Common-disease associated variants systematically localize to the regulatory DNA of specific cell and tissue types, suggesting that the genome-wide activity of regulatory elements can provide key epigenetic context for the interpretation of genetic variation. However, regulatory elements in mammalian genomes are exquisitely sensitive to genomic context and often regulate distant genes. Thus, interpretation of the functional conse- quences of sequence variation at non-coding regulatory elements has been impeded by the lack of a mecha- nistic understanding of genomic regulatory structure and the sequence determinants of long-range interaction. I propose an experimental and computational research plan to address this pressing problem, focusing on four fundamental questions: Do sequence features of distal regulatory elements specify interaction with nearby promoters? To what extent do intervening sequence elements affect long-distance interaction genome-wide? Is long-distance interaction organized into functional domains in mammalian genomes? Do regulatory elements act in modular combinations of reducible activities, or do they instead form constellations of emergent regulato- ry function? This work will dramatically extend our understanding of the genomics of transcriptional regulation, facilitating systems-level analyses of common disease-associated variation in human genomes and industrial applications for genome editing and gene therapy.
The last decade in human genetics has seen an explosion in the number of variants linked to common human traits and diseases, but the majority of these variants fall in non-coding regulatory DNA. Although it is likely that they act by altering the levels or timing of the expression of particular genes, application of these findings to the public health has been impeded by the difficulty of characterizing functional regulatory variation. This proposal includes basic mechanistic work to uncover the sequence determinants of long-distance interaction in mamma- lian genomes and identify domains of independent cell-type specific regulation, promising to dramatically im- prove our ability to connect non-coding regulatory elements to their target genes, with a major impact on our ability to perform systems-level analysis of disease-associated variation.
|Morris, John A; Kemp, John P; Youlten, Scott E et al. (2018) An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet :|