Posted: 31 Mar 2010 01:07 PM PDT
A massive search for a prime suspect in the mystery of the missing heritability has come up empty.
Known as copy-number variations, or CNVs, these extra or missing sequences of the genome have been linked to some rare diseases. Researchers thought they might play a role in common diseases, too. But a comparison of 19,000 genomes found few links to breast cancer, diabetes and six other major killers.
Copy-number variations "are unlikely to contribute to the genetic basis of common human diseases," wrote researchers from the Wellcome Trust Case Control Consortium in a study published March 31 in Nature.
Formed during glitches in gene duplication, CNVs cover as much space on the genome as standard gene mutations, in which individual letters of the genetic code are mixed up.
Standard gene mutations don't appear to explain much of the heredity that clearly exists in many common diseases, a phenomenon that scientists call "missing heritability." To find whether CNVs might play a part, Wellcome Trust researchers comparedCNVs in the genomes of 3,000 healthy people with CNVs in the genomes of 16,000 patients. The patients were equally divided among people with type 1 and type 2 diabetes, bipolar disorder, rheumatoid arthritis, breast cancer, high blood pressure, heart disease and Crohn's disease.
But when the numbers were crunched, CNVs were cleared. No individual CNVs had a powerful effect on disease, nor did large numbers of them.
Though some rare CNVs are linked to disease, and more remain to be found, the bulk appear to do nothing, wrote the researchers.
The missing heritability is still at large.
Image: Mike Towber/Flickr
Citation: "Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls." By the Wellcome Trust Case Control Consortium. Nature, Vol. 464 No. 7289, April 1, 2010.
Posted: 31 Mar 2010 11:13 AM PDT
Almost 10 years after the celebrated completion of the human genome's first draft, the expected revolution in medicine and research has only partly come to pass.
The human genome's sequencing has profoundly influenced basic research and the refinement of genome-reading tools. But those advances have had only limited medical impacts.
"The promise of a revolution in human health remains quite real," wrote Francis Collins, director of the National Institutes of Health, in an essay published March 31 in Nature. "Those who somehow expected dramatic results overnight may be disappointed."
Collins' commentary is one of four published this week in Nature in anticipation of the human genome's upcoming 10th anniversary, which officially falls on June 26. On that date in 2000, Collins — then the head of the NIH's National Human Genome Research Institute — met in the White House with Craig Venter, founder of Celera Genomics, and President Bill Clinton.
In the same room that Merriweather Lewis and William Clark presented Thomas Jefferson with a map of the Louisiana Purchase territories, the researchers announced that the human genome's three billion base pairs of DNA had been mapped. "Humankind is on the verge of gaining immense, new power to heal," proclaimed Clinton. "It will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases."
Mostly lost in the ceremony was the fact that the genome sequence was not truly complete, but only a first draft. About 10 percent of it hadn't yet been read. The parts that had been read, still needed to be verified. Reading the genome had required its breakup into thousands of manageable chunks that needed to be reassembled. Ewan Birney, a Sanger Center geneticist and leader of a group involved in the sequencing, compared the moment to "being given the best book in the world, but it's in Russian, and it's incredibly boring to read."
The human genome's sequencing wasn't formally completed until 2003. Since then, it has guided researchers in investigations of human development and disease. Some of their investigations have yielded new tests and drug targets and insights into the basis of human disease and development. But they've also revealed just how complicated human biology is, and how much remains to be understood.
"Wisely, the president did not attach timetables to his bold predictions," wrote Collins in Nature.
Perhaps the greatest genomic advances of the last decade involve tools. The Human Genome Project — the Collins-led governmental side of the genome-sequencing race, with Venter leading the private side — commenced only when the cost of reading DNA finally approached $1 per unit, or $3 billion for a whole genome. A comparable genome sequence now costs less than $10,000. What took years to complete can be done in a day.
Better tools have driven other genomic advances. The International HapMap project was formed in 2002, and compared the genomes of several hundred people from around the world. This produced a map of genomic hotspots where people — any two of whom are roughly 99 percent identical at the genetic level —are most likely to have DNA differences. This helps researchers narrow their focus on genes involved in disease.
Researchers have also learned that just 1.5 percent of all human genes code for the proteins that make up our cells and tissues. As for what the rest are doing, they are still learning. In 2003, the NIH started the Encyclopedia of DNA Elements, or ENCODE, which supports researchers in identifying functions for the rest of our genes.
Many genes control when protein-coding genes are turned on and off at different places and times in the body, adding a whole new layer of complexity to the genome. This field of study is called epigenomics, and many researchers think it's just as important as genomics. The NIH's Roadmap Epigenomics Program started just two years ago.
Scientists hope these projects will fill the massive gaps that remain in current genetic explanations for most common diseases. Even after the publication of hundreds of genome-wide association studies —the gold standard of disease gene hunting, in which thousands of genomes are scanned and compared —scientists can explain only a fraction of the heritability that clearly exists in common diseases and conditions.
"The ability to make meaningful predictions is still quite limited," wrote Collins. Indeed, personalized genomics companies like 23andMe, Navigenics and deCODE have struggled, as the novelty of genomic information gives way to a realization that it's still of limited medical use.
But all for all that turn-of-the-millennium expectations have been tempered, the genomic age has produced significant medical advances. Analyses of gene disturbances in cancer tissues have produced several promising drugs. Testing for breast cancer mutations is now common. Individual response to about a dozen drugs can be predicted. And even if the big picture isn't yet clear, researchers have thousands of new gene targets, each a providing a foothold on the path to understanding. For some complex diseases, such as schizophrenia, researchers are now looking at genes and physiological systems they never suspected were involved.
Making sense of massive new genomic datasets has fueled the growth of systems biology, now one of the hottest areas of science. And all this research is shaped by another legacy of the genome's sequencing: what Collins calls "the radical ethic of immediate data deposit." Knowledge of the human genome wasn't scattered and hoarded. It was freely shared with any researcher who wanted it.
"My students can gather certain types of experimental data 1,000 and even 10,000 times faster than I could 40 years ago," wrote Robert Weinberg, a Whitehead Institute geneticist, in Nature.
As Venter, now the leader of the eponymous J. Craig Venter Institute, responsible for the designing the first synthetic genome, concluded his essay: "The genome revolution is only just beginning."
Image: A section of the printed human genome/Adam Nieman/Flickr
Citations: "Has the revolution arrived?" By Francis Collins. Nature, Vol. 464 No. 7289, April 1, 2010.
"Multiple personal genomes await." By J. Craig Venter. Nature, Vol. 464 No. 7289, April 1, 2010.
"Dive in, the data's lovely." By Todd Golub. Nature, Vol. 464 No. 7289, April 1, 2010.
"Don't forget the hypotheses." By Robert Weinberg. Nature, Vol. 464 No. 7289, April 1, 2010.
|You are subscribed to email updates from John E Morph's Facebook notes |
To stop receiving these emails, you may unsubscribe now.
|Email delivery powered by Google|
|Google Inc., 20 West Kinzie, Chicago IL USA 60610|