The ALS Association

ALS Ice Bucket Challenge Progress

Whole Exome Sequencing Identifies VCP Gene as a Cause of ALS

More Discoveries Expected

March 22, 2011

“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.

Bryan Traynor, M.D.

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.  The full webinar, including a slide talk by Dr. Traynor and Q&A session with participants, is available here.

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 (valosin-containing 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 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.”

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