[F31] Loss of Conserved Regulatory Elements in Human Brain Evolution
Ente: National Institute of Mental Health
Scadenza: 2029-08-13
Importo max: $41,809
Paese: US
Descrizione
Project Abstract
Cis-regulatory elements (CREs) control the spatial and temporal expression of genes and are central to brain
development. Disruption of these elements contributes to neurological diseases, yet the functional landscape of
non-coding variation remains poorly defined. Human brain evolution is marked by regulatory divergence, but
prior studies have largely focused on accelerated substitutions or enhancer gain. To address the unexplored
dimension of enhancer loss, this project builds upon our recent cross-species single-nucleus multiomic work that
identified 1,091 human-lost CREs, which are deeply conserved enhancers active across other mammals but
inactive in the human brain. These elements are enriched in neuronal CREs, occur near genes such as SRGAP2
and SCN2A, and harbor derived substitutions predicted to disrupt transcription factor binding, suggesting
adaptive regulatory inactivation. The proposed research will test the hypothesis that enhancer loss contributes
to human-specific brain traits and that rare variants in these loci influence risk for neurodevelopmental disorders
(NDDs). Aim 1 will perform rare variant burden analyses across human-lost CREs and other classes of human-
specific regulatory changes to assess whether enhancer loss and gain differentially contribute to disease risk.
Aim 2 will employ massively parallel reporter assays in human iPSC-derived neurons and neural progenitor cells
to assess regulatory activity of human and chimpanzee orthologous sequences and to evaluate rare variants
identified in NDD cohorts. Loci with differential activity will undergo CRISPR inhibition in chimpanzee neurons to
determine the ancestral role of these CREs.
The fellowship provides comprehensive training in experimental and computational genomics at the
University of Alabama at Birmingham and the HudsonAlpha Institute for Biotechnology. Under the mentorship of
Drs. Nicholas Cochran and Gregory Cooper, the candidate will gain expertise in functional genomics, variant
interpretation, and statistical genetics, within a collaborative environment that integrates human disease genetics
with evolutionary biology. This work will determine how enhancer loss has shaped human brain evolution and
how its disruption contributes to neurodevelopmental disease.
Istituzione: UNIVERSITY OF ALABAMA AT BIRMINGHAM
PI: Ashlyn Anderson
Progetto: 1F31MH145830-01
Settori: National Institute of Mental Health
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