(mentions CMT) Decoded Genome Gives New Hope in Confronting Diseases

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Decoded Genome Gives New Hope in Confronting Diseases

By Wade

http://www.nytimes.com/2010/03/11/health/research/11gene.html

Two research teams have independently decoded the entire genome of patients to

find the exact genetic cause of their disease. The approach may offer a new

start in the so far disappointing effort to identify the genetic roots of major

killers like heart disease, diabetes and Alzheimers.

In the decade since the first full genetic code of a human was sequenced for

some $500 million, only a handful of genomes have been decoded, all of healthy

people.

Geneticists said the new research shows that it is now possible to sequence the

entire genome of a patient at reasonable cost and with sufficient accuracy to be

of practical use to medical researchers. One subject's genome cost just $50,000

to decode.

" We are finally about to turn the corner, and I suspect that in the next few

years human genetics will finally begin to systematically deliver clinically

meaningful findings, " said Goldstein, a Duke University geneticist who has

criticized the current approach to identifying genetic causes of common

diseases.

Besides identifying disease genes, the Seattle team was able to make the first

direct estimate of the number of mutations, or changes in DNA, that are passed

on from parent to child. They calculate that of the 3 billion units in the human

genome, 60 per generation are changed by random mutation — considerably less

than previously thought.

The three diseases analyzed in today's reports are caused by single, rare

mutations in a gene.

In one case, A. Gibbs of the Baylor College of Medicine has sequenced

the whole genome of his colleague Dr. R. Lupski, a prominent medical

geneticist who has a nerve disease, Charcot-Marie-Tooth neuropathy. In the

second, Leroy Hood and J. Galas of the Institute for Systems Biology in

Seattle have decoded the genomes of two children with two rare genetic diseases,

and their parents.

More common diseases, like cancer, are thought to be caused by mutations in

several genes, and finding the causes was the principal goal of the $3 billion

human genome project. To that end, medical geneticists have invested heavily

over the last 8 years in an alluring short cut. But the short cut was based on a

premise that is turning out to be incorrect. Scientists thought that the

mutations that caused common diseases would themselves be common. So they first

identified the common mutations in the human population in a $100 million

project called the Hap Map. Then they compared patients' genomes with those of

healthy genomes. The comparisons relied on ingenious devices called SNP chips,

which scan the genome at just a tiny portion of its 3 billion sites. (SNP,

pronounced " snip, " stands for single nucleotide polymorphism.) These projects,

called genome-wide association studies, each cost around $10 million or more.

The results of this costly international exercise have been disappointing. About

2,000 sites on the human genome have been statistically linked with various

diseases, but in many cases the sites are not inside working genes, suggesting

there may be some conceptual flaw in the statistics. And in most diseases the

culprit DNA was linked to only a small portion of all the cases of the disease.

It seemed that natural selection has weeded out any disease-causing mutation

before it becomes common.

The finding implies that common diseases, surprisingly, are caused by rare, not

common, mutations. In the last few months researchers have begun to conclude

that a new approach is needed, one that is based on decoding the entire genome

of patients.

Today's reports, though involving only single gene diseases, suggest that the

whole genome approach can be developed into a way of exploring the roots of the

common, multi-gene disease. " We need a way of assessing rare variants better

than the genome-wide association studies can do, and whole genome sequencing is

the only way to do that, " Dr. Lupski said.

About 10 human genomes have been sequenced so far but all have been of healthy

people. Dr. Gibbs, a specialist in DNA sequencing, decided it was time to decode

the genome of someone with a genetic disease and asked his colleague Dr. Lupski

to volunteer. Mutations in any of 39 genes can cause Charcot-Marie-Tooth, a

disease which impairs nerves to the hands and feet, as well as the muscles those

nerves innovate.

Mutations in any one of 39 genes can cause Charcot-Marie-Tooth. Dr. Lupski

turned out to have mutations in an obscure gene called SH3TC2. The copy of gene

he inherited from his father is mutated in one place and the copy from his

mother in a second.

Both his parents had one good copy of the gene in addition to the mutated one. A

single good copy can generate enough, or nearly enough, of the gene's product

for the nerves to work properly. Dr. Lupski's mother was free of the disease and

his father had only mild symptoms. In the genetic lottery that is human

procreation, two of their eight children inherited good copies of SH3TC2 from

each parent, two inherited the mom's mutation but dad's good copy and are free

of the disease; and four siblings including Dr. Lupski inherited mutated copies

from both parents. These four all have Charcot-Marie-Tooth disease. The results

are reported in today's New England Journal of Medicine.

In Seattle, Dr. Hood and Dr. Galas have also applied whole genome sequencing to

disease. They analyzed the genome of a family of four, in which the two children

each have two single-gene diseases, called 's syndrome and ciliary

dyskinesia. With four related genomes available, the reserchers could identify

the causative genes. They also improved the accuracy of the sequencing, because

DNA changes that did not obey Mendel's rules of inheritance could be classed as

errors in the decoding process.

The Seattle team believes whole genome sequencing can be applied to the study of

the common, multi-gene diseases and plans to sequence more than 100 genomes next

year, starting with multi-generational families. The family whose genomes they

report in today's issue of Science were sequenced by a company with a new DNA

sequencing method, Complete Genomics of Mountain View, California, at a cost of

$25,000 each. Clifford Reid, the company's chief executive, said he was scaling

up to sequence 500 genomes a month and that for large projects the price per

genome would soon drop below $10,000. " We are on our way to the $5,000 genome, "

he said.

Dr. Reid said the Hap Map and genome-wide association studies were not a mistake

but " the best we could do at the time. " But they have not yet revolutionized

medicine, " which we are on the verge of doing, " he said.

B. Goldstein, a statistical geneticist at Duke University who has long had

reservations about the genome-wide association studies, said the whole genome

sequencing approach now possible should allow rapid progress. " I think we are

finally headed where we have long wanted to go. "