1000 genomes, infinite detail

Source: NIH/National Human Genome Research Institute

An international research consortium has launched the 1000 Genomes Project, an ambitious effort that will involve sequencing the genomes of at least a thousand people from around the world to create the most detailed and medically useful picture to date of human genetic variation.

The project involves researchers from the Wellcome Trust Sanger Institute in the UK; the Beijing Genomics Institute in China (BGI Shenzhen) and the US National Human Genome Research Institute (NHGRI).

The project aims to develop a new map of the human genome to provide a view of biomedically relevant DNA variations at a resolution unmatched by current resources.

The data will be made freely available to the international scientific community.

The Sanger Institute's Richard Durbin, co-chair of the consortium, said the project would examine the human genome at a level of detail not attempted before.

"Such a project would have been unthinkable only two years ago," Durbin said. "Today, thanks to amazing strides in sequencing technology, bioinformatics and population genomics, it is now within our grasp."

The new map will enable researchers to more quickly zero in on disease-related genetic variants, speeding efforts to use genetic information to develop new strategies for diagnosing, treating and preventing common diseases, the organisers said.

The scientific goals of the 1000 Genomes Project are to produce a catalogue of variants that are present at one per cent or greater frequency in the human population across most of the genome, and down to 0.5 per cent or lower within genes.

This will likely entail sequencing the genomes of at least 1,000 anonymous people.

"This new project will increase the sensitivity of disease discovery efforts across the genome five-fold and within gene regions at least 10-fold," NHGRI director Francis Collins said.

"Our existing databases do a reasonably good job of cataloguing variations found in at least 10 per cent of a population. By harnessing the power of new sequencing technologies and novel computational methods, we hope to give biomedical researchers a genome-wide map of variation down to the 1 percent level. This will change the way we carry out studies of genetic disease."

The 1000 Genomes Project builds on the human haplotype map developed by the International HapMap Project. The new map will provide genomic context surrounding the HapMap's genetic variants, giving researchers important clues to which variants might be causal, including more precise information on where to search for causal variants.

One use of the new map will be to follow up genome-wide association studies. Not only will it map single nucleotide polymorphisms, but structural variants such as duplications and deletions as well.

The sequencing work will be carried out at the Sanger Institute, BGI Shenzhen and NHGRI's Large-Scale Sequencing Network, which includes the Broad Institute of MIT and Harvard; the Washington University Genome Sequencing Center at the Washington University School of Medicine in St. Louis; and the Human Genome Sequencing Center at the Baylor College of Medicine in Houston. The consortium may add other participants over time.

New sequencing technologies will be used, which the organisers say will lower the price from the hundreds to the tens of millions of dollars.

The first phase of the project will involve three pilots: the first to sequence the genomes of two nuclear families (both parents and an adult child) at deep coverage that averages 20 passes of each genome.

This will provide a comprehensive dataset from six people that will help the project figure out how to identify variants using the new sequencing platforms, and serve as a basis for comparison for other parts of the effort.

The second pilot will involve sequencing the genomes of 180 people at low coverage that averages two passes of each genome. This will test the ability to use low-coverage data from new sequencing platforms to identify sequence variants and to put them in their genomic context.

The third pilot will involve sequencing the coding regions, called exons, of about 1,000 genes in about 1,000 people. This is aimed at exploring how best to obtain an even more detailed catalogue in the approximately two per cent of the genome that is comprised of protein-coding genes.

The organisers say that during its two-year production phase, the 1000 Genomes Project will deliver sequence data at an average rate of about 8.2 billion bases per day, the equivalent of more than two human genomes every 24 hours.

The volume of data - and the interpretation of those data - will pose a major challenge for leading experts in the fields of bioinformatics and statistical genetics.

"The scale is immense," Oxford University's Gil McVean said. "At six trillion DNA bases, the 1000 Genomes Project will generate 60-fold more sequence data over its three-year course than have been deposited into public DNA databases over the past 25 years."

"In fact, when up and running at full speed, this project will generate more sequence in two days than was added to public databases for all of the past year."

Among the populations whose DNA will be sequenced in the 1000 Genomes Project are: Yoruba in Ibadan, Nigeria; Japanese in Tokyo; Chinese in Beijing; Utah residents with ancestry from northern and western Europe; Luhya in Webuye, Kenya; Maasai in Kinyawa, Kenya; Toscani in Italy; Gujarati Indians in Houston; Chinese in metropolitan Denver; people of Mexican ancestry in Los Angeles; and people of African ancestry in the southwestern United States.

The data generated by the 1000 Genomes Project will be held by and distributed from the European Bioinformatics Institute and the US National Center for Biotechnology Information, which is part of the NIH. There will also be a mirror site for data access at BGI Shenzhen.