Thanks for the mutations, Dad. You too, Mom.

Elizabeth Cooney, June 13th, 2011

Our parents give us about 30 new mutations in our genomes, new research from the 1000 Genomes Project tells us, and whether those mutations come from Mom or Dad varied more than expected.

In the first direct comparative analysis of germline mutations – changes in genes that occur during the production of sperm or eggs – scientists at the Broad and elsewhere discovered a big difference between which parent was responsible for the new mutations. They report their results in Nature Genetics.

Measuring the number of new mutations in two families, they found that in one mother-father-child trio, 92 percent of new mutations came from the father. But in the other trio, only 36 percent came from the father.

That’s unusual because one would expect more mutations in the millions of sperm men make compared with the few eggs women produce. In these two families, at least, the mutation rate varied substantially.

For Mark DePristo, manager of Medical and Population Genetics Analysis in the Broad’s Program in Medical and Population Genetics, there’s an even more interesting finding. Searching for these de novo mutations – which average one change in every 100 million DNA letters in an individual’s entire genome – the scientists also found a high rate of new mutations that weren’t traced back to sperm or egg. For every one of these germline mutations, there were 20 or more new mutations that were not inherited.

“There’s the actual study of the mutation process itself, and it’s very interesting at the male and female level,” Mark said. “But there’s also this overarching story of, Wow, there are a lot of nonheritable de novo mutations.”

These mutations may not have any bearing on a person’s health, Mark said. That’s why the paper’s authors caution against potential misdiagnosis based on a snapshot of such individual genetic changes. Mark also warned against over-interpreting mutations that appear in cells several generations away from the original sample.

“It makes interpreting variants only ever seen in a single person very, very challenging,” he said. “You could have the best algorithms in the world that absolutely, positively find some things that are in an individual. But some of these variants will just be artifacts in the cell line that might not be biologically important during the development of the individual.”

Mark and Broad colleagues Kiran Garimella and Mark Daly have contributed to a project that addresses a basic issue in genetics. On the way they also developed highly sensitive and specific analysis tools for next-generation sequencing data.

“This is one of the first uses of this type of data in order to answer this question,” Kiran said. “Our contribution was the methodology to be able to do this in the first place.”

Paper cited:
Conrad DF et al. Variation in genome-wide mutation rates within and between human families. Nature Genetics, published online June 12, 2011.