What can be learned from scanning small details in the vast genetic deserts

The long sequences of DNA, called "gene deserts", are so called because they do not contain genes that encode information needed to produce proteins; But in fact, they are not arid. Some of these DNA sequences function as "amplifiers" - pieces of code that amplify genetic activity

Cancer starts in the genes. When certain genes are expressed too much, or too little, the control mechanisms of the cells on the processes of growth, reproduction and death go wrong, which in many cases, leads to the development of cancer. But in most cases, the attempts of many scientists, in different parts of the world, to identify definite genetic signs for the tendency to develop cancer, did not go well.

"It is possible," says Dr. Amos Tanai, from the Department of Computer Science and Applied Mathematics at the Weizmann Institute of Science, "that the lack of success in this field is due to the fact that the search areas were simply limited and too narrow." This perception led Dr. Tanay, in collaboration with a multidisciplinary team of mathematicians and geneticists from three research groups, to conduct an extensive search for prostate cancer markers in a large "gene desert". Using innovative and powerful methods, they scanned large parts of the human genome, looking for small changes that could increase the risk of developing cancer. Identifying the location and nature of these small changes may greatly increase the "bank of targets" to which anticancer drugs that will be developed in the future can be directed. These findings were recently published in the online journal PLoS Genetics.

The long sequences of DNA, called "gene deserts", are so called because they do not contain genes that encode information needed to produce proteins; But in fact, they are not arid. The genes that code for proteins make up only a small part of the DNA of the human genome. Most of the genetic segments that do not code for proteins, and inhabit the "gene deserts", influence the operation of their neighbors, the genes that code for proteins, and criticize them. Thus, for example, a few years ago it became clear that one of these "deserts", located on chromosome eight, called 8q24, is involved in the development of cancer. It is a genetic sequence about 500,000 bases long (the "letters" of the genetic code). At the time when this discovery was made, scientists did not have tools that could scan such an amount of information. "But the new revolution in the decoding technology of genetic sequences allowed us to study a large sequence in one experiment, and to focus on the genetic variants associated with cancer," says Dr. Tanay.

Together with research students Gilad Landan and Ram Ishak from the Weizmann Institute of Science, Gerhard Koachi and Lee Jia from the University of Southern California, and Matthew Friedman from Harvard University and others, Dr. Tanai used advanced and rapid technologies to measure protein activity on DNA with the aim Map a portion of chromosome eight, spanning several million bases. The results of the genomic scan were analyzed using innovative mathematical methods, which allowed the researchers to condense the millions of measurements collected in the experiment into a "genetic map", in which different sections of the genomic sequence were colored in different colors - depending on the identity of the proteins acting on them.

The map led the researchers to identify "hot spots" - areas where the DNA sequences are not folded but "open", and therefore accessible for activity. Later, in the laboratory, they focused on these hot spots, isolated the suspect genetic sequences, and inserted them - using genetic engineering techniques - into cells, with the aim of examining the way in which they would affect their function. Some of these DNA sequences will function as "amplifiers" - pieces of code that amplify genetic activity. The amplifier sequences of cancer patients were found to have an intensity of activity many times greater than the amplifier sequences in healthy people - even though the change in the DNA sequence itself was limited to only one letter. This is how the scientists managed to reduce the list of genetic changes suspected of causing cancer from many thousands to a few.

Here the question arose: How can a change in one nucleotide (out of the approximately 500,000 "letters" that make up the sequence) cause cancer? And which gene, or genes, exactly, increase their activity under the influence of the suspected variants of the identified genetic enhancers? The answer may be found a little beyond the edge of the 8q24 gene desert, in a gene called Myc. Increased activity of this gene is associated with many types of cancer, so the scientists assume that it is the gene affected by the amplifier in which the changes that were mapped and identified occurred.

The suspect gene (Myc) is indeed the closest neighboring gene to the segments where the genetic amplifier is located, but the actual physical distance between them is very large. The scientists believe that despite this distance, the gene and the amplifier maintain direct communication between them. This theory is based on the way DNA folds and twists to form a tight package. The scientists believe that these dense windings allow physical contact between the two segments whose positions along the continuum are distant from each other. A similar phenomenon was recently observed in another segment of 8q24, so the scientists believe that it may be a common phenomenon that allows segments that are located in the heart of a "genetic desert" to influence genes that code for proteins that are located far away from them. Dr. Tanai: "We are used to thinking of the genetic code as a kind of huge book whose 'pages' (the genes) are numbered sequentially, but in fact it is more like spaghetti - or the Internet, which has links from everywhere to everywhere. Now we are beginning to unravel this tangle and its connection to cancer, and our findings point, we hope, to new directions for the development of future ways of prevention, diagnosis and more effective treatments."

personal
Dr. Amos Tanai was born in Moshav Moledat, and received a bachelor's and master's degree in mathematics from Tel Aviv University. During his studies for his master's degree, he led a research team that developed algorithms for the software company "Schema", and then founded, together with a partner, the start-up company for the development of technology for optical networks, called "Optivara Technologies". He managed the R&D department at this company for two years, but his interest in life sciences led him back to Tel Aviv University, where he received a PhD in computational biology in 2005. After doing post-doctoral research at the Center for Physics and Biology Studies at Rockefeller University, Dr. Tenay to Israel and joined, in 2007, the Department of Computer Science and Applied Mathematics at the Weizmann Institute of Science. "What's exciting about science," he says, "is the constant innovation. You can ask big questions. You can find answers to them. But these answers will always lead to a list of new questions."
Dr. Tanai is married to Rotem and has three children. In his spare time he likes to play jazz on the piano.