Research in the Burns Lab

Interspersed repeats and genetic variation
Specific types of transposons are active in humans, and our lab was one of the first to develop strategies to map insertion sites of these elements in the human genome. Our observations underscored that transposons are major sources of genetic structural variation in human populations (Cell, 2010). Over the next decade, catalogs of commonly-occurring mobile element insertion alleles grew, and our group led efforts to identify those variants that may be relevant to disease risk by integrating information about these insertions with findings of genome wide association studies (GWAS) (PNAS, 2017). Our group has since developed experimental systems to show that inherited transposable element insertion alleles can affect gene expression (Genome Research, 2021) and mRNA splicing (Nucleic Acids Research, 2019), demonstrating molecular mechanisms for how transposons may impact phenotypes. Together, these avenues have shown that we each inherit a unique compliment of transposon insertions – thousands of LINE-1, Alu, SVA, and ERV alleles – and that a specific subset of these have phenotypic effects.
See our review: Nature Reviews Genetics (2019).

LINE-1 ORF1p expression as a cancer biomarker
Our laboratory has had a long-standing interest in transposable element expression in human malignancies. Many cancers undergo epigenetic changes that permit the expression of otherwise silenced transposable elements. Here, we are best known for our research on Long INterspersed Element-1 (LINE-1, L1), the only protein-coding retrotransposon active in modern humans. We were the first to develop and commercialize a monoclonal antibody to detect the LINE-1-encoded RNA-binding protein, open reading frame 1 protein (ORF1p). Using this reagent, we showed that LINE-1 expression is a hallmark of human cancers, including many of the most common and lethal forms of these diseases (Am J Path, 2014). We have more recently shown that ORF1p is detectable in the peripheral blood where it shows promise as a cancer biomarker (Cancer Discovery, 2024). 

LINE-1 ORF2p as a mutagen in cancers
We have shown that cancers that express ORF1p have somatically-acquired LINE-1 insertions that distinguish tumor genomes from a patient’s constitutional genetic make-up. We have led collaborations to map somatically-acquired LINE-1 insertion sites in pancreatic (Nature Medicine, 2015) and ovarian cancers (PNAS, 2017) and participated in larger efforts to identify somatically-acquired insertions as part of the International Cancer Genome Consortium (Nature Genetics, 2020). Using experimental systems that allow us to control expression of LINE-1, we find that LINE-1 causes DNA double-strand breaks (DSBs), which can be ligated to result in deletions and stable, reciprocally translocated chromosomes or unstable dicentric, acentric, or ring chromosomes that undergo subsequent breakage-fusion bridge cycles or chromothripsis (bioRxiv, 2024). These findings compliment cell fitness screen data we reported demonstrating that LINE-1 expression increases selective pressure on cells to lose p53 and imposes molecular dependencies on replication-coupled DNA repair pathways (i.e., Fanconi Anemia-BRCA)(Nature Structural and Molecular Biology, 2020). Together, these studies suggest LINE-1 is a potent mutagenic and selective force driving cancer genome evolution.
See our review: Nature Reviews Cancer (2017). 
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