Trends in Genetics
ReviewGene regulation and the origins of human biological uniqueness
Section snippets
Cis-regulatory change in human evolution
We consider ourselves to be unique among species. Our capacity for invention, language and abstract thought-indeed, the ability to reflect on the issue at all- sets us apart from all other living things, including our closest primate relatives. For most of human history the question of human uniqueness fell within the realm of religion or metaphysics, rather than natural science. With the sequencing of the human genome and the genomes of many non-human primate species, locating the origins of
Identifying cis-regulatory functions in the human genome
Developmental gene regulation is inherently complex. Thousands of genes must be expressed in highly specific spatial and temporal patterns if the embryo is to develop properly. Locating the components of the developmental regulatory code in the human genome is a central preoccupation of genomics, and is the first barrier to identifying human-specific regulatory changes relevant to human evolution. Thousands of promoters have been identified on the basis of their inherent proximity to genes, as
Annotating human-specific gene regulatory functions
The in vivo studies described above, combined with large-scale ex vivo studies such as ENCODE, have begun to reveal the cis-regulatory landscape of the human genome [14]. These studies provide the knowledge base for parallel genome-wide efforts to annotate uniquely human cis-regulatory functions. The outlines of this new field are just beginning to emerge, but two complementary approaches are likely to provide the greatest insight into human-specific biology. In the first approach, genome-wide
The question of adaptation
It has yet to be determined to what extent human-specific, non-coding sequence acceleration indicates adaptive changes in regulatory functions during human evolution. In other words, are the human-specific substitutions in HACNSs the relics of ancient positive selection for DNA sequence changes that increased fitness by altering the activities of cis-regulatory elements, or are they neutral events? The high frequency of human-specific A to G and T to C substitutions in some HARs and HACNSs,
Concluding remarks
We now have the means to identify and characterize the complete repertoire of gene regulatory changes contributing to human evolution. There are several crucial challenges that need to be met. We need to refine and expand maps of human-specific sequence change to include other modes of sequence change, such as indels. We also need to integrate maps of human-specific, cis-regulatory function with atlases of human-specific, trans-factor binding events, epigenetic modifications, and changes in
Acknowledgements
We thank members of the Noonan laboratory for insightful discussions. This work was supported by funds from the Edward J. Mallinckrodt Foundation, the Kavli Institute for Neuroscience, and the Yale University School of Medicine. The authors declare no conflict of interest.
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