Wednesday, April 2, 2008

Ancient mtDNA: clocking up the mutations

A quick post about Hay et al, which I spotted thanks to Pondering Pikaia (Nature news also has a piece on it). I think that this paper is interesting but I think there are some issues in the interpretation.

The paper estimates the mtDNA mutation rate of tuatara (an ancient lineage of reptile living on New Zealand), and find that the mtDNA mutation rate is one of the highest estimated so far. The usual way of estimating mutation rates is to compare sequence divergence between two species (or set of species) where the divergence time of the pair of species (or nodes in the tree relating the species) are known with some precision (this technique is not without its problems, and a lot of work in molecular phylogentics is devoted to solving these problems). However, if you don't have a set of relatively close species or they a lack of fossil record then you are usually out of luck, and the mutation rate can not be estimated. To get around this the authors use patterns of mtDNA diversity in extant and ancient mtDNA to estimate the mutation rate. Usually patterns of population genetic diversity are not in themselves informative about mutation rates, because the diversity within a species is determined by the product of the mutation rate and the effective population size (i.e. the mutation rate and the effective population size are confounded). High diversity within a species could be due to a high mutation rate and a low effective population size, or a low mutation rate and a high effective population size. The inclusion of ancient DNA samples can potentially resolve this confounding; this is because the temporal spacing between the samples, gives information about the rate of coalescence (i.e. the effective population size). This information in turn provides a way of disentangling the effective population size from the mutation rate (see Drummond et al.). The authors use this idea to estimate the mtDNA mutation rate, and have also used this idea before for Penguin ancient mtDNA ( Lambert et al ).

However, as with all population genetic analyzes things are not quite that simple. Violations of the simple coalescent model used to estimate the population size and hence the mutation rate could be problematic. Population size changes (such as a bottleneck) or selection could alter the rate of rate of coalescence through time, and so potentially confuse the estimation of the effective population size and so the mutation rate. Population structure is another potential problem, if the present day samples and ancient DNA samples are not all drawn from the same panmictic population this would also violate the model assumptions and so potentially impact the estimate of the mutation rate. Now the authors sample both extant and ancient specimens from around New Zealand, so population structure may not be a problem though this can not be assumed to be the case. The authors also look at whether exponential population growth changes their results and find that it does not, but it is not clear that other plausible demographic models could not cause biases.

Estimates of mutation rate from this kind of analysis are clearly not problem free, and so may need be treated with some caution. If you are somewhat skeptical of the estimation population demography from mtDNA sequences (and you should be) then you should be somewhat skeptical of estimating mutation rates via this technique. I think that the idea behind this study and the results are really neat, but for the moment I would regard this study as supporting/suggesting a hypothesis that the mutation rate is high rather than definitely showing that this is the case.


Hay JM, Subramanian S, Millar CD, Mohandesan E, Lambert DM.Rapid molecular evolution in a living fossil.Trends Genet. 2008 Mar;24(3):106-9

Drummond AJ, Nicholls GK, Rodrigo AG, Solomon W. Estimating mutation parameters, population history and genealogy simultaneously from temporally spaced sequence data.
Genetics. 2002 Jul;161(3):1307-20.

Lambert DM, Ritchie PA, Millar CD, Holland B, Drummond AJ, Baroni C. Rates of evolution in ancient DNA from Adélie penguins.
Science. 2002 Mar 22;295(5563):2270-3.