Our current research program is focused on deciphering the role of gene regulatory changes in the evolution of uniquely human traits, particularly the expansion and elaboration of the human cerebral cortex. Our initial efforts targeted a class of elements that we and others first characterized over a decade ago: Human Accelerated Regions (HARs). These elements are highly conserved across species but show many human-specific changes, suggesting they encode uniquely human functions of potentially large effect. We have since expanded the scope of our work to globally identify human-specific regulatory innovations using experimental methods. Our current research is aimed at understanding the phenotypes these regulatory changes specify using humanized mouse models, massively parallel genetic screens, and cellular models of primate neurodevelopment.
Specialized Terms: Human Evolution; Evolutionary Dynamics of Gene Regulation; Synthetic Biology; Applications of Ultra-High Throughput Sequencing Technologies; Comparative and Functional Genomics in Vertebrates
Our laboratory has made multiple contributions over the last decade. We were the first to discover that HARs encode transcriptional enhancers with human-specific activity in the developing embryo (Prabhakar et al. 2008). We have since pioneered the development of humanized mouse models to understand how HARs alter developmental gene expression and drive the evolution of novel phenotypes. In a recent study, we found that the HAR HACNS1 upregulates expression of the transcription factor gene Gbx2 in limb bud chondrogenic mesenchyme, suggesting the human-specific gain of function in HACNS1 contributed to changes in skeletal patterning in human limb evolution (Dutrow et al. 2019).
We also developed methods to map and quantify the activity of gene regulatory elements during mammalian organogenesis, and to identify their gene targets (Cotney et al. 2012 and DeMare et al. 2013). Building on this work, we implemented comparative epigenetics approaches to identify uniquely human regulatory innovations by direct analysis of developing human and nonhuman tissues. This work discovered thousands of promoters and enhancers that have gained activity during human limb and neocortical development (Cotney et al. 2013 and Reilly et al. 2015). These studies have also identified biological pathways in limb and cortical development potentially altered by human-specific regulatory changes, providing the basis for understanding their effects using genetic and experimental models. We also leveraged these findings to understand general principles of developmental enhancer evolution and identify specific regulatory innovations contributing to the emergence of the mammalian neocortex (Emera et al. 2016). We also demonstrated that a major autism risk gene, CHD8, directly regulates other autism-associated genes during neurodevelopment, providing an entry point for deciphering gene regulatory networks contributing to autism risk (Cotney et al. 2015).
In the last several years, we have adopted massively parallel screening approaches to characterize gene regulatory functions contributing to the development and evolution of the human brain. We used massively parallel genome editing in human neural stem cells to disrupt thousands of enhancers active during human cortical development and identify enhancers, including HARs, required for neural stem cell self renewal (Geller et al. 2019). This study established a clear biological function for HARs in neurodevelopment. We have also used massively parallel reporter assays in neural stem cells to measure the effect of >32,000 uniquely human sequence changes on enhancer activity (Uebbing and Gockley et al. 2021).
Embryonic and Fetal Development; Genetics; Evolution, Molecular; Genomics; Gene Regulatory Networks; Epigenomics; Neurodevelopmental Disorders