16p11.2: Defining the gene(s) responsible (grant 2)

Several loci, or stretches of chromosomal DNA, have been shown to be defective in individuals with autism. These loci each contain more than one gene, so the next step is to identify the specific genes that are disrupted.

To that end, Alea Mills and her colleagues at Cold Spring Harbor Laboratory in New York are developing a series of mouse models carrying chromosomal defects analogous to those seen in people with autism.

The researchers have been generating mouse models of autism using a molecular biology technique called chromosome engineering, which takes advantage of the fact that the order of genes in the mouse genome is nearly identical to that of the human genome. After determining the boundaries of the affected area of the human chromosome, the researchers replicate the genetic defect in mouse embryonic stem cells, which are then used to produce the mouse models.

Mills has created several mouse models with different numbers of copies of the chromosomal region corresponding to human 16p11.2, an autism-linked chromosomal defect. The researchers have been analyzing the mice for genetic, physiological and behavioral features.

Mills and her team found that the mice show symptoms analogous to those seen in people with autism. They are planning to create an additional series of mice with smaller genetic defects that, together, cover the entire region, in order to home in on the specific genetic mutations underlying the symptoms.

These mouse models may allow researchers to study the consequences of autism-linked genetic alterations using experimental approaches that would not be feasible in a clinic. The mice could also potentially be used to test new drug treatments for autism.