Genomic approaches to studying human-specific developmental traits

Published by The Company of Biologists Ltd | Development Genomic approaches to studying human-specific developmental traits Lucıá F. Franchini 2 Katherine S. Pollard 0 1 0 Institute for Human Genetics, Department of Epidemiology & Biostatistics, University of California , San Francisco, CA 94158 , USA 1 Gladstone Institutes , San Francisco, CA 94158 , USA 2 Instituto de Investigaciones en Ingenierıá Genética y Biologıá Molecular (INGEBI), Consejo Nacional de Investigaciones Cientıf́icas y Técnicas (CONICET) , Buenos Aires C1428 , Argentina Changes in developmental regulatory programs drive both disease and phenotypic differences among species. Linking human-specific traits to alterations in development is challenging, because we have lacked the tools to assay and manipulate regulatory networks in human and primate embryonic cells. This field was transformed by the sequencing of hundreds of genomes - human and non-human - that can be compared to discover the regulatory machinery of genes involved in human development. This approach has identified thousands of human-specific genome alterations in developmental genes and their regulatory regions. With recent advances in stem cell techniques, genome engineering, and genomics, we can now test these sequences for effects on developmental gene regulation and downstream phenotypes in human cells and tissues. Embryonic cells; Genomes; Phenotypic; Evolution; Chimpanzee - Introduction Humans differ from chimpanzees, our closest living relatives, and other mammals in a variety of traits, including disease susceptibilities. Many of these differences have their origins in development. The fossil record shows that some human traits, such as the pelvic morphology associated with upright walking (Harcourt-Smith et al., 2004), evolved around the time of divergence from our common ancestor with chimpanzees about six million years ago. Other traits, such as loss of a prominent brow ridge (Lieberman, 2000), emerged only after modern humans split from Neanderthals and other extinct hominins. Some phenotypes are very recently evolved, as evidenced by variation between modern human populations. These include pigmentation (Hancock et al., 2011), keratinization (Gautam et al., 2015), hair texture (Jablonski and Chaplin, 2014; Kamberov et al., 2013) and high altitude adaptation (Huerta-Sanchez et al., 2014; Simonson et al., 2010; Yi et al., 2010). For many distinctive traits, such as social behaviors, symbolic thought and spoken language (Sterelny, 2011), we have no evidence of the time period of evolution or only indirect evidence from changes in the material culture left behind in the archaeological record. Collectively, human-specific traits have allowed our species to dominate all climates and modify the landscape in a dramatic way *Authors for correspondence (; ) This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. never seen in the history of life on earth. At the same time, our species has acquired a unique profile of susceptibility to different diseases compared with our close relatives. Some examples are AIDS (Varki and Altheide, 2005), cardiovascular disease (Varki et al., 2009), neurodegenerative disease (Finch, 2010) and psychiatric disorders (Crow, 2000, 2007). Our high burden of neurological disease may be an ‘Achilles heel’ associated with cognitive adaptations (Crow, 2000, 2007). To understand the evolutionary forces that shaped human-specific traits and the molecular mechanisms through which changes occurred, we must first track down the genetic alterations underlying phenotypic differences between humans and our close relatives. As in other species, the evolution of human-specific traits must have emerged through genetic modification of developmental, physiological or behavioral programs. Development is a highly constrained and tightly regulated process, orchestrated through complex gene regulatory networks (Davidson and Erwin, 2006). There is a remarkable conservation of development between organisms as evolutionarily distant as cnidarians, insects and mammals. The same molecular pathways control this conserved developmental program across animal lineages. For example, humans, flatworms and cnidarians use the same basic elements of paracrine signaling cascades, such as the Wnt and TGFβ pathways (Finnerty et al., 2004; Carroll, 2005). Transcription factors that regulate development are also highly conserved, and they tend to regulate the same general processes in diverse species, including regulation of body axis patterning by Hox genes (Lemons and McGinnis, 2006), light-sensing organs by Pax6 (Gehring, 2011), head formation by Otx homologs (Yasuoka et al., 2014) and heart morphology by Tinman/Nkx2-5 (Erwin, 1999). This high lev (...truncated)