The Center for Systems Biology of Retrotransposition

Our Center studies mouse and human retrotransposons, focusing on the LINE-1 (L1) autonomous element but expanding as appropriate to non-autonomous elements such as Alu and SVA. These retrotransposons are actively propagating in the genomes of mice and men, and represent complex networked systems within each cell at four or more distinct levels:

Mechanism of replication. Retrotransposons exploit host cell proteins to replicating their genome and insert it into host genomic DNA.

Targeting. Every type of transposable element has some degree of preferential targeting at distinct levels of primary DNA. Sequence, chromatin structure, host proteins and perhaps 3D positioning in the nucleus may all play roles in determining insertion site preference.

Cell and tumor type impact on insertion frequency. How do cellular environments resist or become hospitable for transposition? Why are LINE-1 retrotransposon insertions common in colon cancer but much less so in other tumor types?

Host evolution. The co-evolution of hosts and retrotransposon parasites represents an important yet understudied aspect of retrotransposon biology. We will evaluate several aspects of host response to newly introduced retrotransposons and use models of mammalian gene evolution to identify loci under positive (diversifying) selection involved in adaptive responses to endogenous retrotransposons.

We are a diverse multidisciplinary team of investigators with a variety of relevant areas of expertise with the overarching goal of understanding transposable elements and their hosts through approaches integrating experimental, informational, and computational sciences. In addition to clarifying our concept of transposon-host relationships, the work has implications for using transposable elements for gene therapy and forward genetic screens, and will enhance our understanding of roles they play in human disease as inherited genetic variants and as somatic mutagens. We also look forward to reaching out to the larger “transposon community” to engage them in systems biology work.