New Tool for Cancer Research
“For years, we identified splicing changes inside cancer cells, but it was debated whether they have causative roles or whether they are the consequence of disease-related deregulation,” says Michael C. Ryan, Ph.D., president and bioinformatics specialist at In Silico Solutions.
The general interest in alternative splicing emerged from the concept that, instead of mapping specific genes to a single protein, multiple different protein products can be formed, in a spatial and temporal manner, a process that required the “one gene, one polypeptide” concept to be revisited. Alternative splicing is one strategy to expand the proteome diversity and it has additional roles, such as protein quality control.
At the interface between alternative splicing and cancer research, an area of increasing interest has recently focused on a set of biological programs that is active and establishes specific splicing patterns during distinct stages of growth and development, but is turned off later on, in adult cells. “Some cancer cells appear to be able to find ways to turn these programs back on, and reactivate embryonic versions of the genes,” says Dr. Ryan.
A few years ago, alternative splicing was mostly studied by using microarrays. “While this provided interesting insights, next-generation sequencing currently offers a resolution that is an order of magnitude better,” explains Dr. Ryan.
To provide investigators with a better platform to examine and interpret alternative splicing patterns from RNA-Seq reads, Dr. Ryan and colleagues developed SpliceSeq, a free resource that is powered to capture changes during alternative splicing and explore their functional consequences.
“With SpliceSeq, one can map the reads to each individual exon or splice, so instead of examining the read for each gene, we can individually look at each element of a gene,” says Dr. Ryan. The platform opens the additional possibility to identify splicing patterns across multiple samples, perform comparative analyses, or group samples based on specific criteria, increasing the power of the analysis.
“Moreover, we can translate the reads into protein sequence prediction and subsequently identify the portion of the protein that is being impacted by alternative splicing,” explains Dr. Ryan.
Dr. Ryan and colleagues are currently comparing alternative splicing patterns across The Cancer Genome Atlas (TCGA) data, one of the biggest RNA-Seq repositories. “For the first time, SpliceSeq provides the opportunity to visualize changes at an unprecedented resolution,” explains Dr. Ryan.
Discoveries linked to the biology of RNA shaped seminal biomedical advances. One of the most intriguing aspects of RNA is its ability to fulfill diverse cellular functions, which include informational, structural, catalytic, and regulatory roles.
Many advances in this field, in addition to helping overturn old concepts and opening new perspectives, point toward a much more complex picture, one that unveils the dynamic nature of the scientific inquiry, which Carl Sagan so vividly captured in words: “There is much that science doesn’t understand, many mysteries still to be resolved. We are constantly stumbling on surprises.”