Understanding How Adaptive Changes Shape Human Neurodevelopment
Summary
In their search for the genetic basis of distinctive human traits, the researchers focused on conserved genomic regions, but this approach excludes functional elements that arose from previously neutral regions. Human ancestor quickly evolved regions (HAQERs) are the fastest-evolving regions of the human genome that underwent a burst of positive selection before the split between humans and Neanderthals and then became constrained within hominins. These regions are enriched for bivalent chromatin states and genetic variants associated with neurodevelopmental disease, especially in neurodevelopmental and gastrointestinal tissues. Using a multiplex single-cell in vivo enhancer assay, the researchers discovered that the rapid evolution of HAQERs produced distinct enhancers in the developing cerebral cortex of hominins. They hypothesize that the absence of pleiotropic constraints and high mutation rates in HAQERs made them more prone to rapid adaptation and disease.
Fig.1 Graphical abstract. (Mangan, 2022)
Research Criteria
The researchers developed scSTARR-seq (single-cell self-transcribing active regulatory region sequencing) to discover that rapid sequence divergence in HAQERs generated hominin-unique enhancers in the developing cerebral cortex.
Fig.2 Experimental design. (Mangan, 2022)
Sample Type
Wild type B6 mouse embryos at stages E14.5 and E15.5.
Result—A Multiplex, Single-Cell In Vivo Enhancer Assay Reveals Hominin-Specific Neurodevelopmental Enhancer Activity in HAQERS
They conducted in vivo scSTARR-seq experiments to study the activity of DNA sequences cloned into a STARR-seq vector in the embryonic mouse cerebral cortex. They injected the vector and a transfection reporter plasmid into the cortex and used FACS to sort GFP+ cells for single-cell RNA sequencing. In two independent experiments, they recovered STARR-seq reporter reads, endogenous RNA reads, and transfection reporter reads from 7,170 single cells. They found that six out of 13 HAQERs had significantly greater enhancer activity in hominin ortholog test sequences compared with non-hominin sequences, and HAQER1032 showed a small but statistically significant decrease in enhancer activity in hominin orthologous sequences.
Fig.3 Rapid sequence divergence in HAQERs generated hominin-specific neurodevelopmental enhancers. (Mangan, 2022)
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Reference
- Mangan, R.J.; et al. Adaptive sequence divergence forged new neurodevelopmental enhancers in humans. Cell. 2022, 185(24): 4587-4603.
