Culling the human genome of disease variants using ultraconserved elements Objectives: The immediate goal of the proposed studies is to explore the process by which a very curious set of sequences, called ultraconserved elements (UCEs), appear to recognize deleterious ge- nome rearrangements and then induce cells that carry such rearrangements to cull themselves away. As such, UCEs may embody an activity that could ultimately enable strategies for clearing bodies of diseased cells. Given that genome rearrangements lie at the heart of many diseases, including cancers and neurodevelopmental disorders, the proposed studies have the potential to contribute to the treat- ment of such diseases. Finally, as UCEs remain one of the least understood sequences of the genome, the studies proposed here may also contribute to elucidating the structural and functional aspects of these very enigmatic elements. Health relatedness: The proposed studies will pertain to cancer biology, neurodevelopmental dis- orders, and potentially any disease associated with genome instability, as they stem from a stunningly nonrandom change in the positional relationship between UCEs and the breakpoints of structural vari- ants representing healthy individuals and those representing individuals bearing deleterious genome re- arrangements. Innovation: The proposed studies offer two levels of innovation. First, they suggest that UCEs may constitute a new kind of genetic element, whose function is simply to resist change. This would be in contrast promoters, enhancers, and transcription units, whose functions are to produce an activity or a product. The long-term innovation of the proposed studies lies with the notion that UCEs may embody an endogenous activity which permits cells to assess their genome for deleterious rearrangements and, thus, may ultimately be harnessed as an exquisitely sensitive surveillance system for protecting our bodies against disease.
Specific Aims : The goal of the proposed studies is to explore the potential of using UCEs to clear cell populations and, thus, bodies of deleterious rearrangements. As such, the proposed aims will use computational, genetic, molecular genetic, and imaging technologies to: A. Determine whether UCEs represent a new kind of genetic element. B. Clarify why UCEs appear so responsive to structural variation. C. Screen the genome for genes that underlie the responsiveness of UCEs to structural variation.

Public Health Relevance

/Relevance Culling the human genome of disease variants using ultraconserved elements Ultraconserved elements (UCEs) are a puzzling class of DNA sequences that are ?200 bases long and 100% identical between the reference genomes of distantly related species. As neither protein coding sequences, nor enhancers, nor transcription factor binding sites, nor promoters require such a high level of conservation, the mere existence of UCEs has been a long debated conundrum. The ex- periments described in this application will test a hypothesis for the mechanism of ultraconservation, wherein UCEs partake in a process by which cells are able to sense the presence of deleterious rear- rangements and, if such rearrangements are detected, cull themselves from the population.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Parisi, Melissa
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Harvard Medical School
Schools of Medicine
United States
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McCole, Ruth B; Erceg, Jelena; Saylor, Wren et al. (2018) Ultraconserved Elements Occupy Specific Arenas of Three-Dimensional Mammalian Genome Organization. Cell Rep 24:479-488
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Beliveau, Brian J; Boettiger, Alistair N; Nir, Guy et al. (2017) In Situ Super-Resolution Imaging of Genomic DNA with OligoSTORM and OligoDNA-PAINT. Methods Mol Biol 1663:231-252