Monday, September 7, 2009
I TOLD you you're all mutants
Our typical conception of mutation is drawn from the tragic effects of those relatively rare mutations, induced in our bodies or passed on through germ cells, that lead to diseases (or, in movies to super powers). In fact, we are, each of us, mutants. DNA replication is not perfect, we are born with about 6 or 7 new mutations...
Well, a paper published last week proved my general point while proving me wrong on the detail by a factor of 20 or so. A team of British and Chinese researchers that work with a family that has a unique Y-chromosome linked hearing disorder sequenced the entire sequence of the Y-chromosome from two men and found four mutations. Scaling up from the Y-chromosome to the whole genome then dividing by the combined 13 generations that separate the two men they arrived a mutation rate of 3 x 10-8 changes per nucleotide per generation. That would give us between one and two hundred new mutations.
This finding isn't actually a revelation. We had an idea of the rate of mutation in the human genome before we even knew what a gene was made of. JBS Haldane, one of the founders of evolutionary genetics and perhaps the only person to have enjoyed the First World War, used his theory of mutation selection balance to estimate new haemophilia causing mutations occur about once in every 105 generations. When you consider that the gene responsible for Haemophilia A contains about 7 x 103 nucleotides and changes to many of those won't cause Haemophilia Haldane's estimate looks pretty good.
In fact, the Cool New Stuff in this paper isn't really the number that they've produced - that number is similar Haldane's esimate and to the measurble error rate of the enzymes that replicate our DNA and to the rate inferred by comparing our genome to that of the cimpanzee *. What's really neat is the fact they directly measured the rate by resequencing the whole Y-chromosome - that's more than 10 million bases to sequence, 35 at a time, and put together to check for mutations. The sort of project that would only have been possible as part dedicated genome sequencing projects a couple of years ago. With only two people and four mutations the estimate has wide error bars but it does pave the way to more accurate estimates for particular areas of the genome (including those underlying for diseases) and particular lineages of organisms (which is important for us evolutionary biologists)
I can't revel in my earlier post being confirmed in the broad sense without apologising for misleading you in the details. I was just flat out wrong when I claimed we all have 6 or 7 new mutations - I used a number that I had in my head and didn't bother to look it up. You can see where my number came from once you consider that only about 4% of the genome is functional DNA - 150 mutations in your genome will lead to about 6 mutations in functional regions. Still, the original is (about to be) modified and I am suitably shamed.
* As Larry Moran points out taken together these studies tell us something about the way evolution works. If the observed rate of mutation in DNA replication is not wildly different than the inferred rate of mutation in a pedigree or between closely related species most mutations aren't being selected against - more evidence for the importance of neutral theory in molecular evolution. back to the story ^
 Xue, Y., Wang, Q., Long, Q., Ng, B., Swerdlow, H., Burton, J., Skuce, C., Taylor, R., Abdellah, Z., & Zhao, Y. (2009). Human Y Chromosome Base-Substitution Mutation Rate Measured by Direct Sequencing in a Deep-Rooting Pedigree Current Biology DOI: 10.1016/j.cub.2009.07.032
J. B. S. Haldane (1935). The rate of spontaneous mutation of a human gene Journal Of Genetics DOI: 10.1007/BF02717892
I selected it as one of my MolBio picks of the week at ResearchBlogging,in my blog.
You can check my picks here: http://bit.ly/2OLy0e