Wednesday, 2 September 2009

The mutation rate of DNA

Cell Biology have recently published Yali Xue et al. "Human Y Chromosome Base-Substitution Mutation Rate Measured by Direct Sequencing in a Deep-Rooting Pedigree"

It's an interesting paper, though far enough out of my expertise that I can't comment much on the methodology, which compares the Y chromosomes of two men with a common male-line ancestor, and uses this to work out the mutation rate. This is more straightforward than it would be for other chromosomes, because Y chromosomes are - in the absence of mutation - passed down unchanged from a single parent, and so there isn't the swapping and recombining that goes on with other chromosomes. Similar analysis at a broader and more statistical level has been used to calculate the approximate time period the most recent common male-line ancestor (often called "Y chromosome Adam") lived

The result of it is that Y chromosomes have a mutation rate around 3*10-8 mutations/nucleotide/generation, which isn't far from historical guesses of the rate.

The reporting on the paper scales this up to the entire genome, giving a 100-200 mutations/person rate - in other words, 100-200 of your nucleotides will not have come from either of your parents' base DNA, but will be mutations in the egg and/or sperm and/or very early on in cell division.

What the reporting doesn't say is whether this extrapolation is valid or meaningful. The Y chromosome is not necessarily representative - it contains duplicates of a few things already on the X chromosome, quite a bit of "padding", and a few bits to make a variation on the default human form - and is relatively small for a chromosome. Additionally, unlike the other chromosomes which are regularly mixed, its only major form of change is mutation. This might make it have a different rate, making the 100-200 extrapolation unreliable. The researchers themselves don't make this extrapolation in the paper.

Male-line analysis like this is by far the easiest to do and has only just become plausible, but only works by this method on the Y chromosome. Female-line analysis on mitochondrial DNA (which is always passed mother-to-child, since the mDNA in sperm does not go into the egg) could also be done, but is even less likely to be representative of the mutation rate in the other nuclear chromosomes. I'll stop there before I go into a ramble about how amazing mitochondria are.

It's probably a solvable problem in the future, but don't expect it any time soon. Getting the error bars down on the Y-chromosome estimate and repeating the study with different cousins is likely to happen first.