Researchers make first direct measurement of human genetic mutation rate
1 September 2009
They calculated that there are 100-200 new DNA mutations (single base changes in our DNA sequence that are different from the sequence inherited from our parents) from generation to generation. Almost all were harmless, with no apparent effect on our health or appearance, and only four mutations accumulated over 13 generations.
The findings and method developed by the researchers furthers our understanding of mutation rates and could help us test ways to help reduce mutations. Mutation is the source of genetic variation, which can lead to diseases such as cancer. They also provide a ‘molecular clock’ for measuring evolutionary timescales.
“New mutations are responsible for an array of genetic diseases,” said Dr Chris Tyler-Smith of the Sanger Institute and the study’s coordinator.
“The ability to measure rates of DNA mutation reliably means we can begin to ask how mutation rates vary between different regions of the genome and perhaps also between different individuals.”
Previous measurements of the general human mutation rate were estimates based on a few specific genes or comparisons of human and chimpanzee DNA.
In the new study, the researchers looked at the Y chromosomes of two Chinese men born 13 generations apart. The Y chromosome is passed unchanged from father to son, so mutations accumulate slowly over generations.
The researchers sequenced the chromosomes and compared them with the reference sequence from the original human genome project to find single base pair differences in the sequence.
They found four significant mutations between the Y chromosomes of the two men, despite the many generations of separation. They then calculated that the rate of mutation is equivalent to one mutation in every 15-30 million nucleotides.
“These four mutations gave us the exact mutation rate - one in 30 million nucleotides each generation - that we had expected,” said Dr Tyler-Smith.
“This was reassuring because the methods we used - harnessing next-generation sequencing technology - had not previously been tested for this kind of research.”
Their calculations match estimates made previously by scientists who did not have access to such direct methods, including J B S Haldane, one of the founders of modern genetics.
Haldane studied haemophiliac men in London and, in 1935, estimated that the incidence of the haemophilia-causing mutation was one in 50 000 - equivalent to about one in 25 million nucleotides across the genome.
Image: Single nucleotide polymorphisms. Credit: Wellcome Library, London
Reference
Xue Y et al. Human Y chromosome base substitution mutation rate measured by direct sequencing in a deep-rooting pedigree. Current Biology 2009;doi:10.1016/j.cub.2009.07.032.