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

On Nov 4, 1:07=A0pm, "Robert Karl Stonjek" <rston...@xxxxxxxxxxxxxx>
wrote:
Human Genes: Alternative Splicing Far More Common Than Thought
ScienceDaily (Nov. 4, 2008) - Scientists have long known that it's possib=
le
for one gene to produce slightly different forms of the same protein by
skipping or including certain sequences from the messenger RNA. Now, an M=
IT
team has shown that this phenomenon, known as alternative splicing, is bo=
th
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 universa=
l
feature of human genes," said Christopher Burge, senior author of the pap=
er
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 produ=
ce
multiple protein sequences, depending on which exons are included in the
mRNA transcript, which carries instructions to the cell's protein-buildin=
g
machinery.

Two different forms of the same protein, known as isoforms, can have
different, even completely opposite functions. For example, one protein m=
ay
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 tissu=
e,
for example, might be very rare in brain tissue, so that the alternative
exon functions like a molecular switch. Scientists who study splicing hav=
e a
general idea of how tissue-specificity may be achieved, but they have muc=
h
less understanding of why isoforms display such tissue specificity, Burge
said.

Scientists have also observed that cells express different isoforms durin=
g
embryonic development and at different stages of cellular differentiation=
...
Burge's team is now studying cells at various stages of differentiation t=
o
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 mRN=
A
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, t=
he
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-M=
IT
Division of Health Sciences and Technology, and former MIT postdoctoral
fellow Rickard Sandberg, now at the Karolinska Institutet in Sweden. Othe=
r
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. Retrieve=
d
November 5, 2008, fromhttp://www.sciencedaily.com/releases/2008/11/081102=
134623.htm

Posted by
Robert Karl Stonjek

Alternative splicing is an epigenetic phenomenon of eukaryotic
organisms where various exons of a DNA segment are combined to produce
various proteins (and mRNAs). The discovery of alternative splicing
showed that the concept of the gene (both the classic and molecular
concepts) are fluid and obsolete. All the classic and molecular one-
to-one concepts of gene, as a segment of DNA responsible for a
character, an enzyme, a protein, a polypeptide/peptide etc. are proven
to be untrue.

What we conventionally consider a "gene", a functional segment of DNA,
per se does not determine the protein or the mRNA that is actually
produced. The protein that will be produced is not inherently
determined by the gene itself but by the epigenetic information
(specific chemicals) that is conveyed to it. So, the epigenetic
information in eukaryotes took over the production of proteins: from
the same genetic information, i.e. from the same DNA segment, the
epigenetic information can generate a wide variety of proteins
according to the specific needs of the organism.

In metazoans alternative splicing is characteristic of neurons.

Certainly, pre-mRNA splicing, excision of introns and assemblage of
exons into a translation-ready mRNA, is a constitutive process that
takes place in cells all over the animal body rather than in the CNS
alone. However it is important to remember that
1. no prokaryote unicellular organisms are capable of mRNA splicing,
and
2. unlike the constitutive splicing that occurs in cells throughout
the animal body the manipulative splicing is extensively used in the
nervous system, where it is determined by a neuron-specific system of
splicing. In the CNS, production of different proteins from the same
"gene" is related to the electrical activity of neurons (Mu et al.,
2003;, Lipscombe, 2005).

Neurexins, e.g. are surface cell proteins encoded by three genes that
are exclusively expressed in the brain. Between 600 and 3000 distinct
splicing-generated neurexins are produced by these three genes in the
brain of the developing Xenopus laevis (Ullrich et al., 1995).

Manipulative splicing is very important in the development and the
function of the nervous system. The tremendous molecular diversity of
synapses that enables neurons to recognize their potential target
neurons out of trillions of neurons in the brain derives from the
manipulative splicing (Zeng et al., 2006).

In response to neurobiological phenomena such as chronic stress,
social factors, depression etc. metazoans induce adaptive changes in
manipulative splicing.
Alternative splicing in non-neural tissues is often determined by
hormones which via the hipothalamic-pituitary-terminal glands (adrenal
glands, thyroid, gonads, etc.), ultimately are neurally regulated.

For details on the manipulative splicing and its role in the function
of the nervous system and for neural manipulation of the genetic
information read in chapter 2 of the Epigenetic Principles of
Evolution (2008) subsections Epigenetic Manipulation of Genetic
Information in the CNS and Selective Elimination of Genetic
Information in the CNS. Or visit my website
http://www.epigeneticscomesofage.com


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