Before the advent of whole-genome sequencing, it was a mystery as to why otherwise typical people could parent children born with a condition or disease. Now, it’s clear that many of those cases are linked to de novo mutations. De novo mutations are mutations that are not inherited from either parent’s DNA, but are often present for the first time in the child.
But some supposedly de novo mutations may be inherited — they may have actually been transferred via the father’s sperm. Now, scientists have debuted a new method to measure disease-causing mutations in sperm.
For some people, the new technique could offer answers as to whether a specific genetic mutation underlies their condition. University of California, San Diego researcher Joe Gleeson tells Inverse that when it comes to children with autism, about half of the population has a case that’s linked to de novo mutations. In fact, about 30 to 40 percent of these cases may be linked back to sperm mutations, Gleeson suggests. They can’t explain all cases of autism, but they do make “the largest measurable contribution,” he says.
The method could also help help families accurately assess the risk of their future children developing diseases, including but not limited to autism, he says.
The technique is detailed in a paper published this week in Nature Medicine.
“Ultimately, we think that we could probably reduce severe childhood disease across the population if this kind of technique was widely adopted,” Gleeson says.
The mutation hunt
Gleeson and his colleagues analyzed the sperm of eight fathers who are parents of children diagnosed with autism. All of the children had known de novo mutations underlying their autism.
They specifically looked for examples of mosaicism — when the cells within the same person have a different genetic makeup — in sperm cells. They also used whole-genome sequencing to see if the genetic variants found in the children matched the variants seen in their fathers’ sperm.
In three cases, they could see that the child’s mutation was in the father’s sperm, and they could measure the percent of the sperm cells that carry the mutation. Doing so allows the researchers to quantify the recurrence risk of autism, Gleeson says.
The link between sperm and genetic conditions
The risk between sperm and autism has been described before. Older men are more likely than younger men to have a child with autism, and the risk increases as a man ages. It’s hypothesized that’s because the sperm of older men have accumulated more mutations over time. It could also be because the aging simply degrades sperm, leading to more genetic variation.
In this study, they did not see a correlation between the paternal age and the number of mutations in a father’s sperm, but they did see a correlation between paternal age and the number of mutations a child had. While that may seem counterintuitive, it’s because it becomes increasingly difficult to pinpoint mutations that happen when a father is older. Mutations that emerge as fathers age are present in fewer and fewer cells, and “it gets to be a point where you just can’t measure them after a while,” Gleeson says.
While mutations that arise in the eggs and sperm of parents can cause any number of genetic conditions in a child, it’s a matter of which gene the mutations happen to fall on that determines what condition — if any — a particular child could have. Mutations are more likely to come from father instead of a mother because sperm cells are dividing all the time, while egg cells never divide. That constant dividing makes sperm a particularly vulnerable population of cells.
“They are just hiding there,” Gleeson says. “The father has no idea he is carrying these mutations in his sperm cells and then poof he has a child and the child has a severe disease.”
A test for mutations in sperm?
If the method develops into a clinical test, then expectant fathers could get a sense of whether or not their future children are at risk of developing a range of conditions — not just autism.
The researchers hope that men who are interested in this type of testing could eventually have their sperm sequenced by a company like 23andMe. That could tell them what their risk of having a child with different genetic conditions is, Gleeson says.
What scientists don’t know is if this is something the public actually wants. Generally, parents of children with autism are interested in this sort of service, he says. In the United States, 1 in 59 school age children are autistic. In families who already have a child with autism with a known genetic cause, family planning may be an important consideration, he says.
It is possible that the same mutations will arise in subsequent kids: In this study, they describe a family where all three children contained the mosaic mutation that was present in the father’s sperm.
But what they don’t know is if parents who don’t have any children with autism — or any children period — would be interested in knowing what the risk is, if any. That decision will likely be prompted by personal and societal influences — and in the meantime, researchers will continue to develop the technology that gives families that option.
De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father’s sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.