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The frequency of polymorphisms in maternal- and paternal-effect genes in autism spectrum

Arnold J. Levine, Ph.D.
Institute for Advanced Study

Daniel Notterman, M.D.
Princeton University

Advanced maternal and paternal age have been reported as risk factors for autism spectrum disorders. In general, the genetic quality of eggs and sperm declines over time, reducing the chance of older parents to produce normal offspring. Copy-number variation (CNV) — a type of genetic alteration commonly associated with autism spectrum disorder — is thought to be one of the most common problems with the quality of eggs or sperm in older individuals.

Daniel Notterman at Princeton University and Arnold Levine at the Institute for Advanced Study are investigating a potential link between certain CNVs and autism. In particular, they are studying the association between loss of copy-number in the NCAM-2 gene and autism. Staining for the NCAM-2 protein in tissue sections of human brain showed that NCAM-2 protein is expressed in cells of the hippocampus and the cerebellum, supporting this idea.

Certain variations in DNA sequence — known as single-nucleotide polymorphisms (SNPs) — in two genes known to play a role in egg development in female mice (p63 and p73) are more common in mothers of children with autism than in the general population. Similarly, the p53 gene and possibly the p73 gene are involved in sperm development in male mice, and selected SNPs in some of those genes show a higher frequency in mothers or fathers of children with autism. Several of the genes transcribed by p53, p63 and p73 are involved in DNA repair processes. This suggests that DNA repair and the process of gamete formation, which differ in males and females, may be involved in generating mutations that lead to CNVs and possibly autism spectrum disorders.

Future research led by Levine and Notterman will expand on the nature of the CNVs and diseases where these types of genetic variation are observed.