Relative effects of mutability and selection on single nucleotide polymorphisms in transcribed regions of the human genome

Gorlov, Ivan P.; Gorlova, Olga Y.; Amos, Christopher I.

doi:10.1186/1471-2164-9-292

Cited by 11 publications

(11 citation statements)

References 56 publications

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“…Studies of the most evolutionarily conserved noncoding regions have yielded results that are consistent with the view that most mutations in noncoding regions are only slightly deleterious Kryukov et al, 2005]. The conservation observed may thus be due to variations in the mutation rate rather than selective constraints [Gorlov et al, 2008;Keightley et al, 2005]. Indeed, Keightley et al [2005] have shown that selection in conserved noncoding sequences is significantly weaker in hominids compared to murids, probably a consequence of the low effective population size of hominids resulting in the reduced effectiveness of selection.…”

Section: Mutations In Noncoding Regions Of Functional Significancesupporting

confidence: 66%

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

et al. 2010

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The number of reported germline mutations in human nuclear genes, either underlying or associated with inherited disease, has now exceeded 100,000 in more than 3,700 different genes. The availability of these data has both revolutionized the study of the morbid anatomy of the human genome and facilitated “personalized genomics.” With ∼300 new “inherited disease genes” (and ∼10,000 new mutations) being identified annually, it is pertinent to ask how many “inherited disease genes” there are in the human genome, how many mutations reside within them, and where such lesions are likely to be located? To address these questions, it is necessary not only to reconsider how we define human genes but also to explore notions of gene “essentiality” and “dispensability.” Answers to these questions are now emerging from recent novel insights into genome structure and function and through complete genome sequence information derived from multiple individual human genomes. However, a change in focus toward screening functional genomic elements as opposed to genes sensu stricto will be required if we are to capitalize fully on recent technical and conceptual advances and identify new types of disease‐associated mutation within noncoding regions remote from the genes whose function they disrupt. Hum Mutat 31:631–655, 2010. © 2010 Wiley‐Liss, Inc.

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Section: Mutations In Noncoding Regions Of Functional Significancesupporting

confidence: 66%

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

et al. 2010

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“…In accordance with this expectation, we detected a significant positive correlation between background mutability, which is an estimate of per site mutation rate, and observed frequencies of mutations in cancer patients. In a recent study the fraction of sites harboring SNPs in the human genome was found indeed to correlate very well with the mutability although the later was estimated differently from our study [37]. We also found that cancer mutations not so far observed in cancer patients had much lower expected background nucleotide and codon mutability compared to the observed mutations For some genes, the observed frequency of occurrence of mutations can be predicted purely from their mutability.…”

Section: Discussionsupporting

confidence: 61%

Background mutability shapes observed mutational spectrum in cancer and improves driver mutation prediction

Brown

Goncearenco

et al. 2018

Preprint

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Identifying driver mutations in cancer is notoriously difficult. To date, recurrence of a mutation in patients remains one of the most reliable markers of mutation driver status. However, some mutations are more likely to occur than others due to differences in background mutation rates arising from various forms of infidelity of DNA replication and repair machinery, endogenous, and exogenous mutagens.We used cancer-type and mutagen-specific mutability to study the contribution of background processes of mutagenesis and DNA repair in shaping the observed mutational spectrum in cancer. We developed and tested probabilistic model that adjusts the number of mutation recurrences in patients by background mutability in order to find mutations which may be under selection in cancer.We showed that observed recurrence frequency of cancer mutations scaled with the background mutability, especially for tumor suppressor genes. In oncogenes, however, highly recurring mutations were characterized by relatively low mutability, resulting in a U-shaped trend.Mutations not yet observed in any tumor had relatively low mutability values, indicating that background mutability might limit the mutation occurrence.We compiled a dataset of missense mutations from 58 genes with experimentally validated functional and transforming impacts from different studies. We found that mutability of driver mutations was lower than the mutability of passengers and consequently adjusting mutation recurrence frequency by mutability significantly improved ranking of mutations and driver prediction. Even though no training on existing data was involved, our approach performed similar or better to the existing state-of-the-art methods.

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“…Certainly, initial copy errors have to take place during spermatogenesis for this process to occur; therefore, the endogenous mutability and local sequence context 64 of a nucleotide contribute to this process. As experimental data have shown that the rate of spontaneous transitions at CpG dinucleotides is up to~45 times higher than transversions at non-CpG sites 46,47,65 (Figure 1A), the relative contribution of this effect (compared to selection) is likely to be small, although not insignificant. This is illustrated by the c.1138G>A transition in FGFR3, which is~35 times more commonly reported in de novo cases of achondroplasia than the c.1138G>C transversion; 30,31 although both substitutions encode the same p.Gly380Arg change in FGFR3 and are therefore predicted to exhibit the same strength of positive selection at the protein level, a difference in background rates of mutability at this CpG dinucleotide is likely to explain the relative abundance of each substitution observed in patients with achondroplasia ( Figure 2C).…”

Section: Direct Quantification Of Fgfr2and Fgfr3-associated Pae Mutatmentioning

confidence: 91%

Paternal Age Effect Mutations and Selfish Spermatogonial Selection: Causes and Consequences for Human Disease

Goriely

Wilkie

2012

The American Journal of Human Genetics

303

323

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Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term "paternal age effect" (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the paternal age effect lies in the dysregulation of spermatogonial cell behavior, an effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time-explaining the observed paternal age effect associated with these disorders-and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition.

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Relative effects of mutability and selection on single nucleotide polymorphisms in transcribed regions of the human genome

Cited by 11 publications

References 56 publications

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

Background mutability shapes observed mutational spectrum in cancer and improves driver mutation prediction

Paternal Age Effect Mutations and Selfish Spermatogonial Selection: Causes and Consequences for Human Disease

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