And before that decade is over, the race for the US$1,000 complete human genome sequence will have been won. Provided the sequences are accurate as well as cheap, in conjunction with the HapMap and the CGA they will accelerate our ability to link genes with disease and to customize medicine to the individual.

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In a follow-up to the Human Genome Project, an international consortium of scientists has compiled a partial catalog of genetic “haplotypes,” which should speed the search for the genetic roots of many common diseases. While single-letter differences in DNA (called single-nucleotide polymorphisms or SNPs) cause differences between individuals, from hair color to disease predisposition, haplotypes are groups of SNPs that tend to account for differences among groups of people. A given group may be more susceptible to a given disease, for example [such as people of Ashkenazi Jewish descent, who are more susceptible to Tay-Sachs disease and Gaucher disease.]

There are thought to be around 10 million SNPs, of which the HapMap project, as the haplotype mapping project is known, had identified 300,000 as of last October, among four ethnic groups: Europeans, Japanese, Chinese, and the Yoruba of Nigeria. Grouped into haplotypes, those 300,000 SNPs provide around 90 percent of the information that would be obtained by looking at all 10 million SNPs. That, the researchers say, translates into a 20-fold reduction in the cost of research into the genetic causes of disease.

Indeed, the HapMap has already helped to identify a genetic defect that substantially increases the risk of age-related macular degeneration, and it is being used to identify genetic involvement in diabetes, Alzheimer’s disease, cancer, schizophrenia, asthma, high blood pressure, heart disease, and other medical conditions.

The researchers have so far identified 14 regions of the genome that seem to have changed in different ethnic groups under the pressure of natural selection in different environments. They include the Duffy blood group, which confers resistance to malaria and is almost exclusively seen in black Africans, and lactose tolerance in adults, which arose among cattle herders of northern Europe some 5,000 years ago.

The HapMap covers only the common mutations in DNA and is likely to be useful only if the mutations that cause disease are common, not rare. The CEO of Iceland’s famous DeCode Genetics, which has found several disease genes through a family-based approach, believes that many disease-causing mutations are in fact rare and will therefore elude the HapMap strategy. A HapMap proponent retorts that all the disease genes found so far by DeCode were in fact common. If disease-causing mutations are common, the HapMap “will greatly accelerate the identification of disease-related genetic variation,” according to one expert. If not, it won’t.

Since most of the common variation is inherited from the ancestral human population before modern humans are believed to have dispersed from Africa about 50,000 years ago, the HapMap team cautions conservatism and restraint when exploring genetic links to non-medical human characteristics [apparently meaning racial characteristics.]

Cancer Genome Atlas

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What Rick Weiss of the Washington Post calls “the biggest genetic research endeavor since the landmark human genome project . . . whose total cost could reach $1 billion or more” was announced in December. The goal of the “Cancer Genome Atlas” (CGA) is to map the molecular basis for cancers, so that disease can be finally defeated through targeted molecular therapies, diagnostics to catch the disease at an earlier stage, and preventive interventions to stop the disease from arising in the first place.

Hardly unaware of the egg left on US President Richard Nixon’s face 35 years ago by premature optimism about the defeat of cancer, US National Institutes of Health director Elias Zerhouni was bold enough nevertheless to proclaim that the CGA “is really the beginning of a new era.” He has good reason: First, scientists have learned a lot in those 35 years — for example, that cancer is caused by errors in cellular DNA that can be identified and targeted with molecular medicines; and second, we now have the technology capable of handling the mammoth complexity of mapping the cancer genome (and epigenome) at the molecular level. As Francis Collins, head of the National Human Genome Research Institute (NHGRI) nicely put it: “The planets have aligned to tackle cancer in a comprehensive way that we’ve never had the tools to do before.” Not to be outdone, National Cancer Institute head Andrew von Eschenbach, Collins’ fellow funder of the CGA’s $100 million, 3-year pilot phase, said: “The future will look no more like the past than a butterfly resembles a caterpillar.”

But it will not be easy. Collins said it would be like undertaking thousands of Human Genome Projects, though the precipitous fall in gene sequencing costs should enable the CGA to be completed for less money than the $2 billion HGP.

Towards the $1000 Genome

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In an article summarizing progress towards “the gold ring of $1,000 genomic analysis,” Lynn Graebner of the Silicon Valley/San Jose Business Journal notes that several smaller competitors could leapfrog sequencing market leader Applied Biosystems. They include Solexa, whose US$400,000 sequencers will ship in the second quarter of 2006, lowering the cost of sequencing an individual’s complete genome down to $100,000 or less, and 454 Life Sciences, which is already installing its machines at MIT and Harvard. Solexa’s CEO projects his company can cut the cost to $10,000 within two years.

The US National Human Genome Research Institute (NHGRI) has contributed over $70 million into such efforts in the past 18 months, in the belief that “there will be quite a number of genetic changes you can link to disease,” in the words of an NHGRI official.

Applied is responding to the competitive threat in part through the acquisition of VisiGen Biotechnologies, which has a five-to-10-year plan to sequence a person’s full genome within a day for $1,000. If it succeeds, the joint NHGRI-National Cancer Institute $100 million Cancer Genome Atlas pilot project to map genomic changes linked to all types of cancer in humans, announced at the end of 2005, will be that much more valuable. However, a $1,000 sequence may be of little value if it is not accurate, and in that context Graebner notes an article in the November issue of Nature Biotechnology claiming that 454’s technology is not “up to the standards” of Applied’s.