Selected Publications

Our physical senses are separated not only into distinct experiences but also into specialized regions within the cerebral cortex. Synesthesia is a neurological phenomenon that causes unusual links between sensory experiences, and its molecular basis is completely unknown. We demonstrate that three families who experience color when listening to sounds are connected by rare genetic variants affecting genes that contribute to axonogenesis, a process essential for neuronal connections within and across brain regions. Multiple genes with similar activity patterns during neural development fall within parts of the genome previously linked to the condition. Our results connect synesthetes’ altered structural and functional connectivity to genes that support the development of those connections.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a clear, but heterogeneous, genetic component. Germline mutations in the tumor suppressor Pten are a well-established risk factor for ASD with macrocephaly, and conditional Pten mouse models have impaired social behavior and brain development. Some mutations observed in patients disrupt the normally balanced nuclear-cytoplasmic localization of the Pten protein, and we developed the Ptenm3m4 model to study the effects of a cytoplasm-predominant Pten. In this model, germline mislocalization of Pten causes inappropriate social behavior with intact learning and memory, a profile reminiscent of high-functioning ASD. These animals also exhibit histological evidence of neuroinflammation and expansion of glial populations by 6 weeks of age. We hypothesized that the neural transcriptome of this model would be altered in a manner that could inform human idiopathic ASD, a constitutional condition. Using total RNA sequencing, we found progressive disruption of neural gene expression in Ptenm3m4 mice from 2–6 weeks of age, involving both immune and synaptic pathways. These alterations include downregulation of many highly coexpressed human ASD-susceptibility genes. Comparison with a human cortical development coexpression network revealed that genes disrupted in Ptenm3m4 mice were enriched in the same areas as those of human ASD. Although Pten-related ASD is relatively uncommon, our observations suggest that the Ptenm3m4 model recapitulates multiple molecular features of human ASD, and that Pten operates far upstream of common pathways within ASD pathogenesis.
In Mol Psychiatry

Recent Publications

  • Rare variants in axonogenesis genes connect three families with sound–color synesthesia

    Details PDF Science Friday

  • Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder.

    Details PDF GEO

  • Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.

    Details PDF GEO

  • Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder.

    Details PDF

  • Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production.

    Details PDF

Recent & Upcoming Talks


Rare genetic variants & synaesthesia

How do rare genetic variants influence a person’s likelihood to experience blended senses?

Synaesthesia Genetics (SynGenes)

My MSCA Individual Fellowship is focused on discovering the genetic underpinnings of synaesthesia, a neurological phenomenon where stimulation of one sense causes an automatic secondary perception.

Genetics of Semantic Cognition

Tracking down potentially causative genetic variants in a family with a severe problem connecting meanings to words.

Imaging Genetics of Modern Human Brain Shape

The shape of our modern brain is a relatively recent development. Can we uncover genetic variation introduced during our evolution that continues to influence this trait?

PTEN localization in ASD

During my PhD I studied the neural functions of PTEN tumor suppressor using a novel mouse model. The project ranged from behavioral studies to RNA-sequencing, and we often compared our findings to the clinical phenotypes in patients with PTEN mutations.