The 1,000 Genomes Project

Published Pilot is Promising Prelude

Human chromosomes/
image by George Gastin

December 2010- Genetics is all about variation--especially inherited differences from one individual to the next. After completion of the Human Genome Project that reported the whole genome sequence of a "reference human genome" in 2003, the focus of genomics turned to finding individual differences or variants from the reference sequence.

The first effort in this direction was the HapMap project, which defined more than 3 million single base pair variants or single nucleotide polymorphisms (SNPs) by studying a small number of individuals from three different parts of the globe--Northern Europe, West Africa and Asia.

When the idea for HapMap's successor first was discussed in September 2007 during a workshop in Cambridge (UK), the technological power required to identify rarer variants and extract the roots of all variation in common diseases from the human genome wasn't fully available.

No matter. A bold initiative was launched. A project was named. "Next-gen" sequencing platforms handily emerged, cutting the time and cost involved in accurately plumbing the genetic depths of many, many humans. And now, three years later, The 1,000 Genomes Project Consortium has completed a collection of pilot studies that tested different approaches to cataloging rare genetic variation. The results, published in Nature on Oct. 28, describe the use of advanced technology for eventually sequencing more than 2,500 humans from 27 populations worldwide. Institute of Genetic Medicine Director David Valle, M.D., a member of the project oversight committee, called this publication "the first of several landmark papers on human genetic variation that we expect from the 1,000 Genome team."

"This proves that a comprehensive, deep catalog of human genetic variation can--and will--be achieved," says Aravinda Chakravarti, Ph.D., Consortium steering committee member and professor of medicine, pediatrics and molecular biology and genetics at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins.

The goal of the 1,000 Genomes Project is to find most genetic variants that have frequencies of at least 1 percent in the populations studied and at least 0.5 percent in the coding regions of the genome. Headed by researchers from multiple international genome institutes, the project plans to sequence approximately 2,500 human genomes by 2012. The complete findings, like the pilot studies, will be made public and freely available.

Pilot data already is being used and having an impact on research, Chakravarti confirms.

"Just this weekend, we sequenced a particular region of the genome as part of our ongoing effort to find the genetic basis of sudden cardiac death," he says, "and we compared our findings to the 1,000 Genomes Project data. These comparisons are immediately helpful to identify which variants are the likely causes of the genetic defect."

For the 1,000 Genomes Project, Chakravarti has taken a keen interest in deciding, with others, which humans will be sampled, and why. The samples for the 1,000 Genomes Project mostly are anonymous and have no associated medical or phenotype data.

"Instead of having limited samples--one or very few representatives from Africa, Europe and Asia--we now have many more representatives from those populations as well as from others, including the Americas and South Asia," Chakravarti says. (For a list of all the populations, see http://www.1000genomes.org/about#ProjectDesign)

"We will be learning how to use this resource to find disease genes: Ultimately, that's the rationale for this project."

The data from all these individuals are being analyzed to understand, at the level of the sequence, how many variants are there, how does mutation occur, where does it occur, where does it not occur, and its rate of recurrence.

Scientists currently are able to detect genetic variants in humans at a frequency of 5 percent or greater. The 1,000 Genomes Project aims, within the next couple years, to discover more than 95 percent of the variants (including single nucleotide polymorphisms and copy number variants) with minor frequencies, as low as one percent, across the genome.

"There have been too many years of cynicism and naysaying," Chakravarti says: "First, that the human genome couldn't be sequenced. Well, that's done. Then, that the HapMap project was going to be boring and of no utility. Well, that's done, and quite useful. We've proved that the 1,000 Genomes Project can also be completed and has great utility."

The project unites Hopkins researchers with multidisciplinary teams from institutes around the world. Each will contribute to the enormous sequence dataset and to a refined human genome map that will be freely accessible through public databases to the scientific community and the general public. For more information visit: http://www.1000genomes.org/

--Maryalice Yakutchik