UConn Health professor of genetics and genome sciences Arthur Günzl has received a $450,000 grant from the National Institute of Allergy and Infectious Diseases to investigate the role of introns in a class of parasites, called kinetoplastids, responsible for the neglected tropical human diseases sleeping sickness, Chagas’ disease, and leishmaniasis.
These often lethal diseases are prevalent in tropical areas such as sub-Saharan Africa. The few existing drugs to treat them are toxic, expensive, and not always effective, especially as parasitic resistance to the drugs is on the rise.
Kinetoplastids are a class of organisms characterized by the presence of a kinetoplast—networks of circular DNA inside the single mitochondrion that contain many copies of the mitochondrion’s genome.
The structure of these organisms’ nuclear genomes is also unique in a few ways. The parasites have streamlined genomes in which the genes are arranged in dense arrays and the reading frames, which indicate the start and stop points of protein codes, are separated from each other by only a few hundred base pairs. These organisms have genomes 100 times smaller than humans, but still have about half as many protein-coding genes as we do.
In addition, kinetoplastids’ genomes do not encode many introns, a segment of DNA or RNA that doesn’t code for proteins. Introns appear to have been present in our earliest ancestors, and there are likely reasons why they have persisted through millennia after millennia of evolution.
The human genome includes 207,344 introns but T. brucei, a kinetoplastid Günzl is studying in this grant, contains only two. One of these introns is in the PAP1 gene which encodes a specialized enzyme involved in the maturation of Small Nucleotide RNAs (snoRNA). These small nucleolar RNAs are critical for the production and modification of ribosomes.
The other intron is in the DPB2B gene which encodes a so-called DEAD box RNA helicase. These helicases are important factors in cellular functions including transcription, RNA splicing, and ribosome creation, but the specific function of DPB2B in T. brucei is unknown.
Günzl found that in every kinetoplastid he and his team analyzed, these introns were present in the same location in these two specific genes. This means these introns have been around for 500 million years of evolution and that they serve a critical function for these organisms.
Günzl will investigate the role of these introns and, in the case of the DBP2P gene, the function of the helicase for which it codes.
Since these genes and the apparently vital introns within them are found in every example of kinetoplastids Günzl examined, this research could eventually provide a new target for drugs to treat diseases caused by these parasites.
Moreover, the project may reveal insights into basic eukaryotic biology. Since modern eukaryotes likely evolved from intron-rich ancestors, it appears that the process of genome streamlining eliminated many introns in some of the early-diverged eukaryotes. This process, however, stopped short at the last two introns in T. brucei, indicating the process of intron removal serves an essential role, beyond splicing to create RNA molecules for protein production, that has not been uncovered yet.
“The investigation of odd organisms has led to major biological insights in the past,” Günzl says. “It is our hope that we learn something fundamentally important in this project, too.”
Professor Günzl holds a Ph.D. in biological sciences from the University of Tübingen in Germany. He worked as a postdoctoral fellow at the Max Planck Institute for Molecular Genetics and the Yale University School of Medicine. Günzl’s research interests include the mechanisms of gene expression in T. brucei in hopes of identifying targets for new drugs to combat the parasite.
This project is NIH Grant No.: 1R21AI142149-01