Fascinated by the scale of the impact transposable elements have had on the human genome (around half of the human genome comes from these elements), The McLaughlin Lab wants to understand the genetic mechanisms used by humans to defend against retroelements and the genetic mechanisms used by retroelements to support their own propagation.
This lab previously discovered the rapid evolution of several restriction factors of Long Interspersed Element-1 (L1), the endogenous retroelements most active in humans. This pattern of evolution suggests that L1s have evolved to evade these restriction factors, driving rapid host evolution to keep pace. However, it is unknown how sequence variation in L1s impacts their ability to evade and replicate in the presence of host restriction factors.
This research group is specifically interested in understanding – have transposable elements evolved to evade the defense mechanisms of the human genome? What are the mechanisms of transposable element evasion? What are the consequences to human health of evasive transposable elements replicating at times and places they are normally repressed? To answer these questions, the McLaughlin Lab employs non-traditional combinations of approaches including retrospective analyses of genomes to understand what has happened and prospective experiments to ask what could happen.
They propose to leverage the labs recently generated, diverse panel of more than 130 young human L1s to search for variation in the ability of L1s to replicate in the presence of otherwise effective host restriction factors. This variation could indicate adaptation of an L1 to evade host restriction or adaptation of the host to restrict evasive L1s. In addition to this retrospective analysis of evolutionary history, they propose to ‘speed up’ evolution by building an in vitro evolution system to select for L1s that evade a defined restriction factor. Comparison of these historical and prospective evolutionary approaches will help us decode the selective pressures that drove L1 and human evolution. This research will address a fascinating basic science question about the mechanisms of L1 evolution in the face of the host innate immune system with impact on the understanding of sporadic autoimmune diseases without a clear genetic contribution.