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Human-macaque comparisons illuminate variation in neutral substitution rates

Svitlana Tyekucheva12, Kateryna D Makova13, John E Karro45, Ross C Hardison16, Webb Miller127 and Francesca Chiaromonte12*

Author Affiliations

1 Center for Comparative Genomics and Bioinformatics, The Pennsylvania State University, University Park, PA 16802, USA

2 Department of Statistics, The Pennsylvania State University, University Park, PA 16802, USA

3 Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA

4 Department of Computer Science and System Analysis, Miami University, Oxford, OH 45056, USA

5 Department of Microbiology, Miami University, Oxford, OH 45056, USA

6 Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA

7 Department of Computer Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA

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Genome Biology 2008, 9:R76  doi:10.1186/gb-2008-9-4-r76

Published: 30 April 2008

Abstract

Background

The evolutionary distance between human and macaque is particularly attractive for investigating local variation in neutral substitution rates, because substitutions can be inferred more reliably than in comparisons with rodents and are less influenced by the effects of current and ancient diversity than in comparisons with closer primates. Here we investigate the human-macaque neutral substitution rate as a function of a number of genomic parameters.

Results

Using regression analyses we find that male mutation bias, male (but not female) recombination rate, distance to telomeres and substitution rates computed from orthologous regions in mouse-rat and dog-cow comparisons are prominent predictors of the neutral rate. Additionally, we demonstrate that the previously observed biphasic relationship between neutral rate and GC content can be accounted for by properly combining rates at CpG and non-CpG sites. Finally, we find the neutral rate to be negatively correlated with the densities of several classes of computationally predicted functional elements, and less so with the densities of certain classes of experimentally verified functional elements.

Conclusion

Our results suggest that while female recombination may be mainly responsible for driving evolution in GC content, male recombination may be mutagenic, and that other mutagenic mechanisms acting near telomeres, and mechanisms whose effects are shared across mammalian genomes, play significant roles. We also have evidence that the nonlinear increase in rates at high GC levels may be largely due to hyper-mutability of CpG dinucleotides. Finally, our results suggest that the performance of conservation-based prediction methods can be improved by accounting for neutral rates.