Using recent technological advances in genetics to rapidly acquire data, researchers have linked several genes and chromosomal aberrations to autism. Dr. Warren and colleagues plan to implement these high-throughput methods to address gender differences in autism. One possible explanation is that mutations on the X chromosome trigger the disorder. Consistent with this theory, four autism-associated genes — FMR1, NLGN3, NLGN4, MeCP2 — are located on the X chromosome. But mutations in these genes are either rare among cases of autism or are associated with more complicated syndromes, and they cannot account for the predominance of males with autism. Warren and colleagues plan to determine whether other properties of the X-chromosome might make males more susceptible to autism by performing a series of genetic analyses on a group of nearly 300 males with autism, and compiling a complete list of autism-associated abnormalities on the X chromosome. The researchers first plan to use high-density microarrays to search for small genomic deletions and insertions in the genomes of these individuals. These types of aberrations have recently been implicated in autism, usually appearing for the first time in the autism-affected generation. Males would be particularly vulnerable to mutations arising anew on the X chromosomes, and Warren's experimental approach may reveal the frequency of these aberrations in this population. The researchers also plan to sequence the entire coding regions of the 300 X chromosomes to uncover mutations that could impede protein function. In a third project, the researchers plan to investigate the epigenetic modifications of the genome that regulate gene expression. The control of protein production is as important as protein structure, and by looking for epigenetic modifications, such as methylation, Warren and colleagues aim to uncover genes whose activity is altered without a clear change in the protein-coding sequence. Based on these studies, Warren and colleagues plan to assemble the most comprehensive picture of the X chromosome in autism to date.