Among extant life on Earth, single-celled organisms such as bacteria and Archaea have highly compact and efficient genomes with evolutionary selection against non-coding intergenic space. However, large multicellular organisms including humans have greatly expanded genomes with substantial portions of DNA that have little or no obvious use. In fact, only about 3% of your own genome codes for functional proteins that make up your being. The rest – over 97% – is “dark” DNA, consisting of intronic sequences, extinct endogenous retroviruses, non-coding regions with variable regulatory roles, and the remnants of ancient mobile genetic elements known as transposons.
Many transposon sequences in the human genome are molecular fossils with no biochemical activities on their own. However, there is one called long interspersed element-1 (LINE-1) that is still capable of activity. LINE-1 is a type of transposon called a retrotransposon, a mobile genetic element that uses reverse transcriptase activity to copy its own RNA and insert itself back into the genome of its host.
LINE-1 and related retroelements in other eukaryotes are more than hundreds of millions of years old and share a common ancestor with bacterial group II introns that likely existed billions of years ago. Most LINE-1 sequences in humans are dead and inactive but there are a few that are still functional and capable of retrotransposition. Heavily repressed and regulated in normal cells, they lie dormant in the genome until age, disease, or prolonged stress causes them to awaken. LINE-1 activity is implicated in aging, autoimmunity, inflammatory disorders, and inherited disease. It is notably observed in several cancer types, such as breast and colon cancer where the DNA of tumor cells may be riddled with hundreds of LINE-1 insertions.
We seek to investigate the mechanisms and consequences of LINE-1 activation and retrotransposition in human cells. We work with LINE-1 RNA and proteins in cells and in vitro to understand the implications of its activities and effects in human disease. Our research has the potential to lead to new treatments and therapies for cancer, aging disorders, autoimmune diseases, sterile inflammation, and some genetic disorders.