16p11.2: Defining the gene(s) responsible (grant 1)

  • Awarded: 2010
  • Award Type: Research
  • Award #: 177886

Copy number variations (CNVs), or altered numbers of certain stretches of DNA, have been implicated as a genetic cause of autism. Alea Mills and her colleagues at Cold Spring Harbor Laboratory in New York set out to determine whether CNVs in the chromosomal region 16p11.2 cause autism-like phenotypes. They used chromosome engineering to generate mice with a deletion corresponding to 16p11.2 — one of the most prevalent genomic lesions associated with autism — as well as mice with reciprocal duplication of this region.

Using video monitoring and magnetic resonance imaging, Mills’ team found that mice with an altered dosage of the region corresponding to human 16p11.2 have unique phenotypes. Mice heterozygous for the deletion show neuroanatomical and behavioral phenotypes resembling autism symptoms, including repetitive behavior, sleep deficits and difficulty adapting to a new environment. These behavioral phenotypes correspond with alterations in brain architecture.

Remarkably, behavioral alterations can be detected just two days after birth, suggesting that these phenotypes can be used to identify affected children before the full-blown features of autism have developed.

Mills’ study revealed that deletion causes the most severe phenotypes, and that duplication has milder reciprocal effects. These findings provide the first functional evidence that a compromised dosage of 16p11.2 can cause autism-like phenotypes, opening new avenues for the development of clinical interventions.

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