Finding variants in the human genome

September 01, 2010

New findings show the value of genetic studies across human populations and the value of the latest DNA sequencing technologies to interrogate genetic variation. The results, from the latest phase of the international HapMap Project, are reported in Nature.

The researchers' extensive study of genetic variation in multiple populations will form a framework for future genetic studies of variation and disease: their findings highlight the need to examine various populations in order to tease out the widest collection of genetic variants, as well as the requirement to deploy sequencing technologies to find as many variants as possible.

The HapMap Project seeks to identify signposts on the human genome that will simplify the search for important genetic variants. In the latest phase - HapMap 3 - the researchers looked for variants across the genome in 1184 samples from 11 populations. They chose the large sample set and the wide range of populations to maximize the variation they could capture. The project includes both single-letter differences (single-letter polymorphisms, or SNPs) as well as large differences from the loss, gain or duplication of regions, called copy-number polymorphisms, or CNPs.

"Despite the remarkable achievements following from the Human Genome Project, our knowledge of human genetic variation remains limited," says Professor Richard Gibbs, professor of molecular and human genetics at Baylor College of Medicine in Houston, Texas, and director of the BCM Human Genome Research Center. "Here we have studied more populations and were able to include CNPs in genomewide studies.

"These results tell us more about human genetic variation and about how to study variation successfully."

The results show that rarer variants are distributed more unevenly among populations. This might be expected - evolutionary theory implies that the common variants are generally the older ones, having had greater time to spread through a population - but also cautions that genetic studies should include a wide range of population groups to maximise discovery of more recent, population-specific variants.

"The closer we look at human genetic variation, the greater the granularity," explains Professor Manolis Dermitzakis, from the University of Geneva and one of the project coordinators, and formerly at the Wellcome Trust Sanger Institute. "An important task in genetics is to discriminate between the variants that are important for health and those that are part of the background.

"This new version of the HapMap will help us design ways to do that - to sort the wheat from the chaff."

In addition to the genotyping studies described above, HapMap 3 also sequenced ten segments of 100,000 bases from well-characterized regions of the human genome. Unlike discovery using DNA chips - as used in most studies to date - direct sequencing is not biased towards more common variants, but gives a direct estimate of the frequencies of variants.

The researchers found that most variants were relatively uncommon (found in less than one person in ten), but they also found a large number of rare variants (each found in less than one in 100 people) or 'private' variants (found in only one person). Almost eight of ten variants were new and almost four of ten of those seen in less than one in 100 people were found in only one population.

From the results, the researchers suggest that variants in some genes, including genes involved in the immune system, wound healing and sense of smell, are under selection in different populations. These genes can now be studied to learn about how these systems work and about disease resistance. These findings show the value of having large studies that include many populations and samples to achieve comprehensive understanding of human variation.

"Some have talked about how little has come from the Human Genome Project over the past ten years, but perhaps they forget how little we knew then," says Professor David Altshuler of Massachusetts General Hospital in Boston and the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University in Cambridge, Mass. "It is amazing that we have gone from a genome less than 90 per cent completed to looking at genetic changes in one in 200 people or rarer. A few years ago, we had no idea of the extent of structural variation or how we might sample variants present at low frequency.

"The HapMap and other large-scale projects have transformed our understanding of the human genome and its relation to health and disease."
The HapMap 3/ENCODE 3 data set is publicly available at

Notes to Editors

This research is dedicated to Leena Peltonen for her vital leadership role in this study, and in memory of a valued friend and colleague. Professor Peltonen died in March 2010.

Publication Details
The International HapMap 3 Consortium (2010) Integrating common and rare genetic variation in diverse human populations. Nature doi: 10.1038/nature09298

Participating Centres
A full list of participating centres can be seen at the Nature website.

The HapMap Consortium
Details of the project and participants can be accessed at

Project Funding
The USA National Institutes of Health, the National Human Genome Research Institute, the National Institute on Deafness and Other Communication Disorders and the Wellcome Trust supported the majority of this work. Funding was also provided by the Louis-Jeantet Foundation and the NCCR 'Frontiers in Genetics' (Swiss National Science Foundation).

The Eli and Edythe L. Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.

Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute 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 about the Broad Institute, go to

Baylor College of Medicine (BCM), Houston, Texas is the only private medical school in the greater southwest and is recognized as a premiere academic health science center known for excellence in education, research and patient care. For 2009, U.S. News and World Report ranked BCM 13th overall among the nation's top medical schools for research and 7th for primary care. BCM is also listed 13th among all U.S. medical schools for National Institutes of Health funding, and 2nd in the nation in federal funding for research and development in the biological sciences at universities and college by the National Science Foundation. During the reaccreditation proves in March 2007, BCM received "Accreditation with Commendation" for exemplary performance in fulfilling the accreditation requirements as a provider of continuing medical education.

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. 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.

The Wellcome Trust is a global charity dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests.

Contact details

Don Powell, Wellcome Trust Sanger Institute
+44 (0)1223 496928

Fintan Steele, Broad Institute of MIT and Harvard
1-617 714 7150

Glenna Picton, Baylor College of Medicine
1-713 798 4712

Wellcome Trust Sanger Institute

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to