Retrotransposon sequences make up a significant portion of genomes in virtually all eukaryotes, and are actively propagating in the genomes of mice and men. Retrotransposons and their hosts represent complex networked systems at several levels. These include: 1) Mechanism of replication. Retrotransposon sequences encode no to few proteins, and thus interact with many host cell encoded proteins during the 'life cycle' of their propagation. These tap into pathways existing in the host for other purposes, to achieve the mechanistic steps involved in replicating their genome and inserting it into host genomic DNA. A myriad of host proteins also counter transposable element insertions and must be evaded or overwhelmed by retrotransposons. Systems biology approaches can be used to describe relationships between these physical interactors. 2) Targeting. Each phosphodiester bond in the genome represents a potential target for insertion of a transposon sequence, and yet every type of transposable element has some degree of preferential targeting at distinct levels of genomic organization. Sequences themselves, DNA modifications and chromatin structure, host proteins binding sites, and perhaps three dimensional positioning in the nucleus may all play roles in determining insertion site preference. These system level questions merit renewed consideration that exploit new high throughput methods for identifying retrotransposon insertion sites. 3) Cell-type specific limits to insertion. We will also focus on a very challenging - and medically relevant - systems level question to answer: how cell type specific interactions between mammalian hosts and LINE-1 retrotransposon specifically impact human health and disease. We will delineate how specific cellular environments resist or become hospitable for transposition, and approach questions like 'Why are LINE-1 retrotransposon insertions common in colon cancer but less so in other tumor types?' 4) Host evolution. Species exist in a dynamic state with respect to these genomic invaders, constantly redefining mechanisms of resistance to retrotransposition. To better understand how new retrotransposon challenges are met, we will evaluate several aspects of host response to newly introduced retrotransposons in two experimental systems. We will also use models of mammalian gene evolution to identify loci under positive (diversifying) selection involved in adaptive responses to endogenous retrotransposons. The co-evolution of hosts and retrotransposon parasites represents an important yet understudied aspect of retrotransposon biology. Together, investigators in these topic areas will define our Center for Systems Biology of Retrotransposition.

RELEVANCE (See instructions): The Center for Systems Biology of Retrotransposition will generate unique contributions to systems biology research. As described above, interactions between hosts and transposons are multifaceted and-intricate. Systems approaches hold promise for analyzing and integrating high throughput datasets scaled to capture the complexity of these interactions, as well as for modeling aspects of host-transposon relationships. We expect the field will provide unprecedented opportunities develop systems approaches and to understand and manipulate the vital, highly coordinated relationship between host and transposons in targeted ways.