produced the map using next-generation DNA sequencing technologies
to systematically characterize human genetic variation in 180
people in three pilot studies. Moreover, the full scale-up from
the pilots is already under way, with data already collected from
more than 1,000 people.
studies of the 1000 Genomes Project laid a critical foundation
for studying human genetic variation," said Richard Durbin,
Ph.D., of the Wellcome Trust Sanger Institute and co-chair of
the consortium. "These proof-of-principle studies are enabling
consortium scientists to create a comprehensive, publicly available
map of genetic variation that will ultimately collect sequence
from 2,500 people from multiple populations worldwide and underpin
future genetics research."
variation between people refers to differences in the order
of the chemical units — called bases — that make up DNA in the
human genome. These differences can be as small as a single
base being replaced by a different one — which is called a single
nucleotide polymorphism (abbreviated SNP) — or is as large as
whole sections of a chromosome being duplicated or relocated
to another place in the genome. Some of these variations are
common in the population and some are rare. By comparing many
individuals to one another and by comparing one population to
other populations, researchers can create a map of all types
of genetic variation.
Genomes Project's aim is to provide a comprehensive public resource
that supports researchers aiming to study all types of genetic
variation that might cause human disease. The project's approach
goes beyond previous efforts in capturing and integrating data
on all types of variation, and by studying samples from numerous
human populations with informed consent allowing free data release
without restriction on use. Already, these data have been used
in studies of the genetic basis for disease.
data from the project freely available to the research community,
it is already impacting research for both rare and common diseases,"
said David Altshuler, M.D., Ph.D., Deputy Director of the Broad
Institute of Harvard and MIT, and a co-chair of the project.
"Biotech companies have developed genotyping products to test
common variants from the project for a role in disease. Every
published study using next-generation sequencing to find rare
disease mutations, and those in cancer, used project data to
filter out variants that might obscure their results."
has studied populations with European, West African and East
Asian ancestry. Using the newest technologies for sequencing
DNA, the project's nine centers sequenced the whole genome of
179 people and the protein-coding genes of 697 people. Each
region was sequenced several times, so that more than 4.5 terabases
(4.5 million million base letters) of DNA sequence were collected.
A consortium involving academic centers on multiple continents
and technology companies that developed and sell the sequencing
equipment carried out the work.
these data required many technical and computational innovations,
including standardized ways to organize, store, analyze and
share DNA sequencing data. Launched in 2008, the 1000 Genomes
Project started with three pilot projects to develop, evaluate
and compare strategies for producing a catalogue of genetic
variations. Funded through numerous mechanisms by foundations
and national governments, the 1000 Genome Project will cost
some $120 million over five years, ending in 2012.
work began, sequencing was very expensive, so the project began
with two approaches aimed at increasing efficiency: One strategy,
called "low-pass", combines partial data from many people; the
second, only focused on the part of the genome that encodes
protein-coding genes. By comparing these strategies to "gold
standard" data produced at great completeness and accuracy,
the project was able to show that both the alternative approaches
work well and have complementary strengths. Researchers will
use both strategies in the full-scale project because, although
sequencing costs have decreased, it is still relatively expensive.
shown for the first time that a new approach to sequencing —
low coverage of many samples — works efficiently and well,"
said Gil McVean, Ph.D., Professor of Statistical Genetics at
the University of Oxford. "This proof of principle is now being
applied not only in the 1000 Genomes Project, but in disease
research, as well."
map of human genetic variation includes about 15 million SNPs,
1 million short insertion/deletion changes, and more than 20,000
structural variations. Many of the genetic variants had previously
been identified, but more than half were new. The project's
database contains more than 95 percent of the currently measurable
variants found in any individual, and continuing work will eventually
identify more than 99 percent of human variants.
Gibbs, Ph.D., director of the Human Genome Sequencing Center
at the Baylor College of Medicine (one of the project's sequencing
centers) said, "What really excites me about this project is
the focus on identifying variants in the protein-coding genes
that have functional consequences. These will be extremely useful
for studies of disease and evolution."
map produced some surprises. For example, the researchers discovered
that on average, each person carries between 250 and 300 genetic
changes that would cause a gene to stop working normally, and
that each person also carried between 50 and 100 genetic variations
that had previously been associated with an inherited disease.
No human carries a perfect set of genes. Fortunately, because
each person carries at least two copies of every gene, individuals
likely remain healthy, even while carrying these defective genes,
if the second copy works normally.
to looking at variants that are shared between many people,
the researchers also investigated in detail the genomes of six
people: two mother-father-daughter nuclear families. By finding
new variants present in the daughter but not the parents, the
team was able to observe the precise rate of mutations in humans,
showing that each person has approximately 60 new mutations
that are not in either parent.
completion of the pilot phase, the 1000 Genomes Project has
moved into full-scale studies in which 2,500 samples from 27
populations will be studied over the next two years. Data from
the pilot studies and the full-scale project are freely available
on the project web site, http://www.1000genomes.org/.
studying specific illnesses, such as heart disease or cancer,
use maps of genetic variation to help them identify genetic
changes that may contribute to the illnesses. Over the last
five years, the first generation of such studies (called genome-wide
association studies or GWAS) have been based on an earlier map
of genetic variation called the HapMap. Built using older technology,
HapMap lacks the completeness and detail of the 1000 Genomes
Genomes Project map fills in the gaps between the HapMap landmarks,
helping researchers identify all candidate genes in a region
associated with a disease," said Lisa Brooks, Ph.D., program
director for genetic variation at the National Human Genome
Research Institute, a part of the National Institutes of Health.
"Once a disease-associated region of the genome is identified,
experimental studies must be done to identify which variants,
genes, and regulatory elements cause the increased disease risk.
With the new map, researchers can just look up all the candidate
genes and almost all of the variants in the database, saving
them many steps in finding the causes."
that committed major support to the project include: 454 Life
Sciences, a Roche company, Branford, Conn.; Life Technologies
Corporation, Carlsbad, Calif.; BGI-Shenzhen, Shenzhen, China;
Illumina Inc., San Diego; the Max Planck Institute for Molecular
Genetics, Berlin, Germany; the Wellcome Trust Sanger Institute,
Hinxton, Cambridge, UK; and the National Human Genome Research
Institute, which supports the work being done by Baylor College
of Medicine, Houston, Texas; the Broad Institute, Cambridge,
Mass.; and Washington University, St. Louis, Missouri. Researchers
at many other institutions are also participating in the project
including groups in Barbados, Canada, China, Colombia, Finland,
the Gambia, India, Malawi, Pakistan, Peru, Puerto Rico, Spain,
the UK, the US, and Vietnam. Additional information about the
project, including a list of all participants and organizations,
can be found at http://www.1000genomes.org/
Institutes of Health - "The Nation's Medical Research Agency"
- is a component of the U.S. Department of Health and Human
Services. It is the primary federal agency for conducting and
supporting basic, clinical and translational medical research,
and it investigates the causes, treatments and cures for both
common and rare diseases. For more, visit http://www.nih.gov/.
Human Genome Research Institute is one of 27 institutes and
centers at National Institutes of Health, an agency of the Department
of Health and Human Services. NHGRI's Division of Extramural
Research supports grants for research and for training and career
development. For more, visit http://www.genome.gov/.
Trust is a global charitable foundation dedicated to achieving
extraordinary improvements in human and animal health. It is
independent of both political and commercial interests. For
information, go to http://www.wellcome.ac.uk/.
Trust Sanger Institute, which receives the majority of its funding
from the Wellcome Trust, was founded in 1992. In October 2006,
new funding was awarded by the Wellcome Trust to exploit the
wealth of genome data now available to answer important questions
about health and disease. More information, go to http://www.sanger.ac.uk/.
Molecular Biology Laboratory is a basic research institute funded
by public research monies from 20 member countries and supports
research by approximately 85 independent groups covering the
spectrum of molecular biology. For more information, go to http://www.embl.de/.
Bioinformatics Institute (EBI) is part of the European Molecular
Biology Laboratory (EMBL) and is located on the Wellcome Trust
Genome Campus in Hinxton near Cambridge (UK). For more information,
go to http://www.ebi.ac.uk/.
and Edythe L. Broad Institute of MIT and Harvard, founded in
2003 by MIT, Harvard and its affiliated hospitals, and Los Angeles
philanthropists Eli and Edythe L. Broad, includes faculty, professional
staff and students from throughout the MIT and Harvard biomedical
research communities and beyond, with collaborations spanning
over a hundred private and public institutions in more than
40 countries worldwide. For further information, go to http://www.broadinstitute.org/.
Wellcome Trust Sanger Institute
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