enhancers (ESESs). The average selection coefficient against splice mutations was 48% of that against nonsense mutations. Converting the relative selection coefficients into absolute ones using data on loss-of-function mutations in Saccharomyces cerevisiae and Caenorhabditis elegans, or by analysis of the expected frequency of mutations in the human genome, suggested that genetic drift could play a role in population dynamics of conservative missense and silent mutations.

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Section: Discussionmentioning

confidence: 84%

Strength of the purifying selection against different categories of the point mutations in the coding regions of the human genome

Gorlov¹,

Kimmel²,

Amos³

2006

Human Molecular Genetics

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“…This variant, which can be detected by BsiHKAI digestion of the first fragment of exon 1, proved to be rare, since it was not found in the 33 other tumor samples or in 92 normal individuals. However, the GAG codon is more frequent in human than is the GAA codon (DNA Information and Stock Center), thus excluding the possibility that this alteration makes transcription of the DNA sequence more difficult (Conrad et al 1983). Combined with the lack of an EXT phenotype, this finding implies that this silent alteration is not disease causing.…”

Section: Ext Mutation Analysismentioning

confidence: 99%

EXT-Mutation Analysis and Loss of Heterozygosity in Sporadic and Hereditary Osteochondromas and Secondary Chondrosarcomas

Bovée

Cleton‐Jansen

Wuyts

et al. 1999

The American Journal of Human Genetics

175

157

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Osteochondromas occur as sporadic solitary lesions or as multiple lesions, characterizing the hereditary multiple exostoses syndrome (EXT). Approximately 15% of all chondrosarcomas arise within the cartilaginous cap of an osteochondroma. EXT is genetically heterogeneous, and two genes, EXT1 and EXT2, located on 8q24 and 11p11-p12, respectively, have been cloned. It is still unclear whether osteochondroma is a developmental disorder or a true neoplasm. Furthermore, it is unclear whether inactivation of both alleles of an EXT gene, according to the tumor-suppressor model, is required for osteochondroma development, or whether a single EXT germline mutation acts in a dominant negative way. We therefore studied loss of heterozygosity and DNA ploidy in eight sporadic and six hereditary osteochondromas. EXT1- and EXT2-mutation analysis was performed in a total of 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas. We demonstrated osteochondroma to be a true neoplasm, since aneuploidy was found in 4 of 10 osteochondromas. Furthermore, LOH was almost exclusively found at the EXT1 locus in 5 of 14 osteochondromas. Four novel constitutional cDNA alterations were detected in exon 1 of EXT1. Two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild-type allele in three osteochondromas, indicating that, in cartilaginous cells of the growth plate, inactivation of both copies of the EXT1 gene is required for osteochondroma formation in hereditary cases. In contrast, no somatic EXT1 cDNA alterations were found in sporadic osteochondromas. No mutations were found in the EXT2 gene.

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“…One of the constant efforts of molecular anthropology's fathers such as Morris Goodman was to identify and describe the forces that have shaped human genome evolution (Conrad et al, 1983;Wildman et al, 2003). Based on nucleic acid and protein sequence comparisons between species, they described the evolutionary driving forces that promoted the fixation of new variants on the human lineage (positive selection), and also the forces that have limited the fixation of any new variant (negative selection).…”

Section: Introductionmentioning

confidence: 99%

Current relaxation of selection on the human genome: Tolerance of deleterious mutations on olfactory receptors

Pierron

Cortés

Letellier

et al. 2013

Molecular Phylogenetics and Evolution

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Knowledge and understanding about the selective pressures that have shaped present human genetic diversity have dramatically increased in the last few years in parallel with the availability of large genomic datasets. The release of large datasets composed of millions of SNPs across hundreds of genomes by HAPMAP, the Human Genome Diversity Panel, and other projects has led to considerable effort to detect selection signals across the nuclear genome (Coop et al., 2009; Lopez Herraez et al., 2009; Sabeti et al., 2006, 2007; Voight et al., 2006). Most of the research has focused on positive selection forces although other selective forces, such as negative selection, may have played a substantive role on the shape of our genome. Here we studied the selective strengths acting presently on the genome by making computational predictions of the pathogenicity of nonsynonymous protein mutations and interpreting the distribution of scores in terms of selection. We could show that the genetic diversity for all the major pathways is still constrained by negative selection in all 11 human populations studied. In a single exception, we observed a relaxation of negative selection acting on olfactory receptors. Since a decreased number of functioning olfactory receptors in human compared with other primates had already been shown, this suggests that the role of olfactory receptors for survival and reproductive success has decreased during human evolution. By showing that negative selection is still relaxed, the present results imply that no plateau of minimal function has yet been reached in modern humans and therefore that olfactory capability might still be decreasing. This is a first clue to present human evolution.

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Evidence that natural selection acts on silent mutation

Cited by 11 publications

References 15 publications

Strength of the purifying selection against different categories of the point mutations in the coding regions of the human genome

Strength of the purifying selection against different categories of the point mutations in the coding regions of the human genome

EXT-Mutation Analysis and Loss of Heterozygosity in Sporadic and Hereditary Osteochondromas and Secondary Chondrosarcomas

Current relaxation of selection on the human genome: Tolerance of deleterious mutations on olfactory receptors

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