Israeli Researchers Discover Gene Pattern Shaping the Immune System

February 7, 2019

3 min read

The first DNA sequences were made almost half a century ago, in the early 1970s. Analyses have expanded from individual genes to gene clusters, full chromosomes or the whole genomes of living creatures including humans.

Diagnosing diseases and treating them seem increasingly to require the skills of detectives and jigsaw puzzle fans. This complicated task involves DNA sequencing – determining the order of four nucleic acid bases (adenineguaninecytosine and thymine) in each cell’s DNA.

In 2001, the first copy of the three billion base pairs that assemble the human genome was published. Since then, the price of genetic sequencing has dramatically declined, and rapid sequencing of DNA fragments has become routine in biology and medical laboratories.

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. They are being used in a variety of applied fields such as medical diagnosis,  biotechnologyforensic biologyvirology and biological systematics.

Many studies focus on identification of genetic patterns and genes related to normal functions and disease, but certain genomic regions are still poorly characterized.

A team of researchers from Bar-Ilan University in Ramat Gan, Israel, has 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.

In a just-study published that appears in the prestigious journal Nature Communications, the team of researchers led by Prof. Gur Yaari of Bar-Ilan’s Alexander Kofkin Faculty of Engineering reveal a novel computational tool it has developed to study variations in genes that determine the immune system’s dynamics and used to analyze genetic variation among 100 people. The study was conducted in collaboration with research groups from the US, Norway and Australia.

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 slows mapping of short DNA “reads” (each nucleotide sequences is a “read” that is used later to reconstruct the original sequence) to their exact location within these regions.

“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 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.

“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.

 Similar to 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 is able to 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 more susceptible to the disease caused by the pathogen.

 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 much richer-than-expected pattern 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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