**Author details**

certain neurobehavioral abnormalities, suggesting a role for gene-environment interactions

The phenotypic changes observed in *Dp(11)17/+* and *Df(11017/+* mice are accompanied by changes in gene expression; on average, transcripts in the critical interval are expressed at 138 + 29% of wild-type levels in *Dp(11)17/+* mice, and at 66 + 15% of wild-type levels in *Df(11)17/+* mice [109]. The expression level of these genes can be normalized to roughly that of wild-type mice by crossing *Dp(11)17/+* and *Df(11)17/+* mice to create a double heterozy‐ gote carrying two copies of the genes within the critical region in *cis*, (as opposed to the typi‐ cal *trans* orientation in wild-type mice). However, the presence of the structural variation itself affects expression of genes outside the affected interval, resulting in "genome regula‐ tion" that may ultimately contribute to the phenotype. As a result, these double heterozy‐ gous mice display some abnormal behaviors, including elevated activity levels and

When *Rai1* is over-expressed in mice (*Rai1-Tg*, modeling PTLS), these mice have growth re‐ tardation, are underweight, display anxiety-like behavior, social dominance, motor abnor‐ malities, and have increased motor activity in juvenile mice. Furthermore, there is a dosagedependent exacerbation of this phenotype [106]. These mice also display abnormal maternal behavior, altered sociability, reduced reproductive fitness, and impaired serotonin metabo‐ lism [111]. Together these results suggest that *Rai1-Tg* mice display a complex neurobeha‐ vioral and metabolic phenotype similar to that of mice harboring the *Dp(11)17* CNV, suggesting that *RAI1* is likely responsible for some, if not many of the phenotypes identified in PTLS. Further support for this hypothesis is indicated by studies of *Dp(11)17/Rai1* doubleheterozygous mice with normalized copy number of *Rai1*, but increased dosage of the sur‐ rounding interval; this study revealed that normalization of *Rai1* copy number was able to correct weight differences, and at least partially rescue phenotypes on behavioral tests for

While genetic defects play a part in the etiology of ASD, environmental effects have long been thought to contribute to these disorders. For example, although the majority of SMS/PTLS patients present with either deletion or duplication of the same ~3.7 Mb genedense region, there is significant variability in the clinical phenotype [112]. Furthermore, while there are some significant differences in the incidence of the abnormalities in pa‐ tients with the common deletion/duplication compared to those patients with smaller or larger-sized CNVs, a clear distinction between these sub-groups of patients cannot be made; many of these phenotypes are therefore likely strongly influenced by genetic back‐ ground as well as environmental effects [83, 94]. While gene-environment interactions may potentially explain the source of the variability seen in these syndromes, investiga‐ tion into the specific environmental factors that may affect outcomes for these genomic

in the determination of copy number variation-mediated autism severity [30].

decreased preference for social novelty [109].

264 Recent Advances in Autism Spectrum Disorders - Volume I

locomotor activity, anxiety, and learning and memory [95].

**11. Gene-environment interactions**

disorders has yet to be undertaken.

Melanie Lacaria1 and James R. Lupski1,2

\*Address all correspondence to: jlupski@bcm.edu

1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

2 Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, TX, USA
