Autism and ultraconserved non-coding sequence on chromosome 7q

Autism has been linked to a broad region on chromosome 7q that contains a large number of genes involved in transcription and development. This region is also enriched for ultraconserved non-coding elements, defined as human-rodent sequences that are 100% aligned over > or =200 base pairs, which have a high likelihood of being functional. Therefore, as only a few rare coding variants have been detected in the autism candidate genes on 7q examined to date, we decided to screen these ultraconserved elements for possible autism susceptibility alleles.

We used denaturing high-performance liquid chromatography, and DNA sequencing, to perform variant detection in a total of 146 cases with autism, 96 from the Autism Genetic Resource Exchange and 50 from the Central Valley of Costa Rica, as well as 124 controls from the Polymorphism Discovery Resource Panel. We screened 10 consecutive ultraconserved elements in, or flanking, the genes DLX5/6, AUTS2 and FOXP2 on chromosome 7q.

Although we did find several rare variants in autism cases that were not present in controls, we also observed rare variants present in controls and not cases. The most common variant occurred in controls at a frequency of 3.3%. Interestingly, two ultraconserved elements each harbored three independent variants and one ultraconserved element harbored two independent variants, suggesting that ultraconservation is maintained chiefly by a decreased tendency toward fixation, rather than a significantly lower mutation rate.

Our results show that these sequences are unlikely to harbor major autism susceptibility alleles.