These findings by Julie Kerns, Ph.D., a postdoctoral researcher in the Hutchinson Center’s Basic Sciences Division, published Jan. 25 in the open-access journal PLoS Genetics, present a striking example by which evolutionary studies can directly lead to biomedically important discoveries in the field of infectious diseases.
The immunity gene, called ZAP, is a key player in a newly discovered branch of antiviral defenses in mammals referred to as ‘‘intrinsic immunity.’’ Host proteins like ZAP can target intracellular stages of the viral life cycle to inhibit viral activity. The ZAP gene, first discovered in rats, thwarts a variety of divergent viruses, from retroviruses (like HIV) to alphaviruses (like Sindbis) to filoviruses (like Ebola).
Researchers believe ZAP functions by virtue of its RNA-binding abilities, which recognize specific sequences of the virus and target their viral RNA for destruction. Host-virus interactions are a classic example of genetic conflict in which both entities try to gain an evolutionary advantage over the other. This ‘‘back-and-forth’’ evolution is predicted to result in rapid changes of both host and viral proteins, which results in an evolutionary signature of positive selection, especially at the direct interaction interface.
“This suggests that we might be able to deduce host-virus conflicts purely by looking at rapidly evolving protein segments,” said Kerns, the lead author of the study, which was conducted in collaboration with senior author Harmit Singh Malik, Ph.D., of the Center’s Basic Sciences Division and co-author Michael Emerman, Ph.D., of the Center’s Human Biology Division.
The researchers found that there has been very little sequence evolution in the RNA-binding domain, which suggests that human ZAP may be similar to the rat gene in its viral RNA-binding specificity. However, surprisingly, the rapid evolution characteristic of “intrinsic immunity” genes was concentrated in a protein domain that was not even present in the originally discovered rat gene.
The authors found that humans encode two protein versions, or isoforms, from a single ZAP gene: a shorter version similar to the original rat gene and a longer version that possesses a rapidly evolving poly (ADP-ribose) polymerase (PARP)-like domain. In virological assays, the longer human ZAP protein isoform has higher antiviral activity. Thus, positive selection correctly predicted the more potent antiviral isoform of this protein.
The authors further suggest that ZAP is locked in a conflict with alphaviruses. The discovery of a potential human gene that can restrict alphaviral infection is particularly timely as the mosquito-borne alphavirus, Chikungunya, was responsible for a large epidemic in parts of Southeast Asia in 2006 and is now threatening to invade parts of Europe. The researchers believe this finding has important implications for the understanding of intrinsic immunity against viruses, and could potentially serve as a guide in the development of antiviral therapeutics.
“We think that a particular alphaviral protein may be playing an evolutionary ‘cat-and-mouse’ game with the ZAP gene,” Malik said. “Identifying this protein could lead to novel ways to tackle diseases caused by alphaviruses.”
Kristen Woodward | EurekAlert!
Gene therapy shows promise for treating Niemann-Pick disease type C1
27.10.2016 | NIH/National Human Genome Research Institute
'Neighbor maps' reveal the genome's 3-D shape
27.10.2016 | International School of Advanced Studies (SISSA)
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
27.10.2016 | Materials Sciences
27.10.2016 | Physics and Astronomy
27.10.2016 | Life Sciences