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August 22, 2012

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Dad’s advancing age gives newborns two extra mutations per year, study finds

Aug. 22, 2012
Courtesy of Nature
and World Science staff

Eve­ry year that an adult fa­ther waits be­fore hav­ing a child, leads on av­er­age to two ad­di­tion­al muta­t­ions in that child, a study has found.

Al­though most of these muta­t­ions are likely to be harm­less, sci­en­tists say in­creas­ing av­er­age age among new fa­thers is likely con­tri­but­ing to in­creas­ing rates of au­tism and poorer popula­t­ion health. Some sug­gest col­lect­ing and stor­ing fro­zen sperm from a man’s young­er years might be a way to help side­step the prob­lem.

“It is the age of the fa­ther that is the dom­i­nant fac­tor in de­ter­min­ing the num­ber of de novo [new] muta­t­ions in the child,” wrote Kari Stef­ans­son of the Uni­vers­ity of Ice­land and col­leagues, re­port­ing their find­ings in the Aug. 23 is­sue of the re­search jour­nal Na­ture.

Bi­ol­o­gists had pre­vi­ously known of both this fact and that ad­vanc­ing pa­ter­nal age means more muta­t­ions in the child, al­though the new study puts more ex­act num­bers on the prob­lem, re­search­ers said.

In the stu­dy, sci­en­tists ex­am­ined muta­t­ion rates in 78 Ice­landic parent-off­spring tri­os.

Ep­i­de­mi­ogical stud­ies have linked the fa­ther’s age at con­cep­tion to the risk of schiz­o­phre­nia and au­tism, and oth­er stud­ies have linked new muta­t­ions with these dis­eases, they not­ed. Tak­en to­geth­er with the lat­est re­sults, the au­thors sug­gest that these find­ings em­pha­size the im­por­tance of a fa­ther’s age for the risk of their off­spring de­vel­op­ing schiz­o­phre­nia and au­tism.

The rea­son fa­thers and not moth­ers con­trib­ute to more muta­t­ions as they grow old­er is that the fa­ther’s sperm keeps di­vid­ing through­out his life, po­ten­tially in­tro­duc­ing new ge­net­ic de­fects with each di­vi­sion. In con­trast, the eggs do not ac­tively di­vide in a moth­er of re­pro­duc­tive age, not­ed Uni­vers­ity of Mich­i­gan bi­ol­o­gist Alexey Kon­drashov, who penned a com­men­tary in the re­search jour­nal ac­com­pa­nying the find­ings.

“Al­though a 20-year-old fa­ther trans­mits, on av­er­age, ap­prox­i­mately 25 muta­t­ions to his child, a 40-year-old fa­ther trans­mits around 65,” he wrote. By con­trast, the study found that the num­ber of new muta­t­ions “trans­mit­ted by the moth­er is al­ways roughly 15.”

Re­search shows that as many as 10 per­cent of these new, gen­er­ally small-scale, muta­t­ions are likely to be harm­ful, Kon­drashov added. “It is there­fore rea­sonable to as­sume that the on­go­ing in­crease in the in­ci­dence and prev­a­lence of au­tism in many hu­man popula­t­ions could be due, at least in part, to the ac­cu­mula­t­ion of muta­t­ions re­sult­ing from re­laxed se­lec­tion [eased evolu­tion­ary pres­sures] and a high­er av­er­age pa­ter­nal age — and not only to bet­ter rec­og­ni­tion of cas­es.”

He explained that ad­vanc­ing pa­ter­nal age could con­trib­ute to anoth­er popula­t­ion-wide health con­cern: the fact that ev­o­lu­tion­ary pres­sures on the hu­man spe­cies aren’t what they used to be. In oth­er words, be­cause life is eas­i­er and medi­cine better than in the past, na­ture is far less ruth­less about culling weaker in­di­vid­u­als from our spe­cies. While this is a hap­pi­er situa­t­ion for eve­ry­one alive, it can lead to steep popula­t­ion-wide health and fit­ness de­clines, as ex­pe­ri­ments with flies have shown. 

“If the pa­ter­nal-age ef­fect on the [new] muta­t­ion rate does lead to sub­stanti­ally im­paired health in the chil­dren of old­er fa­thers, then col­lect­ing the sperm of young adult and men cold-stor­ing it for lat­er use could be a wise in­di­vid­ual de­ci­sion,” he wrote—and might al­so help ad­dress the prob­lem of de­creas­ing popula­t­ion-wide fit­ness.

* * *

Every year that a father waits before having a child leads on average to two additional mutations in that child, a study has found. Although most of these mutations are likely to be harmless, scientists say increasing average age among new fathers is likely contributing to increasing rates of autism and poorer population health. Some suggest collecting and storing frozen sperm from a man’s younger years might be a way to help sidestep the problem. “It is the age of the father that is the dominant factor in determining the number of de novo [new] mutations in the child,” wrote Kari Stefansson of the University of Iceland and colleagues, reporting their findings in the Aug. 23 issue of the research journal Nature. Biologists had previously known of both this fact and that advancing paternal age means more mutations in the child, although the new study puts more exact numbers on the problem, researchers said. In the study, scientists examined mutation rates in 78 Icelandic parent-offspring trios. Epidemiological studies have linked the father’s age at conception to the risk of schizophrenia and autism, and other studies have linked new mutations with these diseases, they noted. Taken together with the latest results, the authors suggest that these findings emphasize the importance of a father’s age for the risk of their offspring developing schizophrenia and autism. The reason fathers and not mothers contribute to more mutations as they grow older is that the father’s sperm keeps dividing throughout his life, potentially introducing new genetic defects with each division. In contrast, the eggs do not actively divide in a mother of reproductive age, noted University of Michigan biologist Alexey Kondrashov, who penned a commentary in the research journal accompanying the findings. “Although a 20-year-old father transmits, on average, approximately 25 mutations to his child, a 40-year-old father transmits around 65,” he wrote. By contrast, the study found that the number of new mutations “transmitted by the mother is always roughly 15.” Research shows that as many as 10% of these new, generally small-scale, mutations are likely to be harmful, Kondrashov added. “It is therefore reasonable to assume that the ongoing increase in the incidence and prevalence of autism in many human populations could be due, at least in part, to the accumulation of mutations resulting from relaxed selection and a higher average paternal age — and not only to better recognition of cases.” He added that the advancing paternal age could contribute to another population-wide health concern: the fact that evolutionary pressures on the human species aren’t what they used to be. In other words, because life is easier than in the past, nature is far less ruthless than it used to be about culling weaker individuals from our species. While this is a happier situation for everyone alive, it can lead to steep population-wide health and fitness declines, as experiments with flies have shown. “If the paternal-age effect on the [new] mutation rate does lead to substantially impaired health in the children of older fathers, then collecting the sperm of young adult and men cold-storing it for later use could be a wise individual decision,” he wrote—and might also help address the problem of decreasing population-wide fitness.