Creative Minds: Bacteria, Gene Swaps, and Human Cancer

Posted on February 18, 2016 by Dr. Francis Collins

Julie Dunning Hotopp

When Julie Dunning Hotopp was a post-doctoral fellow in the early 2000s, bacteria were known for swapping bits of their DNA with other bacteria, a strategy known as lateral gene transfer. But the offloading of genes from bacteria into multicellular organisms was thought to be rare, with limited evidence that a bacterial genus calledWolbachia, which invades the cells of other organisms and takes up permanent residence, had passed off some of its DNA onto a species of beetle and a parasitic worm. Dunning Hotopp wondered whether lateral gene transfer might be a more common phenomenon than the evidence showed.

She and her colleagues soon discovered that Wolbachiahad engaged in widespread lateral gene transfer with eight species of insects and nematode worms, possibly passing on genes and traits to their invertebrate hosts [1]. This important discovery put Dunning Hotopp on a research trail that now has taken a sharp turn toward human cancer and earned her a 2015 NIH Director’s Transformative Research Award. This NIH award supports exceptionally innovative research projects that are inherently risky and untested but have the potential to change fundamental research paradigms in areas such as cancer and throughout the biomedical sciences.

Unlike insects and worms, people don’t harbor lots of bacteria in their cells. But the human body does play host to a diverse array of microbes, collectively known as the human microbiome. Dunning Hotopp, now an associate professor of microbiology and immunology at the University of Maryland School of Medicine, Baltimore, began wondering several years ago while pursuing this new research trail whether it was possible that bacterial DNA might also make its way into the human genome—probably not into the germline (the part that gets passed to future generations), but into various cells of the body (so-called somatic cells).

Dunning Hotopp searched for signs of bacterial gene transfer in publicly available data from the Human Genome Project, the 1000 Genomes Project, and The Cancer Genome Atlas. There, dispersed within this vast body of data, she found something others had overlooked: thousands of instances in which bacterial DNA had apparently become enmeshed in the DNA within human cells taken from about one out of every three people [2]. Interestingly, evidence of lateral gene transfer turned up much more frequently in cancerous cells than in healthy human cells. Microbial sequences were especially frequent in the genomes of acute myeloid leukemias (AML) and stomach cancers, and Dunning Hotopp’s latest NIH award will enable her to conduct additional studies for further confirmation.

It’s not yet clear whether bacterial DNA in human genomes causes cancer, or if cancer cells are somehow more prone to receiving DNA from microbial sources. As a next step, Dunning Hotopp plans to genetically engineer some of the insertions she’s uncovered into human cells in the lab to better understand their functional consequences and potential relationship to cancer.

The search for bacterial DNA in human sequences requires great care to ensure that any findings aren’t due to bacterial contamination of samples. In fact, one reason it’s taken this long to confirm the existence of bacterial DNA in the human genome is because evidence of bacterial sequences, once found, has often been thrown out!

To address this problem and help streamline the search for lateral gene transfer in the human genome, Dunning Hotopp and her colleagues are devising bioinformatics tools, which they intend to share with the scientific community. As these tools become available, I’ll look forward to learning what she and others will uncover.

References:

[1] Widespread lateral gene transfer from intracellular bacteria to multicellular eukaryotes. Dunning Hotopp JC, Clark ME, Oliveira DC, Foster JM, Fischer P, Muñoz Torres MC, Giebel JD, Kumar N, Ishmael N, Wang S, Ingram J, Nene RV, Shepard J, Tomkins J, Richards S, Spiro DJ, Ghedin E, Slatko BE, Tettelin H, Werren JH. Science. 2007 Sep 21;317(5845):1753-6.

[2] Bacteria-human somatic cell lateral gene transfer is enriched in cancer samples. Riley DR, Sieber KB, Robinson KM, White JR, Ganesan A, Nourbakhsh S, Dunning Hotopp JC. PLoS Comput Biol. 2013;9(6):e1003107.

Links:

Julie Dunning Hotopp (University of Maryland School of Medicine, Baltimore)

NIH Human Microbiome Project (NIH)

Dunning Hotopp NIH Project Information (NIH RePORTER)

NIH Director’s Transformative Research Award Program (NIH)

NIH Support: Common Fund