Genetics, although ostensibly complicated, is all around us. In our immediate social circle, we often come across genetics at display. Some examples are obvious: The kids wear glasses because both parents wear them. But others are not as straightforward: How is the daughter so tall when both parents are short? These inexplicable traits are often the result of de novo mutations, which are mutations that occur in a child whose parents do not possess that trait.
Autism spectrum disorder (ASD), a neurodevelopmental disorder commonly associated with social abnormalities, language impairments, and repetitive behaviors, is genetically heterogeneous. Perturbation of one particular gene is unlikely to contribute towards autism, but in combination with other genetic mutations and/or environmental factors, the cumulative effect could be manifested as ASD.
Even though ASD is highly heritable, families report sporadic cases of ASD in their child, possibly due to de novo mutations. Previous studies have reported that children of men who are 50 years or older have an increased risk of having ASD compared to fathers who are 30 years or younger . Right now, it is not clear what mechanisms contribute to this paternal-age effect, but de novo mutations in the male reproductive cells has been proposed as a major causal link in this disorder.
To better understand the association between paternal age and autism, a group of researchers  studied the effect of a man’s age on his grandchild’s risk of autism. While it’s true that even healthy children inherit ‘silent’ de novo mutations from their father, the researchers hypothesized that if these ‘silent’ mutations accumulate over generations, then the cumulative burden of mutations inherited by the child can tip the “ASD risk scale” and increase the likelihood that the grandchild will have autism. The results of their study supported their hypothesis and showed that men who fathered daughters when they were 50 years or older were 79% more likely to have a grandchild with autism than men who were fathers in their twenties (with sons, the risk was 67%).
Why does paternal age play a significant role in autism development?
The germline cells or reproductive cells in men (spermatocytes) undergo more cell divisions than those in a woman (oocytes). Sperms are produced continuously throughout the reproductive life of a man, and therefore, the number of cell divisions increases with age. Each time a cell divides, the chances of developing mutations increase. Over generations, these accumulated mutations reach a threshold, and the collection of diverse mutations results in an autistic phenotype.
What does this mean for children with older fathers and grandfathers?
While there was an increase in the incidence of ASD in families with older grandparents, the risk was relatively small, as autism was still very infrequent even in the families with the oldest grandparents. However, these results give more insights into the complex genetic patterns of ASD and the effect that lifestyle choices may have on neurodevelopmental disorders.
1. Hultman C.M., Sandin S., Levine S.Z., Lichtenstein P. & Reichenberg A. (2010). Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies, Molecular Psychiatry, 16 (12) 1203-1212. DOI: 10.1038/mp.2010.121
2. Frans E.M. Autism Risk Across GenerationsA Population-Based Study of Advancing Grandpaternal and Paternal Age Autism Risk, JAMA Psychiatry, 1. DOI: 10.1001/jamapsychiatry.2013.1180
3. Geschwind D.H. (2009). Advances in Autism, Annual Review of Medicine, 60 (1) 367-380. DOI:10.1146/annurev.med.60.053107.121225
4. Crow J.F. (2000). The origins, patterns and implications of human spontaneous mutation, Nature Reviews Genetics, 1 (1) 40-47. DOI: 10.1038/35049558
Images adapted from Corbis and made by Anita Ramanathan.
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