Adaptive sequence divergence forged new neurodevelopmental enhancers in humans.
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2022-11
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Searches for the genetic underpinnings of uniquely human traits have focused on human-specific divergence in conserved genomic regions, which reflects adaptive modifications of existing functional elements. However, the study of conserved regions excludes functional elements that descended from previously neutral regions. Here, we demonstrate that the fastest-evolved regions of the human genome, which we term "human ancestor quickly evolved regions" (HAQERs), rapidly diverged in an episodic burst of directional positive selection prior to the human-Neanderthal split, before transitioning to constraint within hominins. HAQERs are enriched for bivalent chromatin states, particularly in gastrointestinal and neurodevelopmental tissues, and genetic variants linked to neurodevelopmental disease. We developed a multiplex, single-cell in vivo enhancer assay to discover that rapid sequence divergence in HAQERs generated hominin-unique enhancers in the developing cerebral cortex. We propose that a lack of pleiotropic constraints and elevated mutation rates poised HAQERs for rapid adaptation and subsequent susceptibility to disease.
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Mangan, Riley J, Fernando C Alsina, Federica Mosti, Jesús Emiliano Sotelo-Fonseca, Daniel A Snellings, Eric H Au, Juliana Carvalho, Laya Sathyan, et al. (2022). Adaptive sequence divergence forged new neurodevelopmental enhancers in humans. Cell, 185(24). pp. 4587–4603.e23. 10.1016/j.cell.2022.10.016 Retrieved from https://hdl.handle.net/10161/28964.
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Scholars@Duke
Timothy E Reddy
Debra Lynn Silver
How is the brain assembled and sculpted during embryonic development? Addressing this question has enormous implications for understanding neurodevelopmental disorders affecting brain size and function. In evolutionary terms, our newest brain structure is the cerebral cortex, which drives higher cognitive capacities. The overall mission of my research lab is to elucidate genetic and cellular mechanisms controlling cortical development and contributing to neurodevelopmental pathologies and brain evolution. We study neural progenitors, essential cells which generate neurons and are the root of brain development. We are guided by the premise that the same mechanisms at play during normal development were co-opted during evolution and when dysregulated, can cause neurodevelopmental disease.
My research program employs a multifaceted strategy to bridge developmental neurobiology, RNA biology, and evolution. 1) We investigate how cell fates are specified, by studying how progenitor divisions influence development and disease. 2) We study diverse layers of post-transcriptional regulation in neural progenitors. We investigate RNA binding proteins implicated in development and neurological disease. Using live imaging, we also investigate how sub-cellular control of mRNA localization and translation influences neural progenitors. 3) A parallel research focus is to understand how human-specific genetic changes influence species-specific brain development. Our goal is to integrate our efforts across these three major lines of research to understand the intricacies controlling brain development.
Craig Lowe
Craig Lowe is an Assistant Professor in the Department of Molecular Genetics and Microbiology. His research interests are in understanding how traits and characteristics of humans, and other vertebrates, are encoded in their genomes. He is especially focused on adaptations and disease susceptibilities that are unique to humans. To address these questions, Craig uses both computational and experimental approaches. Craig's recent research has been on differences in how genes are regulated between species, or between different individuals within a species, and how this causes traits to differ. All students in Craig's lab are exposed to an interdisciplinary environment; current lab members have backgrounds in mathematics, computer science, neuroscience, developmental biology, and genetics. Each year Craig teaches one or two courses on rotating topics of: ancient DNA, ethical issues in genomics, and software development for genetic analyses.
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