After proposing the double helix structure of DNA in 1953, Francis Crick, James Watson, Rosalind Franklin, and Maurice Wilkins altered the scientific landscape forever. Their model was featured in Nature, one of the most prominent scientific journals in the world. Now, a little over half a century later, a landmark discovery in genetics research by University of Toronto researchers Yoseph Barash and John Calaraco, has earned the May 6 cover of Nature for unveiling a second genetic code.
The team of U of T researchers from Prof. Benjamin Blencowe’s lab in the Centre for Cellular and Biomolecular Research, and Prof. Brendan Frey’s lab in the Department of Electrical and Computer Engineering has deciphered this new code using interdisciplinary research and state of the art technology. They developed a computer algorithm to predict how segments of messenger RNA—the single-stranded successor of DNA—generate products like proteins and enzymes through a process called alternative splicing.
First observed in 1977, alternative splicing is responsible for human complexity as over 80% of human genes are alternatively spliced. Barash and Calaraco explain that scientists initially hypothesized single gene codes for only one protein or enzyme—essentially a “one-gene-one-protein” hypothesis. However, after scientists mapped the human genome and found only 20,000 genes in total, they realized that the relationship between genes and proteins in humans must be far more complicated, since the human body uses at least 100,000 different proteins. A nematode worm has almost the same number of genes as a human being, so what is it that gives humans their complexity?
Scientists have recently hypothesized that one gene holds genetic information that can code for multiple proteins, making way for a “one-gene, multiple proteins” hypothesis. This is where alternative splicing comes in. When DNA is transcribed into messenger RNA, you are left with a genetic code. Some parts of this code, called introns, are removed, while others, called exons, are retained. Alternative splicing is the process by which different introns and exons are removed and retained respectively, resulting in different messages from the same gene.
“The best analogy is a reel of film,” says Calaraco. “When you’re making a movie, the primary film reel contains all information from the film. During the editing process, the editor decides what to keep in and take out. And depending on how the editing is done, a different interpretation of the movie occurs. There is more frequent use of the editing process happening in humans. This is analogous to the transition from DNA to RNA to protein.”
Barash adds, “Sometimes from one gene you can get several thousand different messages.”
Despite the evidence supporting alternative splicing, Barash and Calaraco didn’t stop there. They dove deeper in their search for the mechanisms underlying alternative splicing, looking specifically at the reasons for splice variance in different types of cells and tissues.
After years of research, Calaraco, Barash, Blencowe, Frey and their team of researchers; Weijun Gao, Qun Pan, Xinchen Wang, and Ofer Shai; have developed computer algorithms to predict the product of alternative splicing. Their computational method predicts and interprets the sequence of genes in RNA, and dictates which parts of the sequence are important for controlling the decisions that are being made by the machinery that controls splicing.
Barash and Calaraco’s research has paved the way for furthering our understanding of genetic diseases. Calaraco explains that an estimated 15-50% of diseases originate from splicing defects, and that genetic mutations that give rise to genetic diseases somehow impact the splicing process.
He adds, “When we’ve figured out the splicing code and are able to predict how perturbations in the genetic sequence can influence splicing decisions, then we can start looking at how mutations can contribute to defects in splicing. This may end up leading to the etiology of a disease. As a result, we might be able to better understand what we can correct when things go wrong.”
Barash and Calaraco are very pleased with the results of their research. “It’s a milestone in the field,” says Barash. “Hopefully in the future we’ll go even further and perhaps others will improve on our research.”
Calaraco adds, “It’s like putting together a jigsaw puzzle with 80% of the pieces. No matter how well you do, there’s always going to be pieces left behind. You’re actually dealing with some parts that are black boxes, and as those pieces fill in, things are going to get even better.”
