West LA Times

Researchers at UCLA and the University of Pennsylvania have created a comprehensive catalog of gene-isoform variation in the developing human brain. This dataset provides significant insights into the molecular basis of neurodevelopmental and psychiatric disorders, potentially paving the way for targeted therapies.

Published in Science, the study details how transcript expression varies by cell type and maturity, indicating that changing gene-isoform expression levels are crucial to understanding brain development. The researchers used third-generation long-read sequencing technologies to capture complete RNA molecules and profile the full-length transcriptome of two major regions of the developing neocortex: the germinal zone and the cortical plate.

Dr. Luis de la Torre-Ubieta from UCLA stated, “We knew, based on our previous research, that isoform regulation is a key molecular feature for understanding brain development and genetic risk for neuropsychiatric disorders.” He co-led the study with Dr. Michael Gandal from the University of Pennsylvania.

The researchers uncovered 214,516 unique isoforms—over 70% previously unstudied—and found that changes in isoform expression levels are important for neurogenesis, differentiation, and cell fate. Thousands of isoform switches occurring during brain development were identified, implicating RNA-binding proteins in cellular identity decisions. These findings also provide new insights into genetic risk mechanisms for neurodevelopmental and neuropsychiatric disorders.

De la Torre-Ubieta noted, “We found that high-confidence risk genes for autism or neurodevelopmental disorders tend to be genes that have more isoforms, and those isoforms are expressed differently during neurogenesis.”

For this study, six developing human neocortex tissue samples representing mid-gestation (15 to 17 weeks post-conception) were obtained. Dr. Gandal emphasized that these samples enabled significant novel transcript discovery: “These databases haven’t incorporated or represented these critical time points; we can dramatically expand our understanding of how genes are regulated in human brain development.”

The findings could have therapeutic implications by identifying novel treatment approaches in gene therapy trials or targeted therapeutic trials for individuals with rare mutations associated with psychiatric or neurodevelopmental disorders. In addition to advancing genetic diagnoses of such disorders, this data helps families understand predispositions to certain conditions.

Gandal shared this dataset with colleagues at Children’s Hospital of Philadelphia to help interpret neurogenetics diagnostically. He remarked, “Having this knowledge brings us one step closer to being able to develop targeted treatments and understand genetic mechanisms in a much more specific way.”

Other contributors include Ashok Patowary, Pan Zhang, Celine K. Vuong from UCLA; Connor Jops from Penn; Naihua Gong from Penn; Daniel Vo from Penn; Xusheng Wang from Penn; Chunyu Liu from Penn; Xinzhou Ge from UCLA; Kangcheng Hou from UCLA; Minsoo Kim from UCLA; Michael Margolis from UCLA; Bogdan Pasaniuc from UCLA; Jingyi Jessica Li from UCLA.

The research was supported by various institutions including Simons Foundation Autism Research Initiative and National Institute of Mental Health.