Unravelling new complexity in the genome

A major surprise emerging from genome sequencing projects is that humans
have a comparable number of protein-coding genes as significantly less
complex organisms such as the minute nematode worm Caenorhabditis elegans.
Clearly something other than gene count is behind the genetic differences
between simpler and more complex life forms.

Increased functional and cellular complexity can be explained, in large
part, by how genes and the products of genes are regulated. A University of
Toronto-led study published in the latest issue of Genome Biology reveals
that a step in gene expression (referred to as alternative splicing) is more
highly regulated in a cell and tissue-specific manner than previously
appreciated and much of this additional regulation occurs in the nervous
system. The alternative splicing step allows a single gene to specify
multiple protein products by processing the RNA transcripts made from genes
(which are translated to make protein).

"We are finding that a significant number of genes operating in the same
biological processes and pathways are regulated by alternative splicing
differently in nervous system tissues compared to other mammalian tissues,"
says lead investigator Professor Benjamin Blencowe of the Banting and Best
Department of Medical Research and Centre for Cellular and Biomolecular
Research (CCBR) at the University of Toronto

According to Blencowe, it is particularly interesting that many of the genes
have important and specific functions in the nervous system, including roles
associated with memory and learning. However, in most cases the
investigators working on these genes were not aware that their favorite
genes are regulated at the level of splicing. Blencowe believes that the
data his group has generated provides a valuable basis for understanding
molecular mechanisms by which genes can function differently in different
parts of the body.

Blencowe attributes these new findings in part to the power of a new tool
that he, together with his colleagues including Profs. Brendan Frey
(Department of Electrical and Computer Engineering) and Timothy Hughes
(Banting and Best, CCBR), developed a few years ago. This tool, which
comprises tailored designed microarrays or "gene chips" and computer
algorithms, allows the simultaneous measurement of thousands of alternative
splicing events in cells and tissues. "Until recently researchers studied
splicing regulation on a gene by gene basis. Now we can obtain a picture of
what is happening on a global scale, which provides a fascinating new
perspective on how genes are regulated," Blencowe explains.

A challenge now is to figure out how the alternative splicing process is
regulated in a cell and tissue-specific manner. In their new paper in Genome
Biology, Dr. Yoseph Barash, a postdoctoral fellow working jointly with
Blencowe and Frey, has provided what is likely part of the answer. By
applying computational methods to the gene chip data generated by Matthew
Fagnani (an MSc student) and other members of the Blencowe lab, Barash has
uncovered what appears to be part of a "regulatory code" that controls
alternative splicing patterns in the brain.

One outcome of these new studies is that the alternative splicing process
appears to provide a largely separate layer of gene regulation that works in
parallel with other important steps in gene regulation. "The number of genes
and coordinated regulatory events involved in specifying cell and tissue
type characteristics appear to be considerably more extensive than
appreciated in previous studies," says Blencowe. "These findings also have
implications for understanding human diseases such as cancers, since we can
anticipate a more extensive role for altered regulation of splicing events
that similarly went unnoticed due to the lack of the appropriate technology
allowing their detection."

Source: University of Toronto
http://www.physorg.com/news106242954.html

Posted by
Robert Karl Stonjek