Variação críptica na taxa de mutação humana

sexta-feira, setembro 17, 2010

Cryptic Variation in the Human Mutation Rate

Alan Hodgkinson1, Emmanuel Ladoukakis1¤, Adam Eyre-Walker1*

1 Centre for the Study of Evolution, School of Life Sciences, University of Sussex, Brighton, United Kingdom


The mutation rate is known to vary between adjacent sites within the human genome as a consequence of context, the most well-studied example being the influence of CpG dinucelotides. We investigated whether there is additional variation by testing whether there is an excess of sites at which both humans and chimpanzees have a single-nucleotide polymorphism (SNP). We found a highly significant excess of such sites, and we demonstrated that this excess is not due to neighbouring nucleotide effects, ancestral polymorphism, or natural selection. We therefore infer that there is cryptic variation in the mutation rate. However, although this variation in the mutation rate is not associated with the adjacent nucleotides, we show that there are highly nonrandom patterns of nucleotides that extend ~80 base pairs on either side of sites with coincident SNPs, suggesting that there are extensive and complex context effects. Finally, we estimate the level of variation needed to produce the excess of coincident SNPs and show that there is a similar, or higher, level of variation in the mutation rate associated with this cryptic process than there is associated with adjacent nucleotides, including the CpG effect. We conclude that there is substantial variation in the mutation that has, until now, been hidden from view.

Author Summary 

Understanding the process of mutation is important, not only mechanistically, but also because it has implications for the analysis of sequence evolution and population genetic inference. The mutation rate is known to differ between sites within the human genome. The most dramatic example of this is when a C is followed by G; both the C and G nucleotides have a rate of mutation that is between 10- and 20-fold higher than the rate at other sites. In addition, is it known that the mutation rate may be influenced by the nucleotides flanking the site. Here we show that there is also very substantial variation in the mutation rate that is not associated with the flanking nucleotides, or the CpG effect. Although this variation does not depend upon the adjacent nucleotides, there are nonrandom patterns of nucleotides surrounding sites that appear to be hypermutable, suggesting there are complex context effects that influence the mutation rate.

Citation: Hodgkinson A, Ladoukakis E, Eyre-Walker A (2009) Cryptic Variation in the Human Mutation Rate. PLoS Biol 7(2): e1000027. doi:10.1371/journal.pbio.1000027

Academic Editor: Nick H. Barton, University of Edinburgh, United Kingdom

Received: July 8, 2008; Accepted: December 12, 2008; Published: February 3, 2009

Copyright: © 2009 Hodgkinson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: AH and AEW were funded by the Biotechnology and Biological Sciences Research Council, EL and AEW by the European Community, and AEW by the National Evolutionary Synthesis Center.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: Mya, million years ago; SNP, single-nucleotide polymorphism

* To whom correspondence should be addressed. E-mail:

¤ Current address: Department of Biology, University of Crete, Iraklio, Greece