Recent years have seen major strides in our understanding of the complex genetics of autism spectrum disorder (ASD). However, while large-scale epidemiological studies estimate the heritability of ASD at 50-95 percent, the underlying etiology remains unknown for the vast majority of ASD cases, limiting the development of effective therapeutic strategies.

The human-specific Long INterspersed Element-1 (LINE-1; L1Hs) retrotransposons are the only known active and autonomous subclass of mobile elements in the human genome. These transposons are normally contained through silencing mechanisms that are not well understood, and their dysregulation is causally implicated in multiple human disorders.

Maria Chahrour — in collaboration with John Abrams (University of Texas Southwestern Medical Center) — has preliminary findings from postmortem brain tissue that both L1Hs RNA and protein levels are increased in the ASD brain relative to unaffected individuals. This raises the compelling possibility that eruptions of activity in L1Hs transposons contribute to ASD pathogenesis.

Chahrour’s team proposes to assess this possibility in both human ASD samples and in animal models of ASD. To do so, the group will utilize publicly available ASD RNA-seq data sets to comprehensively profile L1Hs dysregulation in distinct brain regions and cell types in human postmortem samples. In parallel, the team will test whether increasing retrotransposon activity in a mouse brain is sufficient to induce cellular phenotypes (e.g., changes in neuronal morphology, synapses) and behavioral changes (e.g., deficits in social behavior, repetitive behaviors) relevant for ASD. Outcomes from these studies may uncover a new molecular explanation for ASD, exposing fresh opportunities for diagnosis and treatment.