Stem Cell Center, Yale: Stem Cell Genetics
What makes us human? Our capacities for invention, language and abstract thought set us apart from all other living things. With the sequencing of the human genome and the genomes of our closest primate relatives, locating the origins of such uniquely human characteristics has become a tractable genetic problem.
Many human traits are based on anatomical changes, including increased brain size and changes in the morphology of the limbs, that evolved due to genetic changes in development. Our laboratory uses a combination of computational and in vivo experimental approaches to study human-specific changes in developmental gene regulation. We are pursuing an integrated strategy that synthesizes maps of human-specific accelerated evolution in noncoding DNAs, in vivo analysis of cis-regulatory elements, and functional genomic atlases of human development to reveal the genetic basis of unique human biology.
Extensive Research Description
Most studies of human-specific sequence change have focused on protein coding genes. The reasons for this are twofold: genes are well annotated, and the genetic code allows the direct identification of amino acid replacements from substitutions in DNA sequence. Although it has long been appreciated that gene regulatory changes influenced human evolution, our poor understanding of how regulatory functions are encoded in the genome has hindered efforts to identify such changes. However, recent advances have made it possible to comprehensively study the evolution of gene regulation in humans. Genome-wide in vivo and ex vivo screens have identified thousands of distant-acting cis-regulatory elements. Global studies of gene regulation and chromatin state in human cells are revealing the large-scale regulatory architecture of the genome.
We are exploiting these advances to identify human-specific changes in developmental gene regulation that contributed to human evolution. Our interest in developmental gene regulatory change is motivated by the recognition that many complex human-specific traits, including language and sophisticated tool use, are based in part on physical changes – such as increased brain size or complexity, or changes in limb shape and proportions – that fundamentally require changes in development. Global identification of developmental enhancers in the human genome, in tandem with many other studies, strongly support a modular regulatory architecture for many developmental genes, in which an array of multiple discrete, partially redundant cis-regulatory elements interact to define the total expression pattern of a particular gene. There is a growing consensus that functional changes in cis-regulatory modules were critical to the morphological evolution of many species, including humans.
We are studying changes in developmental gene regulation during human evolution on multiple levels. We are refining statistical methods to quantify the rate of human-specific sequence change in noncoding DNA, in order to identify regulatory elements that changed rapidly in human evolution. We are characterizing individual cis-regulatory elements with human-specific developmental functions by reverse genetic analysis in mouse models. Finally, we are developing functional genomics methods to directly compare mechanisms of gene and genome regulation in human and non-human primate development.
- Reilly SK, Yin J, Ayoub AE, Emera D, Leng J, Cotney J, Sarro R, Rakic P, Noonan JP. (2015). Evolutionary changes in promoter and enhancer activity during human corticogenesis. Science 347:1155-9.
- Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP. (2015). The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat. Commun. 6:6404.
- Cotney J, Leng J, Yin J, Reilly SK, DeMare LE, Emera D, Ayoub AE, Rakic P, Noonan JP. (2013). The evolution of lineage-specific regulatory activities in the human embryonic limb. Cell 154:185-196.
- DeMare LE, Leng J, Cotney J, Reilly SK, Yin J, Sarro R, Noonan JP. (2013). The genomic landscape of cohesin-associated chromatin interactions. Genome Res. 23:1224-34.
- Cotney J, Leng J, Oh S, DeMare LE, Reilly SK, Gerstein MB, Noonan JP. (2012). Chromatin state signatures associated with tissue-specific gene expression and enhancer activity in the embryonic limb. Genome Res. 22:1069-80.
- Ayoub AE, Oh S, Xie Y, Leng J, Cotney J, Dominguez MH, Noonan JP, Rakic P. (2011). Transcriptional programs in transient embryonic zones of the cerebral cortex defined by high-resolution mRNA sequencing. Proc. Natl. Acad. Sci. USA 108:14950-55.
- Noonan JP, McCallion AS. (2010). Genomics of long-range regulatory elements. Annu. Rev. Genomics. Hum. Genet. 11:1-23.
- Prabhakar S, Visel A, Akiyama JA, Shoukry M, Lewis KD, Holt A, Plajzer-Frick I, Morrison H, Fitzpatrick DR, Afzal V, Pennacchio LA, Rubin EM, Noonan JP* (2008). Human-specific gain of function in a developmental enhancer. Science 321:1346-50. *Corresponding author
- Prabhakar S*, Noonan JP*, Pääbo S, Rubin EM. (2006). Accelerated evolution of conserved noncoding sequences in humans. Science 314: 786 *Equal contribution