Internship Presentations

Systems Analysis of Essential Autism Genes in Early Mammalian Development

Josephine Millard

Mentors: Dr. Sharmila Basu, MindSpec, Inc.; and Dr. Karen Ross, Department of Biochemistry and Molecular & Cellular Biology, Georgetown University.

Date/Time: May 3rd, 2022 at 12:00pm.

Abstract: Recent advances in genomic technologies have started to uncover the genetic architecture associated with autism spectrum disorder (ASD). ASD gene encoded proteins have been largely discovered in biological pathways related to synaptic function, transcriptional regulation, and chromatin modification. AutDB/SFARI Gene ( is a multi-modular database of curated information describing autism-associated genes of varying confidence. As of December 2021, AutDB holds ~1,300 genes in the Human Gene Module and 295 of these genes have annotated genetic mouse models in the Animal Module. Experiments using mouse models have led to the observation of genes which are essential in development. These essential genes are required for the continued development of the embryo and can result in embryonic, perinatal, or neonatal lethality upon homozygous knockout. Autism-associated genes have shown significant enrichment for essential genes in homozygous knockout models. Upon heterozygous knockout of these genes, mice show neurodevelopmental phenotypes consistent with the autism phenotype. In this project, homozygous lethal phenotypes were explored using curated data from AutDB and from the International Mouse Phenotyping Consortium (IMPC: Analysis of IMPC lethal genes indicated significant enrichment of autism-associated genes at each timepoint of development assessed. The next objective was to explore how temporal classification might affect prevailing mechanisms of lethality and prospective ASD etiology. In order to understand the systems architecture of these lethal genes, classes of early lethality timepoint were made and corresponding interaction networks of varying depth were examined. Different enriched biological processes were observed between the embryonic lethal ASD gene sets and the perinatal-to-postnatal lethal, high-confidence ASD gene sets, plus their respective interactors. Early embryonic lethal networks were enriched with general terms related to cell compartment organization and DNA binding. The late embryonic lethal networks were specific to PI3K/AKT, ERBB, and FGFR1 signaling pathways, pointing to a role in neuronal and vascular differentiation. A group of high-confidence ASD genes which are lethal in the perinatal to postnatal period were also examined. This network had significant enrichment of SWI/SNF complex proteins and other terms related to chromatin organization, along with neurexin and neuroligin synaptic scaffolding proteins. ASD specific mechanisms related to this phenomenon of enrichment in essential genes can be further investigated by observing the spatial relationship of expression between these developmental classes. Further, it is possible that additional factors such as epigenetic miRNA interactions modulate expression of many of these genes and operate in producing this specific lethal phenotype. Further investigation of this phenomenon should consider both of these factors.

Spring 2022