March 10, 2010
Full Genome Sequenced In 5 People In Disease Search

The cost of genome sequencing has now fallen far enough that scientists are able to sequence the entire genome of people with rare genetic diseases to identify their causes.

James Lupski, a physician-scientist who suffers from a neurological disorder called Charcot-Marie-Tooth, has been searching for the genetic cause of his disease for more than 25 years. Late last year, he finally found it--by sequencing his entire genome. While a number of human genome sequences have been published to date, Lupski's research is the first to show how whole-genome sequencing can be used to identify the genetic cause of an individual's disease.

The project, published today in the New England Journal of Medicine, reflects a new approach to the hunt for disease-causing genes--an approach made possible by the plunging cost of DNA sequencing. Part of a growing trend in the field, the study incorporates both new technology and a more traditional method of gene-hunting that involves analyzing families with rare genetic diseases. A second study, the first to describe the genomes of an entire family of four, confirmed the genetic root of a rare disease, called Miller syndrome, afflicting both children. That study was published online yesterday in Science.

For some genetic diseases there's not just one mutation that causes them. Lupski got 2 different rare mutations from his parents. Several other mutations are known to cause his neurological disorder Charcot-Marie-Tooth.

$250 genomes in 5 years?

It took 13 years and an investment of nearly $1 billion to sequence the first human genome in the early 2000s. When the Seattle team launched its analysis in 2009, the cost had plummeted to $20,000 per genome. The lab work took a month.

Today, the price is approaching $10,000. Lifton predicts $250 genomes within five years — cheaper than many medical tests.

At what price would you get your full genome sequenced? Your answer probably depends in part on what you expect you'll be able to do with the information in your daily life. The identification of genetic sequences that determine the ideal diet would certainly make a full genome sequencing worth at least $250 to me.

The sequencing of Lupski's genome turned up hundreds of thousands of genetic differences not yet identified in other humans. As the total pool of fully sequenced genomes grows the number of new mutations found will decline with each new genome added.

On a more philosophical note, the whole genome sequencing provided Lupski clues to what makes an individual.

"My genome has 3.5 million differences from the reference genome (sequenced in the original human genome project)," he said. "I have hundreds of thousands of differences from all the other genomes that have been sequenced. I expect that to hold true for others. Everyone is truly unique."

The sequencing of the family of 4 found that the number of new mutations per generation is lower than previously estimated.

Led by scientists at the Seattle-based Institute for Systems Biology, the study, published Thursday, March 11, 2010 in Science Express, sequenced the entire genome of a family of four—the parents, daughter, and son. By comparing the parents' DNA sequences to those of their children, the researchers estimated with a high degree of certainty that each parent passes 30 mutations—for a total of 60—to their offspring.

Scientists long had estimated that each parent passes 75 gene mutations to their children.

Most of these new mutations probably have no functional significance. But trying to tease out which mutations cause differences in our health or abilities is really hard to do for most mutations. If a mutation causes only a small difference in health or ability and very few people carry it then it is hard to compare people to detect a difference caused by that mutation.

Share |      Randall Parker, 2010 March 10 11:35 PM  Biotech Genetic Diseases


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