Researchers at UCSD, McGill University and the Dana-Farber Cancer Institute concluded that proteins encoded by a single gene can each play distinct roles within the human body. The study, published in “Cell” on Feb. 11, examines how alternative splicing can give rise to specific sequences that code for functionally different proteins.
The discovery provides a potential explanation for the complexity of organisms whose genomes contain relatively few protein-coding genes, an understanding that may allow researchers to link specific protein isoforms to the development of certain diseases.
Protein isoforms are proteins that, despite being produced by the same gene, have structural variations that give rise to distinct functions. Shuli Kang, a researcher at the University of Southern California who completed post-doc work at UCSD, explained to the UCSD Guardian how studying these individual protein isoforms in detail has revealed a connection between their unique sequences and functions.
“Most human genes encode multiple isoforms via alternative splicing, resulting in 100,000 distinct isoforms that could be produced from approximately 20,000 protein-coding genes,” Kang said. “It remains largely unclear, however, to what extent isoforms encoded by a common gene have divergent functions at the proteome scale. Our results provided the first systematic evidence that the gene functions can be mediated by isoform specific sequences.”
While each gene is capable of producing many proteins with significantly divergent roles, some of these isoforms are more common than others. Previous studies have compared the activity of the most common isoform produced from a single gene to the activities of its protein siblings in order to understand their specific roles.
This recent study, however, examines individual isoforms in terms of their interactions with other, non-sibling human proteins. David Hill, a researcher at Dana-Farber, elaborated on their process of cloning different isoforms in order to study these interactions.
“We first attempted to clone as many isoforms as we could from five human tissues for approximately 1,500 human genes for which we already had at least one clone,” Hill told the Guardian. “As a first step toward characterizing the functional diversity among pairs of alternatively spliced isoforms encoded by a common gene, we decided to concentrate on a set of genes representing about 10 percent of all human protein-coding genes, including genes implicated in Mendelian diseases, genes encoding proteins known to be involved in cell-cycle regulation, or encoding proteins that were already known to have one or more interacting protein partners. We took whatever we obtained from the cloning.”
Shiang added that after cloning this large set of protein isoforms, the team of researchers analyzed their interactions with other proteins in order to understand their role in the human body.
Through understanding the roles of individual isoforms, scientists may be able to associate specific protein forms with disease-causing mutations, a discovery that may allow them to improve current treatments by targeting these mutations. These mutations, however, do not always result in drastic alterations of a protein’s function: While siblings that differ by as little as a single mutation in their DNA may play vastly different roles, others with greater mutations have been found to have similar functions.
Hill explains how this breakthrough might help fill in some blanks in the map of protein interactions in the human body while also revealing the pathways through which diseases occur.
“Genetic variation leading to diseases such as cancer needs to be understood in terms of which isoforms actually carry the mutation and whether they are actually expressed in the relevant tissue,” Hill said. “I expect that we will continue to discover that different isoforms from genes already known to be associated with a specific disease will be found to play roles in other very distinct diseases or to possibly counteract the activity of another isoforms of that gene.”