News: Human Genes - Alternative Splicing Far More Common Than Thought

Human Genes: Alternative Splicing Far More Common Than Thought
ScienceDaily (Nov. 4, 2008) - Scientists have long known that it's possible
for one gene to produce slightly different forms of the same protein by
skipping or including certain sequences from the messenger RNA. Now, an MIT
team has shown that this phenomenon, known as alternative splicing, is both
far more prevalent and varies more between tissues than was previously
believed.

Nearly all human genes, about 94 percent, generate more than one form of
their protein products, the team reports in the Nov. 2 online edition of
Nature. Scientists' previous estimates ranged from a few percent 10 years
ago to 50-plus percent more recently.

"A decade ago, alternative splicing of a gene was considered unusual,
exotic . but it turns out that's not true at all - it's a nearly universal
feature of human genes," said Christopher Burge, senior author of the paper
and the Whitehead Career Development Associate Professor of Biology and
Biological Engineering at MIT.

Burge and his colleagues also found that in most cases the mRNA produced
depends on the tissue where the gene is expressed. The work paves the way
for future studies into the role of alternative proteins in specific
tissues, including cancer cells.

They also found that different people's brains often differ in their
expression of alternative spliced mRNA isoforms.

Human genes typically contain several "exons," or DNA sequences that code
for amino acids, the building blocks of proteins. A single gene can produce
multiple protein sequences, depending on which exons are included in the
mRNA transcript, which carries instructions to the cell's protein-building
machinery.

Two different forms of the same protein, known as isoforms, can have
different, even completely opposite functions. For example, one protein may
activate cell death pathways while its close relative promotes cell
survival.

The researchers found that the type of isoform produced is often highly
tissue-dependent. Certain protein isoforms that are common in heart tissue,
for example, might be very rare in brain tissue, so that the alternative
exon functions like a molecular switch. Scientists who study splicing have a
general idea of how tissue-specificity may be achieved, but they have much
less understanding of why isoforms display such tissue specificity, Burge
said.

Scientists have also observed that cells express different isoforms during
embryonic development and at different stages of cellular differentiation.
Burge's team is now studying cells at various stages of differentiation to
see when different isoforms are expressed.

Isoform switching also occurs in cancer cells. One such switch involves a
metabolic enzyme and contributes to cancer cells burning large amounts of
glucose and growing more rapidly. Learning more about such switches could
lead to potential cancer therapies, Burge said.

Until now, it has been difficult to study isoforms on a genome-wide scale
because of the high cost of sequencing and technical issues in
discriminating similar mRNA isoforms using microarrays. The team took mRNA
samples from 10 types of tissue and five cell lines from a total of 20
individuals, and generated more than 13 billion base pairs of sequence, the
equivalent of more than four entire human genomes.

The sequencing was done by researchers at biotech firm Illumina, using a new
high-throughput sequencing machine.

Lead authors of the paper are graduate student Eric Wang of the Harvard-MIT
Division of Health Sciences and Technology, and former MIT postdoctoral
fellow Rickard Sandberg, now at the Karolinska Institutet in Sweden. Other
authors are Christine Mayr, a postdoctoral associate at the Whitehead
Institute; Stephen Kingsmore of the National Center for Genome Resources;
and Shujun Luo, Irina Khrebtukova, Lu Zhang and Gary Schroth of Illumina.

The research was funded by the National Institutes of Health, the Knut &
Alice Wallenberg Foundation and the Swedish Foundation for Strategic
Research.


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Adapted from materials provided by Massachusetts Institute of Technology.
Massachusetts Institute of Technology (2008, November 4). Human Genes:
Alternative Splicing Far More Common Than Thought. ScienceDaily. Retrieved
November 5, 2008, from
http://www.sciencedaily.com/releases/2008/11/081102134623.htm

Posted by
Robert Karl Stonjek


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