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  • Catalog of Gene-Isoform Variation in Developing Human Brain

    A collaborative team led by researchers at UCLA and the University of Pennsylvania has created the first comprehensive catalog of gene-isoform variation in the developing human brain. This dataset offers crucial insights into the molecular basis of neurodevelopmental and psychiatric brain disorders, potentially leading to targeted therapies.

    Published in Science, the research highlights how transcript expression varies by cell type and maturity, emphasizing the importance of changing gene-isoform expression levels in understanding human brain
    development.


    Techniques and Technologies
    Gene-isoform diversity, arising mainly from alternative splicing, contributes to the body's complexity by producing varied proteins, or isoforms. This process is especially prevalent in the brain. Dr. Luis de la Torre-Ubieta of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, co-leader of the study, 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.” However, previous studies could not systematically investigate cell-type-specific splicing due to limitations in sequencing technologies. The researchers leveraged third-generation long-read sequencing technologies to capture complete RNA molecules, profiling the full-length transcriptome of two major regions of the developing neocortex: the germinal zone and the cortical plate. This technology revealed 214,516 unique isoforms, with over 70% being previously uncharacterized.

    Key Findings
    The study identified thousands of isoform switches during brain development, highlighting the role of RNA-binding proteins in cellular identity and fate decisions. The researchers also linked these isoform switches to genetic risk mechanisms for neurodevelopmental and psychiatric disorders. “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,” explained de la Torre-Ubieta. This suggests that specific isoform dysregulation may be a mechanism underlying these disorders.

    Data and Sample Analysis
    The researchers analyzed six developing human neocortex tissue samples from the mid-gestation period (15 to 17 weeks post-conception). This critical developmental window marks the emergence of the brain's complexity. “These tissue samples enabled a striking level of novel transcript discovery,” noted Dr. Michael Gandal, co-leader of the study. “And because these databases haven’t incorporated or represented these critical time points, we can dramatically expand our understanding of how genes are regulated in the context of human brain development.”

    Therapeutic Implications
    The researchers believe that these findings have strong therapeutic implications, potentially informing gene therapy trials and targeted treatments for individuals with rare mutations linked to psychiatric or neurodevelopmental disorders. The data also improves genetic diagnosis of neurodevelopmental disorders, helping families better understand predispositions to certain conditions.

    Gandal has shared the dataset with colleagues at the Children’s Hospital of Philadelphia, who are using this resource to interpret neurogenetic data better diagnostically. “I’m really excited to leverage this resource to help patients,” said Gandal. “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.”

    Publication Details
    Ashok Patowary et al., Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms. Science 384, eadh7688 (2024). DOI:10.1126/science.adh7688

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