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| 2. |
- Axelsson, Erik, et al.
(author)
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Comparison of the chicken and turkey genomes reveals a higher rate of nucleotide divergence on microchromosomes than macrochromosomes.
- 2005
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In: Genome Res. - 1088-9051. ; 15:1, s. 120-5
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Journal article (peer-reviewed)abstract
- A distinctive feature of the avian genome is the large heterogeneity in the size of chromosomes, which are usually classified into a small number of macrochromosomes and numerous microchromosomes. These chromosome classes show characteristic differences in a number of interrelated features that could potentially affect the rate of sequence evolution, such as GC content, gene density, and recombination rate. We studied the effects of these factors by analyzing patterns of nucleotide substitution in two sets of chicken-turkey sequence alignments. First, in a set of 67 orthologous introns, divergence was significantly higher in microchromosomes (chromosomes 11-38; 11.7% divergence) than in both macrochromosomes (chromosomes 1-5; 9.9% divergence; P = 0.016) and intermediate-sized chromosomes (chromosomes 6-10; 9.5% divergence; P = 0.026). At least part of this difference was due to the higher incidence of CpG sites on microchromosomes. Second, using 155 orthologous coding sequences we noted a similar pattern, in which synonymous substitution rates on microchromosomes (13.1%) were significantly higher than were rates on macrochromosomes (10.3%; P = 0.024). Broadly assuming neutrality of introns and synonymous sites, or constraints on such sequences do not differ between chromosomal classes, these observations imply that microchromosomal genes are exposed to more germ line mutations than those on other chromosomes. We also find that dN/dS ratios for genes located on microchromosomes (average, 0.094) are significantly lower than those of macrochromosomes (average, 0.185; P = 0.025), suggesting that the proteins of genes on microchromosomes are under greater evolutionary constraint.
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| 3. |
- Smith, Nick G C, et al.
(author)
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A low rate of simultaneous double-nucleotide mutations in primates.
- 2003
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In: Molecular biology and evolution. - 0737-4038 .- 1537-1719. ; 20:1, s. 47-53
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Journal article (peer-reviewed)abstract
- The occurrence of double-nucleotide (doublet) mutations is contrary to the normal assumption that point mutations affect single nucleotides. Here we develop a new method for estimating the doublet mutation rate and apply it to more than a megabase of human-chimpanzee-baboon genomic DNA alignments and more than a million human single-nucleotide polymorphisms. The new method accounts for the effect of regional variation in evolutionary rates, which may be a confounding factor in previous estimates of the doublet mutation rate. Furthermore we determine sequence context effects by using sequence comparisons over a variety of lineage lengths. This approach yields a new estimate of the doublet mutation rate of 0.3% of the singleton rate, indicating that doublet mutations are far rarer than previously thought. Our results suggest that doublet mutations are unlikely to have caused the correlation between synonymous and nonsynonymous substitution rates in mammals, and also show that regional variation and sequence context effects play an important role in primate DNA sequence evolution.
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| 4. |
- Smith, Nick G C, et al.
(author)
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Deterministic mutation rate variation in the human genome.
- 2002
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In: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 12:9, s. 1350-6
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Journal article (peer-reviewed)abstract
- Several studies of substitution rate variation have indicated that the local mutation rate varies over the mammalian genome. In the present study, we show significant variation in substitution rates within the noncoding part of the human genome using 4.7 Mb of human-chimpanzee pairwise comparisons. Moreover, we find a significant positive covariation of lineage-specific chimpanzee and human local substitution rates, and very similar mean substitution rates down the two lineages. The substitution rate variation is probably not caused by selection or biased gene conversion, and so we conclude that mutation rates vary deterministically across the noncoding nonrepetitive regions of the human genome. We also show that noncoding substitution rates are significantly affected by G+C base composition, partly because the base composition is not at equilibrium.
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| 5. |
- Webster, Matthew T, et al.
(author)
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Compositional evolution of noncoding DNA in the human and chimpanzee genomes.
- 2003
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In: Molecular biology and evolution. - 0737-4038 .- 1537-1719. ; 20:2, s. 278-86
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Journal article (peer-reviewed)abstract
- We have examined the compositional evolution of noncoding DNA in the primate genome by comparison of lineage-specific substitutions observed in 1.8 Mb of genomic alignments of human, chimpanzee, and baboon with 6542 human single-nucleotide polymorphisms (SNPs) rooted using chimpanzee sequence. The pattern of compositional evolution, measured in terms of the numbers of GC-->AT and AT-->GC changes, differs significantly between fixed and polymorphic sites, and indicates that there is a bias toward fixation of AT-->GC mutations, which could result from weak directional selection or biased gene conversion in favor of high GC content. Comparison of the frequency distributions of a subset of the SNPs revealed no significant difference between GC-->AT and AT-->GC polymorphisms, although AT-->GC polymorphisms in regions of high GC segregate at slightly higher frequencies on average than GC-->AT polymorphisms, which is consistent with a fixation bias favoring high GC in these regions. However, the substitution data suggest that this fixation bias is relatively weak, because the compositional structure of the human and chimpanzee genomes is becoming homogenized, with regions of high GC decreasing in GC content and regions of low GC increasing in GC content. The rate and pattern of nucleotide substitution in 333 Alu repeats within the human-chimpanzee-baboon alignments are not significantly affected by the GC content of the region in which they are inserted, providing further evidence that, since the time of the human-chimpanzee ancestor, there has been little or no regional variation in mutation bias.
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| 6. |
- Webster, Matthew T., et al.
(author)
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Compositional evolution of the human and chimpanzee genomes
- 2003
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In: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 20:2, s. 278-286
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Journal article (other academic/artistic)abstract
- We have examined the compositional evolution of noncoding DNA in the primate genome by comparison of lineage-specific substitutions observed in 1.8 Mb of genomic alignments of human, chimpanzee, and baboon with 6542 human single-nucleotide polymorphisms (SNPs) rooted using chimpanzee sequence. The pattern of compositional evolution, measured in terms of the numbers of GC→AT and AT→GC changes, differs significantly between fixed and polymorphic sites, and indicates that there is a bias toward fixation of AT→GC mutations, which could result from weak directional selection or biased gene conversion in favor of high GC content. Comparison of the frequency distributions of a subset of the SNPs revealed no significant difference between GC→AT and AT→GC polymorphisms, although AT→GC polymorphisms in regions of high GC segregate at slightly higher frequencies on average than GC→AT polymorphisms, which is consistent with a fixation bias favoring high GC in these regions. However, the substitution data suggest that this fixation bias is relatively weak, because the compositional structure of the human and chimpanzee genomes is becoming homogenized, with regions of high GC decreasing in GC content and regions of low GC increasing in GC content. The rate and pattern of nucleotide substitution in 333 Alu repeats within the human-chimpanzee-baboon alignments are not significantly affected by the GC content of the region in which they are inserted, providing further evidence that, since the time of the human-chimpanzee ancestor, there has been little or no regional variation in mutation bias.
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| 7. |
- Webster, Matthew T., et al.
(author)
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Gene expression, synteny, and local similarity in human noncoding mutation rates
- 2004
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In: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 21:10, s. 1820-1830
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Journal article (peer-reviewed)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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| 8. |
- Webster, Matthew T, et al.
(author)
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Male-driven biased gene conversion governs the evolution of base composition in human alu repeats.
- 2005
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In: Mol Biol Evol. - 0737-4038. ; 22:6, s. 1468-74
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Journal article (peer-reviewed)abstract
- Regional biases in substitution pattern are likely to be responsible for the large-scale variation in base composition observed in vertebrate genomes. However, the evolutionary forces responsible for these biases are still not clearly defined. In order to study the processes of mutation and fixation across the entire human genome, we analyzed patterns of substitution in Alu repeats since their insertion. We also studied patterns of human polymorphism within the repeats. There is a highly significant effect of recombination rate on the pattern of substitution, whereas no such effect is seen on the pattern of polymorphism. These results suggest that regional biases in substitution are caused by biased gene conversion, a process that increases the probability of fixation of mutations that increase GC content. Furthermore, the strongest correlate of substitution patterns is found to be male recombination rates rather than female or sex-averaged recombination rates. This indicates that in addition to sexual dimorphism in recombination rates, the sexes also differ in the relative rates of crossover and gene conversion.
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| 9. |
- Webster, Matthew T, et al.
(author)
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Microsatellite evolution inferred from human-chimpanzee genomic sequence alignments.
- 2002
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 99:13, s. 8748-53
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Journal article (peer-reviewed)abstract
- Most studies of microsatellite evolution utilize long, highly mutable loci, which are unrepresentative of the majority of simple repeats in the human genome. Here we use an unbiased sample of 2,467 microsatellite loci derived from alignments of 5.1 Mb of genomic sequence from human and chimpanzee to investigate the mutation process of tandemly repetitive DNA. The results indicate that the process of microsatellite evolution is highly heterogeneous, exhibiting differences between loci of different lengths and motif sizes and between species. We find a highly significant tendency for human dinucleotide repeats to be longer than their orthologues in chimpanzees, whereas the opposite trend is observed in mononucleotide repeat arrays. Furthermore, the rate of divergence between orthologues is significantly higher at longer loci, which also show significantly greater mutability per repeat number. These observations have important consequences for understanding the molecular mechanisms of microsatellite mutation and for the development of improved measures of genetic distance.
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