Mutation rates vary widely within and between human families, with surprising differences between fathers and mothers, according to a new study published online in Nature Genetics this week. The researchers were also surprised to find mutation rates tend to be slower than anticipated, with each individual on average inheriting some 60 mutations from the previous generation. The findings suggest genetic tests could run the risk of misdiagnosing patients with a high mutation rate because samples may not typify the mutations present in the rest of the body.

The study is thought to be the first direct whole-genome measure of human mutation that answers the questions: how many new mutations does a child have, and did most come from the mother or the father?

Using whole genome sequences from the 1000 Genomes Project, the researchers, including study co-leader Dr Matt Hurles, Senior Group Leader at the Wellcome Trust Sanger Institute near Cambridge, UK, measured directly the numbers of mutations in two families.

The results confirmed that our DNA changes from generation to generation, but surprisingly, each one of us receives on average only about 60 new mutations in our genome from our parents.

Study co-leader Dr Philip Awadalla, a professor at the University of Montreal in Canada, said:

“In principle, evolution is happening a third as slowly as previously thought.”

Mutations, or variations in the “spelling” of the millions of “words and phrases” in the text of the human genome, arise whenever DNA is replicated. Mutations occur in sperm or egg cells and are passed on when those cells create new humans.

And because males produce millions more gametes (sperm) than females (eggs), there is a widely held view that fathers pass on more mutations than mothers.

However, the researchers found a surprising range of variation among families as to which parent passed on the most mutations:

“Most strikingly, in one family, we observed that 92% of germline DNMs [de novo mutations] were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline,” they wrote.

Hurles told the press that:

“We human geneticists have theorised that mutation rates might be different between the sexes or between people.”

“We know now that, in some families, most mutations might arise from the mother, in others most will arise from the father. This is a surprise: many people expected that in all families most mutations would come from the father, due to the additional number of times that the genome needs to be copied to make a sperm, as opposed to an egg,” he added.

Finding new mutations is no easy task: the researchers were looking for changes that on average only occur once in millions of letters of the “text” of our DNA.

Previous studies that have measured the mutation rate in humans has either averaged across both sexes or measured the rate over several generations. This is the first to look at how mutation rates vary from a specific parent to a child in more than one case.

Awadalla explained that they were able to do this because of new developments in experimental technologies and their new analytical algorithms.

“This has allowed us to find these new mutations, which are like very small needles in a very large haystack,” said Awadalla.

For the study, the researchers examined the genomes of two families, each comprising mother, father, and one child. They looked for changes in DNA in the children’s genomes that were not present in the genomes of their parents. Altogether they examined nearly 6,000 possible mutations.

There are three ways these mutations could have arisen: either during sperm production in the fathers, egg production in the mothers, or in the children’s bodies as their own DNA replicated during normal cell division.

For this study, the researchers concentrated on sorting out the mutations that came from sperm or egg cells. And that is when they found in one family, the child inherited 92% of the mutations from the father wheares in the other family the child only inherited 36% from the father.

They said this was a complete surprise, and raises as many questions as answers. For example, because they only examined one child in each family, they can’t say if the variation in numbers of new mutations is because of the nature of the parents, or because of the nature of their sperm and egg: for instance, would a different sperm and/or egg from the same parent give rise to about the same number, or a vastly different number, of mutations?

Could you have two siblings from the same genetic parents, with one sibling having a low rate of mutations while the other has a high one?

An important clinical implication is a person with a high natural mutation rate (this study suggests it could be as much as ten times more than a person with a low rate) could be at a higher risk of misdiagnosis of a genetic disease because the samples used in the testing could contain mutations not present in other cells of their body.

The researchers hope to use the new technology and algorithms to look at more families and address these and other questions such as what effect might the age of the parents have, and how might different environmental pressures affect mutation rates. Many such questions are of great concern to prospective parents.

Awadalla said “we also need to be looking at other kinds of mutations, such as structural variations within our genetic code”.

“Variation in genome-wide mutation rates within and between human families.”
Donald F Conrad, Jonathan E M Keebler, Mark A DePristo, Sarah J Lindsay, Yujun Zhang, Ferran Casals, Youssef Idaghdour, Chris L Hartl, Carlos Torroja, Kiran V Garimella, Martine Zilversmit, Reed Cartwright, Guy A Rouleau, Mark Daly, Eric A Stone, Matthew E Hurles, and Philip Awadalla for the 1000 Genomes Project.
Nature Genetics, Published online 12 June 2011; doi:10.1038/ng.862

Additional sources: Wellcome Trust Sanger Institute, University of Montreal.

Written by: Catharine Paddock, PhD