Thursday, January 31, 2008

This Week's Citation Classic

DNA replication is amazingly accurate, but it's not perfect. And that's a good thing. If no errors were made during DNA replication, there would be no evolution. Ultimately mutation is the source of genetic variation, and genetic variation is the basis of evolutionary change: some mutants are more fit than others, and therefore are fruitful and multiply.

But what is the mutation rate? For a long time, this question was impossible to answer. While it was possible to estimate the deleterious mutation rate by observing phenotypic changes in offspring or changes in amino acid sequences, estimation of the genome-wide mutation rate had to await the advent of DNA sequencing.

When sequences finally started pouring in, estimates of genome-wide mutation rates varied wildly. One of the first studies to put this data in perspective was this week's citation classic:

JW Drake. 1991. A Constant Rate of Spontaneous Mutation in DNA-Based Microbes. PNAS 88: 7160-7164. doi:10.1073/pnas.88.16.7160

John Drake, the head of the Laboratory of Molecular Genetics at the National Institute of Environmental Health Sciences, compared the mutation rates for several microbial organisms, including yeast, bacteriophages, bacteria and filamentous fungi (i.e. those that had been sequenced at that time). He found a deep general trend. His abstract conveys the message much better than I could:

"Their average mutation rates per base pair vary by ~16,000-fold, whereas their mutation rates per genome vary by only ~2.5-fold, apparently randomly, around a mean value of 0.0033 per DNA replication. The average mutation rate per base pair is inversely proportional to genome size. Therefore, a nearly invariant microbial mutation rate appears to have evolved. Because this rate is uniform in such diverse organisms, it is likely to be determined by deep general forces, perhaps by a balance between the usually deleterious effects of mutation and the physiological costs of further reducing mutation rates."

Drake has made a career of estimating mutatation rates, and evolutionary biologists now have a stronger command of how variation is generated among organisms. It's such an important parameter in many evolutionary models.

How about humans? How many mutations do we have on average? Estimating mutation rates is not easy, as the methods section of Drake's paper should make clear. Different techniques, however, seem to consistently produce estimates of 1 to 6 point non-silent mutations in coding DNA per individual in humans. In a later paper, Drake gives ~64 as the total number of non-silent and silent point mutations per individual.

Photo: Replicating mtDNA.

No comments:

Post a Comment