Humans possess unique biological features compared to other primates. Among the most important of these are a larger and more complex cerebral cortex, and morphological changes in the limbs that allow humans to use sophisticated tools and walk upright. The evolution of these physical innovations has long been thought to involve sequence changes that altered gene regulation in development. However, the locations of such changes are only now beginning to be revealed, and their effects on gene expression and development remain unknown. The goal of this research project, which was initiated in 2010, is to identify regulatory elements with human-specific developmental activities and determine their biological impact. In the current funding period, we have focused on mapping sites likely to encode uniquely human promoter or enhancer functions using two complementary strategies. The first is experimental analysis of conserved noncoding sequences that show accelerated evolution in humans, which we and other groups have shown include developmental enhancers with human-specific activities. The second is comparative epigenetic analysis of limb and cortex development in human, rhesus macaque and mouse, to directly identify promoters and enhancers that have gained activity in humans. Sequences that exhibit both human-specific evolutionary acceleration and increased activity based on epigenetic marks are prime candidates for encoding novel regulatory functions with potentially large biological effects. Our priority in this renewal is to generate and study humanized mouse models for human accelerated regions that show epigenetic gains in the developing human limb or cortex. We will use CRISPR/Cas9 genome editing technology to rapidly generate genetically modified mice by gene targeting in single cell mouse embryos. We will then conduct genome-wide molecular analyses of embryonic development in these models to identify global changes in gene expression and regulation. Guided by the results of these studies, we will carry out targeted phenotypic analysis of limb and cortex development in humanized mice to identify biological processes altered by human-specific regulatory changes.

Public Health Relevance

Humans exhibit many unique biological differences compared to other species. Among the most important of these are our larger and more complex brain, and changes in our limbs that allow us to use tools and walk upright. Our goal is to characterize the genetic changes in human evolution that drove changes in human brain and limb development. Understanding human biological uniqueness is of fundamental scientific importance and will contribute to the study of disorders unique to humans, including neurodevelopmental and neuropsychiatric diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Krasnewich, Donna M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Sarro, Richard; Kocher, Acadia A; Emera, Deena et al. (2018) Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development. Development 145:
Wilderman, Andrea; VanOudenhove, Jennifer; Kron, Jeffrey et al. (2018) High-Resolution Epigenomic Atlas of Human Embryonic Craniofacial Development. Cell Rep 23:1581-1597
Liu, Yuwen; Liang, Yanyu; Cicek, A Ercument et al. (2018) A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies. Am J Hum Genet 102:1031-1047
Sousa, André M M; Zhu, Ying; Raghanti, Mary Ann et al. (2017) Molecular and cellular reorganization of neural circuits in the human lineage. Science 358:1027-1032
Reilly, Steven K; Noonan, James P (2016) Evolution of Gene Regulation in Humans. Annu Rev Genomics Hum Genet 17:45-67
Emera, Deena; Yin, Jun; Reilly, Steven K et al. (2016) Origin and evolution of developmental enhancers in the mammalian neocortex. Proc Natl Acad Sci U S A 113:E2617-26
Cotney, Justin; Muhle, Rebecca A; Sanders, Stephan J et al. (2015) The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat Commun 6:6404
Reilly, Steven K; Yin, Jun; Ayoub, Albert E et al. (2015) Evolutionary genomics. Evolutionary changes in promoter and enhancer activity during human corticogenesis. Science 347:1155-9
Cotney, Justin L; Noonan, James P (2015) Chromatin immunoprecipitation with fixed animal tissues and preparation for high-throughput sequencing. Cold Spring Harb Protoc 2015:191-9
Liu, Li; Lei, Jing; Sanders, Stephan J et al. (2014) DAWN: a framework to identify autism genes and subnetworks using gene expression and genetics. Mol Autism 5:22

Showing the most recent 10 out of 18 publications