Kostka, D., Hubisz, M. J., Siepel, A., Pollard, K. S. (March 2012) The role of GC-biased gene conversion in shaping the fastest evolving regions of the human genome. Mol Biol Evol, 29 (3). pp. 1047-57. ISSN 0737-4038
Abstract
GC-biased gene conversion (gBGC) is a recombination-associated evolutionary process that accelerates the fixation of guanine or cytosine alleles, regardless of their effects on fitness. gBGC can increase the overall rate of substitutions, a hallmark of positive selection. Many fast-evolving genes and noncoding sequences in the human genome have GC-biased substitution patterns, suggesting that gBGC-in contrast to adaptive processes-may have driven the human changes in these sequences. To investigate this hypothesis, we developed a substitution model for DNA sequence evolution that quantifies the nonlinear interacting effects of selection and gBGC on substitution rates and patterns. Based on this model, we used a series of lineage-specific likelihood ratio tests to evaluate sequence alignments for evidence of changes in mode of selection, action of gBGC, or both. With a false positive rate of less than 5% for individual tests, we found that the majority (76%) of previously identified human accelerated regions are best explained without gBGC, whereas a substantial minority (19%) are best explained by the action of gBGC alone. Further, more than half (55%) have substitution rates that significantly exceed local estimates of the neutral rate, suggesting that these regions may have been shaped by positive selection rather than by relaxation of constraint. By distinguishing the effects of gBGC, relaxation of constraint, and positive selection we provide an integrated analysis of the evolutionary forces that shaped the fastest evolving regions of the human genome, which facilitates the design of targeted functional studies of adaptation in humans.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Base Composition/genetics Base Sequence *Evolution, Molecular Gene Conversion/*genetics Genome, Human/*genetics Humans Likelihood Functions *Models, Genetic *Selection, Genetic Sequence Alignment |
| Subjects: | bioinformatics bioinformatics > genomics and proteomics > alignment > sequence alignment evolution bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes |
| CSHL Authors: | |
| Communities: | CSHL labs > Siepel lab |
| Depositing User: | Matt Covey |
| Date: | March 2012 |
| Date Deposited: | 14 Jan 2015 20:47 |
| Last Modified: | 14 Jan 2015 20:47 |
| PMCID: | PMC3278478 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/31076 |
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