Repetitive sequences drive genome variation and plasticity

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

ABSTRACT The mechanisms by which mammalian genomes maintain stability through generations and divisions are important, and de-regulation of these cellular programs can lead to somatic mosaicism, disease, and cancer. Many multicellular eukaryotic genomes are replete with repeats that include ancient repeat mobility events, actively mobilizing transposable elements, and large segmentally duplicated regions. Human variation caused by transposable element mobility and structural rearrangements between repeats comprises more than a quarter of variants larger than fifty base pairs in the human population. These structural variants can lead to the insertion of promoter sequences, transcription factor binding sites, and even gene duplication events in mice and humans. Thus, mammalian genomes are comprised largely of repeat sequences, yet the role these sequences play in generating genomic instability, the factors that deter this instability, and the gene regulatory differences due to repeat variation are still poorly understood. Moreover, much of our knowledge on the genomic stability of repeats is derived from studies in yeast or from the use of reporter assays that interrogate discrete repeat sequences and distances. In the past five years, we have developed a robust research program using molecular genomics combined with computational biology to investigate the consequences of repetitive sequences on human and mouse genomes. In the next five years, we will identify repeat mediated rearrangements across large numbers of individuals and diverse species using our established approaches, interrogate how transposons have diversified gene regulation across a half million years of mouse evolution and the epigenetic and transcriptional consequences of this variation, and will identify the guardians of repeat mediated genomic stability and mobility. We will approach the proposed work with a diverse team of computational biologists, tool developers, graduate students, post-baccalaureate researchers, and summer students. The long-term goals of our research are to understand how mammalian genomes guard against variation in the context of repetitive sequences and how repeats can diversify genomes and gene regulation in short evolutionary timespans.