PROJECT SUMMARY Transposable Elements (TEs) make up a large fraction of vertebrate genomes, including half of the human genome. The mutagenic properties of TEs are well documented and they are important drivers of genetic variation between and within species. However, how this enormous source of genetic variation has shaped the evolution and biology of species remains poorly understood. Our MIRA project is designed to yield transformative insights into the biological significance of TEs in evolution and disease. Our previous research has focused on the long-term impact of vertebrate TEs in driving genetic innovations. Notably, we showed that TEs have been a recurrent source of raw sequence material co- opted during vertebrate evolution to create new cis-regulatory elements driving changes in gene expression and new protein-coding genes underlying the emergence of novel cellular functions. Most of these events involved ancient TEs long inactive transpositionally. In this next funding cycle, we are turning our attention to young TEs -- those recently or currently mobile. We focus on the developmental impact of young TEs in humans and in zebrafish, a powerful model organism for studies of vertebrate development. By focusing on the functional impact of young retroelements in embryonic development we will uncover the molecular underpinnings of evolutionarily recent biological innovations. Notably, we will investigate the regulatory contribution of TEs in defining features of the human placenta, such as its deep invasion into maternal decidual tissue, and the functional significance of endogenous viral-like particles produced in the early stages of human embryonic development. Our work will also uncover general principles that lead to the cooption of specific TE sequences for cellular function. Specifically, we will test a new provocative model of host-TE interaction in which organismal development becomes dependent on TE- encoded products. We will test this ‘addiction model’ by studying the trans-regulatory activities of Gag (capsid) proteins encoded by endogenous retroviruses in human and zebrafish for which we have obtained preliminary evidence they modulate embryonic developmental processes. The outcomes of this project are expected to shift our view of host-TE interactions from conflicting to mutualistic. Our studies will also yield new mechanistic insights into poorly understood disease processes, such as pregnancy loss by preeclampsia and neurodevelopmental disorders, implicating the dysregulation of young TEs.