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- Smith, Nick G.C., et al.
(författare)
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Evidence for turnover of functional noncoding DNA in mammalian genome evolution
- 2004
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Ingår i: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 84:5, s. 806-813
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Tidskriftsartikel (refereegranskat)abstract
- The vast majority of the mammalian genome does not code for proteins, and a fundamental question in genomics is: What proportion of the noncoding mammalian genome is functional? Most attempts to address this issue use sequence comparisons between highly diverged mammals such as human and mouse to identify conservation due to negative selection. But such comparisons will underestimate the true proportion of functional noncoding DNA if there is turnover, if patterns of negative selection change over time. Here we test whether the inferred level of negative selection differs between different pairwise species comparisons. Using a multiple alignment of more than a megabase of contiguous sequence from eight mammalian species, we find a strong negative relationship between inferred levels of negative selection and pairwise divergence using 21 pairwise comparisons. This result suggests that there is a high rate of turnover of functional noncoding elements in the mammalian genome, so measures of functional constraint based on human–mouse comparisons may seriously underestimate the true value.
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| 3. |
- Webster, Matthew Thomas, et al.
(författare)
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Fixation biases affecting human SNPs?
- 2004
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Ingår i: Trends in Genetics. - : Elsevier BV. - 0168-9525 .- 1362-4555. ; 20:3, s. 122-126
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Tidskriftsartikel (refereegranskat)abstract
- Under neutrality all classes of mutation have an equal probability of becoming fixed in a population. In this article, we describe our analysis of the frequency distributions of >5000 human SNPs and provide evident of biases in the process of fixation of certain classes of point mutation that are most likely to be attributable to biased gene conversion. The results indicate an increased fixation probability of mutations that result in the incorporation of a GC base pair. Furthermore, in transcribed regions this process exhibits strand asymmetry, and is biased towards preserving a G base on the coding strand. Biased gene conversion has the potential to explain both existence of isochores and the compositional asymmetry in mammalian transcribed regions.
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| 4. |
- Webster, Matthew T., et al.
(författare)
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Gene expression, synteny, and local similarity in human noncoding mutation rates
- 2004
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 21:10, s. 1820-1830
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Tidskriftsartikel (refereegranskat)abstract
- The human genome is organized with regard to many features such as isochores, Giemsa bands, clusters of genes with similar expression patterns, and contiguous regions with shared evolutionary histories (synteny blocks). In addition to these genomic features, it is clear that mutation rates also vary across the human genome. To address how mutation rates and genomic features are related, we analyzed substitution rates at three classes of putatively neutral noncoding sites (nongenic, intronic, and ancestral repeats) in approximately 14 Mb of human-chimpanzee alignments covering human chromosome 7. Patterns of mutation rate variation inferred from substitution rate variation differ among the three site classes. In particular, we find that intronic mutation rates are strongly affected by the breadth of expression of the genes in which they reside, with broadly expressed genes exhibiting low mutation rates, probably as a consequence of the transcription-coupled repair process acting in the germ line. All site classes show significant local similarities in mutation rate at the megabase scale, and regional similarities in nongenic mutation rate covary with blocks of synteny between the human and mouse genomes, indicating that the evolutionary history of a genomic region is an important determinant of mutation rate.
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