Scientists found a human genetic element in a poxvirus and discovered it was both an important gene for brain function and a jumping gene capable of moving and inserting itself in genomes.
A study published Sept. 24 in Science reports that the gene, called BC200, combines a mix of characteristics that have never been seen before.
BC200 is mostly expressed in neurons but originated millions of years ago from a transposon or ‘jumping gene’, a non-coding genetic element known for its ability to move and insert itself in genomes.
Transposons can insert blocks of DNA in a gene and disrupt function, leading to disease, but in the long-term they can be a constructive force in evolution to regulate or assemble new beneficial genes. While transposons account for half of human DNA, most of them are inactive, with a very small number of them remaining mobile and able to replicate within genomes.
Until now, no one has observed a human gene that is both mobile and required for bodily functions.
“Genes that come from transposable elements and that are repurposed for cellular functions are typically no longer transposable,” said Cedric Feschotte, the Barbara McClintock Professor in the Department of Molecular Biology and Genetics in the College of Agriculture and Life Sciences and a senior author of the study “BC200 was itself created from a mobile element but has retained its mobility and yet it is also clearly serving a cellular function. Somehow evolution hasn’t been able to untangle these two things,” Feschotte said.
Co-authors include Cheng Sun, professor of evolutionary genomics at Capital Normal University in Beijing, China; and Ellen Pritham, who was an assistant professor at the University of Texas at Arlingtonwhen the work was done.
The researchers first identified BC200 in 2010, when Feschotte was a faculty member at University of Texas, Arlington, and Cheng was a postdoctoral researcher in Feschotte’s and Pritham’s joint lab. At the time, Cheng was investigating human transposons in viral genomes using specialized software and genome databases, and he found two insertions of BC200 in a molluscum contagiosum virus (MCV), an infectiousbut largely benign human poxvirus that causes warts. Though the team recognized the importance of the discovery, they didn’t write a paper on it at the time.
Feschotte and Cheng recently met at a conference, and Cheng mentioned that he and his graduatestudent, Pu Gao, the paper’s first author, had resurrected the project. “I can’t believe we never got scooped on this,” Feschotte said.
A progenitor of BC200 was co-opted in a common primate ancestor from an ancient transposon roughly 40 million years ago and has jumped to MCV twice within modern human history (since the era of Homo sapiens), about 100,000 years ago.
There have been a few other documented cases of transposable elements in other species inserting in viruses, including in the late 1980s when researchers in a lab setting documented for the first time the insertion of a transposon from moth cells they were studying in culture to a baculovirus, known to infect insects.
“This was to my knowledge the first clear example of a transposon escaping its host genome to hop onto a virus,” Feschotte said, “which led to the idea that perhaps if viruses can cross species boundaries, then you may have a mechanism for the spread of these elements across species.”
Then in 2007, a group from Japan discovered a transposable element embedded in a rodent poxvirus, though the transposon originated in a snake, raising the likelihood that the virus also infected reptiles, though it had never been studied. “I think [at the time] it was the first and only case of a clearly vertebrate transposable element escaping into a virus in the wild,” Feschotte said.
BC200 is only found in humans and related primates and was discovered in the late 1980s as anabundant non-coding RNA in human neurons. Although BC200’s physiological function is poorly understood, evidence suggests it may be involved in regulating the translation of neuronal messenger RNAsinto proteins. It is also found in low levels in germ cells – sperm and eggs – making it potentially capable of generating inheritable insertions in other areas of the genome.
The researchers also suspect that it jumped in skin cells since these are the only cells known to be infected by MCV. The gene is also aberrantly expressed in some tumors and overexpressed in the brains of Alzheimer’s disease patients, suggesting its jumping ability could also play roles in these diseases.
Feschotte said he and colleagues would like to explore whether the molluscum contagiosum virus is using BC200 for its own purpose of manipulating human host cells. They are also interested in better understanding the gene’s role in disease, such as breast and other types of tumors, where it is abnormally expressed, and whether it is jumping in cancer cells and causing mutations.
Nobel Prize winner Barbara McClintock, Class of 1923, M.A. 1925, Ph.D. 1927, for whom Feschotte’sprofessorship is named, discovered transposons in the 1940s.
This work was supported by the National Natural Science Foundation of China, the University of Texas, Arlington, and Cornell.
