The ability to sequence the entire genomes–the sequence of almost every letter of an individual’s DNA–of parents and their children has for the first time allowed scientists to directly measure how fast our species is mutating. Preliminary studies are coming up with some surprising findings, including more variation than initially thought. A more accurate measure of the number of spontaneous genetic changes passed down from generation to generation will allow scientists to better estimate the timing of key events in our evolutionary history, as well as to evaluate whether some families are more likely to have children suffering from developmental disorders.
These mutations, thought to result from mistakes in DNA replication during the creation of sperm or eggs, are the basis for evolution. Some changes are benign, some are harmful–spontaneous mutations have been linked to autism and other developmental disorders–and some confer special advantages on their bearer. “Mutation is a good thing,” says Don Conrad, a researcher at the Wellcome Trust Sanger Institute, in the United Kingdom. “We need to be able to respond to changes in our environment.”
Last March, Leroy Hood and collaborators at the Institute for Systems Biology in Seattle, sequenced the complete genomes of a nuclear family of four, the first published example of a family having their genomes sequenced. By comparing the sequence of parents and offspring, researchers could calculate the rate of spontaneous mutations arising in the human genome from one generation to the next. The rate equates to about 70 mutations per child, lower than previous estimates.
Don Conrad has now followed up those estimates with his own analysis of family genomes, comparing mutation rates in two different nuclear families who were sequenced as part of the 1000 genomes project, an international collaboration to assess new sequencing technologies and examine genetic variability across different populations. Conrad’s study confirmed Hood’s figure, but it was also the first to separate out mutation rates from whole genome data based on gender. Previous indirect estimates suggest that the mutation rate is three to six times higher in men than women, a phenomena thought to be explained by the fact that sperm undergo many more cell divisions during development than do eggs. In preliminary findings presented last week at the Personal Genomes conference in Cold Spring Harbor, New York, he found that the father in a family from Utah had a mutation rate 11 times higher than the mother, higher than any previously reported figures. In the second family, from Africa, the maternal mutation rate was higher than the paternal one, which is contrary to the prevailing theory.
By simulating how mutation rates would vary had the parents in the two families switched partners, Conrad calculated that there could be as much as a tenfold difference in rates among individuals. He cautions that the work is based on data from just two families and needs to be replicated in larger samples. “I’ll be exited to see what people come up with over the next six months, as they analyze sequences of more families,” he says. One drawback in the study is that scientists don’t know what age the parents were when they had their children; older parents tend to have more mutations in their gametes. In addition, the sequencing used DNA derived from cells from each individual, rather than direct DNA samples, though Conrad says he controlled for any errors this might have introduced.
It’s not yet clear what determines an individual’s mutation rates, though genetics likely play a major role. A mutation in a DNA repair enzyme, for example, could increase error rates in the replication of a genome. Environmental factors are also a possibility, however, Conrad says that no one has yet identified specific culprits. X-rays and toxic chemicals affect DNA in so-called somatic cells, or adult tissue, rather than the germline cells that go on to form eggs and sperm. It’s also not yet clear what the consequences of a highly variable mutation rate would be, though it’s possible that families with higher rates would be more likely to have children with sporadic disease.