April 2011 - The ALS Association Greater Sacramento

Page 13
Research: Whole Exome Sequencing Identifies VCP Gene as a Cause of ALS
“Whole exome sequencing” is a revolutionary technology in gene
discovery, and ALS is one of the first neurologic diseases to which
this technique has been applied. “ALS is leading the field in this
regard,” said Bryan Traynor, M.D., of the National Institute of Aging,
in a webinar hosted by the ALS Association.
Dr. Traynor has made significant contributions to the field of ALS
research, and has been closely involved with The Association in
guiding ALS research funding and project development, noted ALS
Association Chief Scientist Lucie Bruijn, Ph.D., who hosted the webinar.
Over the next two years, Dr. Traynor hopes to perform whole
exome sequencing on blood samples from 400 families with familial
ALS. To become part of that exciting research study, see the end of
this article for contact information. Family Studies are the Key to
Rapid Gene Discovery
There are two strategies for finding genes that cause disease, Dr.
Traynor explained, called “cohort studies” and “family studies.” In a
cohort study, the genomes (that is, the entire genetic makeup) of
thousands of individuals are screened, to find small changes, called
variants, which are associated with the disease. Such a study, also
called a “genome-wide association study,” was originally hoped to
be a way of rapidly finding disease genes, but the task is proving
more difficult than once thought. As a result, said Dr. Traynor,
“Everybody is coming back to family studies.”
Family studies were the standard way of finding genes from the
beginning of the gene-hunting era. Family studies were used to find
the first ALS gene, SOD1, and the more recent ones TDP-43 and
FUS.
A family study begins with a family, some of whose members have
ALS and others who don’t. By comparing their DNA, it is possible to
find a small differences in their DNA that correlate with presence of
the disease. The problem with family studies, until quite recently,
was that they required extremely painstaking work, and were therefore,
quite slow. In addition, researchers needed samples from at
least five family members with the disease, a challenge in a rapidly
progressive disease like ALS.
All that has changed in the past year, with the development of a
revolutionary new way to do family studies, called “whole exome
sequencing.” This has been made possible by recent progress in
gene sequencing techniques combined with a vast increase in computing
power.
Most Mutations are in Exons
The genome is the entire DNA inheritance of a person. But only a
small fraction of the genome encodes proteins, and it is the code for
proteins—the genes—that hold the key to understanding ALS. Each
of our 30,000 genes is divided into segments, called exons, about 10
per gene.
“The vast majority of the mutations that cause human diseases lie
in the exons,” Dr. Traynor explained. “We know that’s where the
mutations are, and we now have the ability to sequence them.”
The entire set of exons in the genome, called the “exome,” can now
be sequenced extremely rapidly, and because the data retrieved is
so much more detailed, as few as two family members with ALS are
needed to perform each study. This makes it much more practical
to perform family studies and is setting the stage for rapid discovery
of new ALS genes.
In a typical study from a single family, Dr. Traynor said, “we find
about 100,000 variants per individual. So how do we whittle it
down to what we are looking for?”
If a particular sequence variant is present in an individual without
ALS, it is probably not responsible for the disease, so it can be excluded
as a cause of the disease. Conversely, any variant not shared
between the two family members with the disease can be excluded.
VCP is the Newest ALS Gene
Using this type of strategy, Dr. Traynor and colleagues recently announced
the discovery of a new ALS gene, called VCP (valosincontaining
protein). After finding the gene in the initial family, they
found it in four unrelated families with familial ALS.
Now that the gene has been discovered, Dr. Traynor and others are
trying to understand the protein’s function, and how mutations
cause ALS. One clue may be that six identical copies of the protein
link up, and that disease-causing mutations may prevent that linkage.
With the discovery of VCP, genes for about half of all cases of familial
ALS have been identified. “That underscores the rate at which
genomic technology is advancing, and the rate at which we can apply
that to understanding ALS.” Each new gene also becomes a
candidate for screening those with sporadic ALS, since some people
with no family history nonetheless may have a gene mutation as a
cause.
Dr. Traynor plans to sequence the exomes of 400 ALS families over
the next two years. “VCP is just the start. The next two years is
going to tell a marvelous story about familial ALS.”
To perform this large-scale sequencing, Dr. Traynor is seeking families
with a familial form of ALS to donate samples for sequencing. If
you are willing to donate a blood sample for this research project,
contact Dr. Traynor’s assistant, Cynthia Crews, by email at
ccrews@nia.nih.gov or by phone at 301-451-3826.
“The field of ALS research grew tremendously as a result of the discovery
of the first ALS gene, SOD1,” Dr. Bruijn said. Genes help us
build tools and models, to help us understand what is causing the
disease.”