New sequencing method reveals how transposons move and shape the genome

Cornell researchers have found that a new DNA sequencing technology can be used to study how transposons move within and bind to the genome. Transposons play critical roles in immune response, neurological function and genetic evolution, and implications of the finding include agricultural advancements and understanding disease development and treatment. 

In a paper published Nov. 21 in iScience, senior author Patrick Murphy, Ph.D. '13, associate professor of molecular biology and genetics in the College of Agriculture and Life Sciences, and co-authors demonstrate that a high-resolution genome mapping technique called CUT&Tag can overcome shortcomings in existing sequencing methods to enable study of transposons. Once derided as "junk DNA," transposons make up half the human genome and are descended from ancient viruses encountered by our evolutionary ancestors. 

If you survive a viral infection, the virus becomes dormant, but the virus's DNA sticks around. If that DNA gets into a sperm or an egg cell, then it can be passed on to the next generation and every descendant from there on. This process has happened thousands and thousands of times over evolutionary history. This ancient viral DNA – transposons – is not just junk sitting there taking space in our genome. It has become an integral part of our genome that helps us and other organisms to function."

Patrick Murphy, Ph.D. '13, associate professor of molecular biology and genetics, College of Agriculture and Life Sciences

Transposons were first discovered in the late 1940s in maize by Barbara McClintock, Class of 1923, M.A. 1925, Ph.D. 1927 – work that earned her the 1983 Nobel Prize in physiology or medicine. In humans, when transposons "jump" into different positions in the genome, they create a genetic mutation that can cause harm, grant protection or lead to evolutionary change.

For example, transposon-driven mutations can cause diseases, including hemophilia and certain cancers. They can also offer protection against some modern-day infections. At the very earliest stages of human development, certain transposons activate and enable creation of stem cells. They are also active in placental development, which enabled mammalian evolution. 

For as much as is known about transposons, far more remains a mystery, Murphy said. This is because standard methods used for decades to study genetic material have involved breaking open cells and separating liquid from solid materials. Scientists have studied the liquid portion and largely thrown away the solid, because there was no way to study it (thus the "junk DNA" moniker assigned in the 1970s).

"What our study finds is that the solid part is where all the transposons are," Murphy said. 

CUT&Tag was introduced by researchers at the Fred Hutchinson Cancer Research Center in Seattle in 2019 as a way to study chromatins – the DNA and proteins that form chromosomes. In their iScience paper, Cornell researchers have found that CUT&Tag also enables new exploration into the transposon-heavy half of the human genome. The possibilities for applied impact from this basic discovery are massive, Murphy said.

For example, some cancer therapies work by activating transposons in the genome, which elicit the immune system to attack the cancer. Better understanding of these mechanisms could drive more targeted therapies. 

"Because of these new methods and technologies, I think in the next five to 10 years we're going to be entering a golden age where we start to really understand how transposons work, and whether they can be taken advantage of in things like clinical therapy, fertility treatment and understanding organismal development," Murphy said. "It's so basic; it's going to have wide, sweeping impacts on agriculture, plants, microorganisms, humans, disease, speciation studies and many others."

First author of the paper is Brandon Park, formerly a doctoral student in Murphy's lab at the University of Rochester (Murphy moved to Cornell this year). Other Cornell co-authors are: Shan Hua, a postdoctoral associate in Murphy's lab; researcher Karli Casler; and Kristin Murphy, Ph.D. '13, a senior research associate in the College of Veterinary Medicine. Additional co-authors come from the lab of Mitchell O'Connell, associate professor at the University of Rochester. 

The research was supported by the National Institutes of Health.