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by Ingrid Fadelli , Medical Xpress
“Prior work had shown that all human brains have the same primary spatial pattern of gene expression (C1) reflecting the hierarchy of connections between neurons,” Richard Dear, co-author of the paper, told Medical Xpress. “Our hypothesis was that there is probably more than one pattern organizing how the twenty-thousand human genes are expressed across our brains.”
The primary objective of the recent study by Dear and his colleagues was to uncover new spatial patterns of gene expression. They hoped that these new patterns would shed light on so-called “transcriptional programs,” the biological mechanisms through which the human brain develops both in health and disease.
“The key challenge for this study was the limited data available,” Dear said. “The Allen Human Brain Atlas remains the only gene expression dataset with high spatial resolution across the brain, and it was collected from only six healthy donors. We therefore had to find a way to identify patterns in these limited data that we were confident represent general transcriptional programs shared across all human brains.”
As part of their study, the researchers ran various computational analyses to validate their results, including a permutation test for robustness and validation in three distinct types of independent data. They also searched for associations between the new transcriptional programs and previously published data related to brain organization, development, gene expression, and genetic variation associated with brain function in both health and disease.
“What was most striking was how each new analysis that we performed converged on the same consistent story,” Dear explained. “The second pattern of gene expression (C2) relates to cognitive metabolism and autism, while the third pattern (C3) relates to brain plasticity in adolescence and schizophrenia. Critically, both patterns were identified and validated entirely in brains from neurotypical donors.”
Dear and his collaborators are the first to link neurotypical brain gene expression to autism and schizophrenia across three common types of prior results (i.e., case-control neuroimaging, differential gene expression, and genome-wide association studies). Their results suggest that data collected using these distinct techniques, which previously appeared to be unrelated, can in fact be traced back to the same transcriptional programs that guide the development of healthy human brains.
“The next step for us will be to dive deeper into the biology of the three patterns to understand them at a more mechanistic level, leveraging recently published single-nucleus RNA sequencing data,” Dear added. “For example, we hope to discover the key genes or transcription factors guiding the expression of the C1–C3 patterns early in development across different cell types. We also hope that these three patterns and the optimized analysis code we developed will be a resource for other scientists seeking to understand the genetic underpinnings of the brain’s spatial organization.”