Primates and their endogenous retroelements have coevolved for so long that almost half the human genome is derived from retroelements sequences. However, the replication of retroelements has the potential to inflict substantial harm by jumping into essential genes or activating the immune system to drive autoimmunity. To combat these deleterious effects on their genome, hosts have evolved a battery of restriction factors to block the replication of retroelements. Despite their importance to host fitness, I have found that many of these retroelements restriction factors have evolved rapidly during primate evolution, suggesting they have been recurrently selected for functional innovation. I hypothesize that primates and their endogenous retroelements are engaged in an `evolutionary arms race', or a recurrent cycle of evasion and restriction - retroelement adaptation to evade host restriction followed by host adaptation to restrict the newly evasive retroelement. In addition, my preliminary findings suggest that some restriction factors like APOBEC3A may also have been co- opted to restrict infectious viruses in addition to endogenous retroelements.
In Aim 1, I propose to characterize the causes and consequences of the rapid evolution of the APOBEC3A and APOBEC3B restriction factors, including how these factors may be evolving to chase L1 retroelements and how co-option of APOBEC3A to restrict infectious viruses has affected its ability to restrict endogenous retroelements.
In Aim 2, I propose to test the hypothesis that L1TD1 (a rapidly evolving, stem cell-specific gene that was domesticated from a portion of L1) functions as a retroelements restriction factor.
In Aim 3, I propose to use evolutionary analyses, as well as engineer an in vitro evolution system to test whether variation can indeed increase retroelement replication and exert selective pressure on the host. While my past training has enabled me to generate these intriguing hypotheses, my immediate goals are to gain the additional training in virology, molecular evolution, and retroelement biology that are absolutely necessary for me to experimentally test these ideas. I have assembled an accomplished and highly skilled group of mentors/collaborators to provide me with this additional training. During the two year mentored phase, I will train with Dr. Michael Emerman to learn virology. My mentor, Dr. Harmit Malik will provide additional training in the computational analysis of repetitive elements, and Dr. John Moran will provide collaboration and training on my development of new reagents and techniques to study retroelements. This future training combined with my graduate and postdoctoral experience will enable me to pursue a multifaceted approach to understanding the biology and evolution of retroelements and their hosts. These experiments will also establish novel mechanisms by which this evolution may drive human disease.
Almost half of the human genome derives from the sequence of endogenous retroelements, and as a result, humans have an array of control mechanisms to block the deleterious effects of element replication. While loss of these restriction factors causes disease, we propose to investigate the hypothesis that variation in elements themselves may represent an unappreciated form of genetic variation in humans that could result in autoimmunity or cancer. We also have evidence that selection to restrict infectious viruses could result in a loss of control of retroelements, which could cause genetic disease.