Bar-Ilan University researchers discover a mosaic-like gene deletion and duplication pattern shaping the immune system

By Judy Siegel-Itzkovich

Knowing DNA sequences has greatly advanced not only basic biological research; the sequencing techniques have dramatically advanced and the storage of big data of their findings is growing exponentially.

DNA sequences  are being used in a variety of applied fields such as medical diagnosis,  biotechnologyforensic biologyvirology and biological systematics. Many studies focus on the identification of genetic patterns and genes related to normal functions and disease, but certain genomic regions are still poorly characterized.

In a study just published in the prestigious journal Nature Communications, a team of researchers, led by iReceptor Plus coordinator Prof. Gur Yaari of Bar-Ilan’s Alexander Kofkin Faculty of Engineering, have developed a computational tool for analyzing genetic changes related to the immune system. With this step forward, the onset of many autoimmune diseases – such as multiple sclerosis and celiac disease – as well as infectious diseases such as hepatitis C and influenza, and various forms of cancer can be predicted.

The study was conducted in collaboration with the group of Prof. Ludvig Sollid from the university of Oslo, who is also part of the iReceptor Plus consortium, and with research groups from the US, and Australia. It presents a novel computational tool to study variations in genes that determine the immune system’s dynamics and used to analyze genetic variation among 100 individuals.

The Bar Ilan research team (from left to right): Ayelet Peres, Moriah Gidoni, Dr. Pazit Polak, and Prof. Gur Yaari, with the presented mosaic.

Current knowledge of the regions that determine the immune system’s function is very limited. The reason for this is the repetitive structure of those regions, which impedes mapping of short DNA fragments to their exact location within these regions.

“Analysis of antibody repertoires by high-throughput sequencing is of major importance in understanding adaptive immune responses. Our knowledge of variations in the genomic loci encoding antibody genes is incomplete, mostly due to technical difficulties”, they wrote. “The partial knowledge results in conflicting gene assignments between different algorithms.”

“Despite limited knowledge about those regions, they are critically important for a deeper understanding of the immune system, as well as for prediction of diseases and development of novel tools for personalized medicine in cancer, inflammation, autoimmune diseases, allergies and infectious diseases,” asserted Prof. Yaari.

Our immune system can adapt itself to countless living threats (bacteria, viruses and other disease-producing pathogens), even those that continuously evolve. “Among other mechanisms, this is done through a huge repertoire of receptors expressed by B and T white blood cells,” added Moriah Gidoni, a doctoral student who participated in the study, and is also a member of the iReceptor Plus Bar Ilan team.

“The human body contains tens of billions of B cells, each of which expresses a different antibody receptor that can bind a different pathogen. How can such a huge diversity of antibodies be achieved, when the genomic regions encoding for antibodies are relatively short? Diversity is achieved by each B cell expressing only a small number of DNA fragments that are randomly chosen from the entire region, which together encode for a complete antibody,” explained Gidoni.

Like other human characteristics, the genomic region encoding the immune receptors varies in people, and each person has two such regions that are inherited from the mother and the father. The fragments encoding each antibody are selected in each B cell from only one chromosome, and therefore it is highly valuable to map the fragments that are found on each chromosome, which are the pool from which that person can encode antibodies.

For example, a person who is missing certain fragments is unable to produce certain antibodies, which can make it difficult for him or her to fight a certain germ, making him or her more susceptible to the disease caused by this germ.

According to the researchers, an indirect way to learn about the genetic variations in these regions is to read genetic sequences of mature B cells after they have already chosen which fragments, they express. From these data, the genetic variety within each person can be determined.

“The analysis showed a pattern much richer-than-expected of deletions and duplications of many genomic regions,” said Yaari. “Despite the critical importance of these genomic regions for our understanding of the immune system and a wide variety of diseases, our knowledge so far has been limited to what was under the standard sequencing lamppost. Computational tools like the one recently developed by our group enable a completely different point of view on this very important genomic region that contains a large wealth of valuable biological and medical information.”

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