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Identifying Genetic Variants on the Y Chromosome of Males with Autism

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One of the most puzzling aspects of autism is the observation that boys are four times more likely to be on the spectrum than girls. Understanding the genetic basis for this significant male to female ratio bias may provide clues towards understanding the cause of autism. Given the well-established genetic basis of autism, it is possible that the gender bias resides in the sex chromosomes (X and Y) themselves. Women carry two X chromosomes while men have one X (inherited from mother) and one Y (inherited from father). Therefore, if a genetic alteration (called a mutation) occurs on the Y chromosome that can lead to autism, only men will be affected. If a mutation occurs on the X chromosome, females can be shielded because they carry a second backup copy of chromosome X. Indeed, a handful of genes on the X chromosome have been identified in which mutations can lead to autism in males (examples include the PTCHD1, NLGN3 and NLGN4 genes). However, these genes only account for a few percent of families with autism, and considering all other genes on the 22 other (non-XY) chromosomes, only about 15% of the genetic causes of autism are known. We believe that many of the genes still to be found involved in autism may reside on the Y chromosome. The hypothesis is that extra or missing copies (or segments of copies) of the Y chromosome underlie much of autism. A clue that guides this conjecture is that males with an extra copy of chromosome Y have an increased incidence of autism. Moreover, many genes on the Y chromosome are important in brain development. Importantly, the Y chromosome also has a very high frequency of spontaneous mutations. To date, very few research studies have looked into the association of chromosome Y with disorders. This is mainly due to its complex and repetitive DNA sequence structure, which has been difficult to examine using conventional genetic technologies. Revolutionary developments in genome sequencing experiments, however, now promise to allow previous shortfalls to be overcome allowing the Y chromosome to be studied in autism. The latest genome sequencing technologies will be to examine if the Y chromosome is involved in autism. This research has the potential to provide a broad range of research training from biomedical to clinical, as well as state-of-art technical training in genome-scale analyses, which support my career development as an independent scientist.