Tuesday, February 3, 2009

Cryptic Mutational Hotspots

The discovery of cryptic mutational hotspots in the human genome makes us think about the many processes underlying the determinants of mutation rates.

As discussed by Laurent Duret in the paper's1 accompanying primer2, there are neighbor-dependant mutational processes (that is, the mutation rate can vary between adjacent sites as a consequence of context). In this paper on the latest issue of PLoS Biology1, "the authors investigated the pattern of single nucleotide polymorphism (SNP) in human populations, at sites that are known to be polymorphic in chimpanzee" (see Duret's primer for a intro on the concepts discussed on the research paper), finding that there is an excess (3 times) of coincident SNPs over the number expected under the null hypothesis (which would be "SNPs are randomly distributed in the two genomes"). Interestingly, they show that this is apparently not (or at least not completely) attributable to the context and also not because of ancestral polymorphisms present in the last common ancestor of human and chimpanzee. They go on to study the possible involvement on selection to explain these conserved SNPs (positive and negative), and they conclude that the data does not support that hypothesis.

Why is this important? Briefly,
a precise knowledge of genome-wide mutation patterns is crucial for many issues in genetics (for example diseases) or evolutionary biology 2

From the authors:
We conclude that there is substantial variation in the mutation that has, until now, been hidden from view.

Here's the citation:

Cryptic Variation in the Human Mutation Rate

Alan Hodgkinson, Emmanuel Ladoukakis, Adam Eyre-Walker

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.

1 Hodgkinson A, Ladoukakis E, Eyre-Walker A (2009)Cryptic Variation in the Human Mutation Rate. PLoS Biol 7(2): e27 doi:10.1371/journal.pbio.1000027

2 What is a Primer? It provides a concise introduction into an important aspect of biology highlighted by a current PLoS Biology research article.
Duret L (2009) Mutation Patterns in the Human Genome: More Variable Than Expected. PLoS Biol 7(2): e27 doi:10.1371/journal.pbio.1000027