DNA Polymorphism Discovery Resource

In 1998, Francis Collins, then director of the US National Human Genome Research Institute, or NHGRI, announced the creation of a tool for discovering genetic variation called the DNA Polymorphism Discovery Resource, or PDR. The PDR was a collection of cell lines housed in a central biobank. Scientists made those cell lines from blood samples they obtained from 450 US residents of diverse ancestry. They created the PDR to help researchers discover a particular type of genetic variation called single nucleotide polymorphisms, or SNPs. A SNP is a variation in a single letter of DNA at a particular location along a DNA molecule. SNPs can serve as markers when scientists look for associations between specific DNA regions and human traits, including common diseases like heart disease and cancer. Although as of 2024 the PDR is no longer available, it enabled scientists to identify more than a million SNPs spread over the whole human genome, a necessary precursor to studies aimed at identifying genetic variation that contributes to health and illness.

1. Single-Nucleotide Polymorphisms
2. Origins of the PDR
3. Composition of the PDR
4. Ethical Aspects of Creating the PDR
5. Putting the PDR to Use

Single-Nucleotide Polymorphisms

The purpose of the PDR was to allow scientists to identify gene variations, primarily SNPs, located across the human genome. SNPs occur approximately once every one thousand letters, or base pairs, in the human genome, which means that any person’s genome contains four to five million SNPs on average. SNPs result from the process of mutation, which is when the sequence of DNA changes over time. If a mutation occurs in a person’s sperm or egg cells, then that person can pass that mutation on to their children, who in turn can pass it on to their children. If a SNP occurs in a gene, it can change the function of that gene, in some cases leading to disease. Sickle cell disease, for example, is the result of a one-letter change, a SNP, in the gene that encodes hemoglobin, the protein that carries oxygen in the blood. The SNP leads to improperly folded hemoglobin, which can cause blood cells to change their shape and get stuck in blood capillaries, causing extreme pain and even death.

Most SNPs are not located within genes. That is because genes make up just a small percentage of the total DNA in a person’s genome, and so most SNPs fall in the large stretches of DNA that occur between genes. SNPs found in those regions are useful as markers, or signposts, in the genome. Scientists can compare SNPs both within and between groups of people, for example a group of people with a particular trait such as a disease and a group without the disease. If some SNPs are consistently associated with the presence of the disease, then that suggests there is genetic variation located near that SNP that plays a role in the disease.

Origins of the PDR

Pressure from the private industry was one motivation for the creation of the PDR. As reported at the time by science journalists, in the mid-1990s, several pharmaceutical and biotechnology companies were gearing up to identify and potentially patent SNPs, which prodded Collins and other leaders at the NHGRI to create the PDR. For example, in 1997, the medical device company Abbott Laboratories of Abbott Park, Illinois, announced it would partner with the biotechnology company Genset in Paris, France, to identify and patent SNPs, with the eventual goal of targeting drugs to patients with a specific genetic profile. The pharmaceutical company Bristol-Myers Squibb in New York City, New York, sponsored another SNP discovery effort in partnership with Whitehead Institute of Biomedical Research in Cambridge, Massachusetts, aimed at making a proprietary digital diagnostic tool to identify SNPs. As journalists covering those efforts reported, Collins and other scientific leaders were concerned that if individual labs and companies were able to patent SNPs, then they would lock up those tools for genetic discovery in private collections, leaving them inaccessible to other scientists. As an unnamed geneticist told a reporter for Science, it was a game of chicken between Collins and the companies to see who could get to the SNPs first.

Early discussions of what became the PDR took place at a meeting of the NHGRI advisory council held on September 11, 1997. The meeting participants, which included several representatives of drug makers and pharmaceutical companies, explicitly discussed launching what they called a preemptive strike against the commercialization of SNPs. According to a 1997 Science article by science journalist Eliot Marshall, while Collins stated he believed it was important to preserve public access to SNPs, he also stated it would be too expensive and possibly controversial for the NHGRI to create a SNP repository on its own. In November of 1997, Collins and two colleagues published an article in Science describing the need for an urgent solution to the SNP-patenting problem. They recommended that a consortium of institutes at the National Institutes of Health and other federal research agencies collaborate to fund an effort to discover SNPs and place them in public databases without restrictions on their use. They also stated that they welcomed participation by the private sector in that public effort. Between the end of 1997 and the end of 1998, scientists at the NHGRI, the Centers for Disease Control and Prevention, the National Institutes of Environmental Health Sciences, and several individual investigators worked to assemble the cell lines that became the PDR.

The PDR grew out of the Human Genome Project, which was an international effort to sequence the DNA in one entire human genome that began in 1990 and ran until 2003. In its first phase, the Human Genome Project did not focus on identifying genetic variation between individuals. Rather, the goal was to map all the genes in, and sequence the complete DNA of, one entire human genome with the aim of better understanding human diseases. However, by 1998, in part due to commercial pressure, the goals of the Human Genome Project had shifted. In an article published in Science in October 1998, Collins, who was the director of the project, and several colleagues announced a series of new goals for the Human Genome Project, including the identification of DNA sequence variation, with an initial focus on SNPs. Collins and colleagues stated the need for a public resource of DNA samples and cell lines to achieve the goal of identifying SNPs. Less than two months later, in December of 1998, Collins and two colleagues, Lisa Brooks from the NHGRI in Bethesda, Maryland, and Aravinda Chakravarti from Case Western Reserve University in Cleveland, Ohio, announced the creation of the PDR. In their announcement, published in the journal Genome Research, they stated that finding genetic variants on a large scale was a natural extension of the Human Genome Project. To help facilitate the collection of SNPs, Collins and colleagues announced that the National Center for Biotechnology Information, another branch of the US National Institutes of Health, had created a database, dbSNP, to house the SNPs that scientists discovered.

Composition of the PDR

The PDR consisted of immortalized cell lines from 450 anonymous, unrelated individuals with diverse ancestry who were all living in the US at the time of donation. There were equal numbers of males and females represented. Of the 450 individuals represented, 120 were European American, 120 were African American, 120 were Asian American, sixty were Mexican American, and thirty were Native American. All samples came from individuals who gave informed consent to be a part of the PDR. Once they had curated a panel of cell lines representing diverse ancestries, the researchers stripped all identifying information, including medical conditions, personal traits, and ancestry, from the samples before including them in the PDR. They deposited the samples in a biobank called the Coriell Institute for Medical Research, located in Camden, New Jersey.

The PDR’s assemblers’ decision to include individuals of diverse ancestries reflected their goal of capturing as much genetic variation as possible in their samples. Humans are remarkably genetically similar. Any two random individuals living anywhere in the world share 99.9 percent of their DNA sequence. However, in the 0.1 percent of DNA that differs between people lies the genetic basis for their unique traits, including their susceptibility to disease. The distribution of genetic variation among humans reflects the history of human migration since prehistoric times. Modern humans evolved in Africa around 300,000 years ago and subsequently spread out from there beginning between 40,000 and 100,000 years ago. As a result of that migration pattern, there is greater genetic variation within African populations than there is within non-African populations. And yet, available DNA collections at the time of the PDR contained relatively little DNA from people with African ancestry. The PDR assemblers therefore specifically sought to include samples from African Americans. Existing DNA collections at the time also contained little DNA from Native Americans or those with Asian ancestry, and that was another stated reason that the PDR assemblers sought to include a diverse sampling of individuals.

Ethical Aspects of Creating the PDR

The decision of the PDR assemblers to omit personal information from the samples stemmed in part from ethical considerations. For example, if researchers included information about an individual’s health as well as their ancestry with their cell line, it might be possible for researchers to identify specific disease-associated alleles that are more common in certain groups than in others, which could run the risk of stigmatizing those groups. Several Native American individuals that scientists contacted for blood samples raised a concern that researchers might still try to identify the ancestry of the individuals in the database. Those Native American individuals agreed to participate in the PDR only on the condition that researchers would not attempt to identify an individual’s ancestry. Consequently, the NHGRI explicitly prohibited any researcher using the PDR to attempt to identify an individual’s ancestry or ethnicity when studying their cell line.

Another reason the organizers decided to omit personal information from the cell lines was their experience with the Human Genome Diversity Project, an effort dating from the early 1990s that had planned to collect DNA samples from indigenous populations around the world with the goal of better understanding human evolutionary history and migration. That project proved controversial for several reasons. For one, representatives of indigenous groups expressed concerns that researchers would patent the indigenous DNA and use it to generate profits for companies that would not share the information with the groups who provided their DNA. In addition, some scientists criticized the Project planners’ methodological assumptions, including the idea that contemporary, living indigenous populations were somehow more genetically pure, or frozen in time, than other peoples. As a result of those controversies, the Human Genome Diversity Project never received the funding necessary to proceed and it stalled in its planning stage. In anonymizing the PDR samples, the NHGRI sought to avoid similar controversies.

Ethical questions also emerged in discussions over where the DNA samples for the PDR should come from. Researchers initially sought to acquire ready-made cell lines from the National Institute of Health’s National Center for Health Statistics, which from 1989 to 1994 had conducted the National Health and Nutrition Examination Survey, or NHANES, a large epidemiological study of health in the US. As part of that survey, researchers collected blood samples from more than 17,000 individuals from around the US. Later, a scientist at the US Centers for Disease Control and Prevention converted more than 8,000 of those blood samples into immortalized cell lines. It was those cell lines that the PDR assemblers initially sought to use. However, the consent form that NHANES participants had signed did not include mention of putting their DNA in a database, so there was no ethical way to include the samples without going back to the same individuals to get their consent. Ultimately, the National Center for Health Statistics obtained the necessary consents to provide several hundred DNA samples for the PDR.

Putting the PDR to Use

When the PDR became available in 1998, several individual researchers and groups used it to search for SNPs. The largest effort was a joint collaboration called The SNP Consortium, or TSC. On the private side of TSC were several large pharmaceutical companies including Bristol-Myers Squibb, Glaxo Wellcome, Novartis, Pfizer, Roche, and SmithKline Beecham, as well as the agrochemical maker Monsanto. Each of those companies contributed three million dollars towards the project. On the philanthropical side, the Wellcome Trust of Britain put in another fourteen million dollars. The academic centers involved were the Whitehead Institute in Cambridge, Massachusetts, the Sanger Center in the UK, Washington University in St. Louis, Missouri, Cold Spring Harbor Laboratories in Cold Spring Harbor, New York, and Stanford University in Palo Alto, California. The SNP Consortium’s goal was to identify 300,000 SNPs in two years.

The SNP Consortium and the public Human Genome Project eventually pooled their SNP data and announced the combined map of SNPs in the February 2001 issue of Nature, the same issue in which the publicly funded Human Genome Project published its draft sequence of the entire human genome. Together, the two groups had identified more than 1.4 million SNPs. That map of SNPs allowed scientists to begin looking for associations between SNPs and common human diseases.

At that time of writing in 2024, the Coriell Institute website indicates that the PDR is closed, and the samples are no longer available. The institute did not provide any further information about why the resource closed. The Coriell Institute houses several other collections of human cell lines and DNA samples that researchers can use to study human genetic variation.

Sources

1. Cavalli-Sforza, L. Luca. “The Human Genome Diversity Project: Past, Present, and Future.” 

   Nature Reviews Genetics 6 (2005): 333–40.

2. CD Genomics. “Fact Sheet: Single Nucleotide Polymorphisms (SNPs).” CD Genetics. 

   https://www.cd-genomics.com/blog/fact-sheet-single-nucleotide-polymorphisms-snps/ (Accessed August 5, 2024).

3. Clancy, Suzanne. “Genetic Mutation.” Nature Education 1 (2008): 187.

4. Cleveland Clinic. “Sickle Cell Disease.” Cleveland Clinic. 

   https://my.clevelandclinic.org/health/diseases/12100-sickle-cell-disease (Accessed 

   August 5, 2024).

5. Collins, Francis S., Ari Patrinos, Elke Jordan, Aravinda Chakravarti, Raymond Gesteland, 

   LeRoy Walters, and the members of the DOE and NIH planning groups. “New Goals for the U. S. Human Genome Project: 1998–2003.” Science 282 (1998): 682–9.

6. Collins, Francis S., Lisa D. Brooks, and Aravinda Chakravarti. "A DNA Polymorphism 

   Discovery Resource for Research on Human Genetic Variation." Genome Research 8 (1998): 1229–31. https://genome.cshlp.org/content/8/12/1229.full.pdf (Accessed August 5, 2024).

7. Collins, Francis S., Mark S. Guyer, and Aravinda Chakravarti. "Variations on a Theme: 

   Cataloging Human DNA Sequence Variation." Science 278 (1997): 158–1.

8. Collins, Francis S., and Monique K. Mansoura. "The Human Genome Project: Revealing the 

   Shared Inheritance ofAll Humankind." Cancer: Interdisciplinary International Journal of the American Cancer Society 91 (2001): 22–5.

9. Coriell Institute for Medical Research. “Polymorphism Discovery Resource.” Coriell Institute 

   for Medical Research. https://www.coriell.org/1/NIGMS/Collections/Polymorphism-Discovery-Resource (Accessed August 8, 2024).

10. Holden, Arthur L. "The SNP Consortium: Summary of a Private Consortium Effort to Develop 

    an Applied Map of the Human Genome." Biotechniques 32 (2002): S22–26.

11. International Human Genome Sequencing Consortium. “Initial Sequencing and Analysis of 

    the Human Genome.” Nature 409 (2001): 860–921.

12. International SNP Map Working Group. "A Map of Human Genome Sequence Variation 

    Containing 1.42 million Single Nucleotide Polymorphisms." Nature 409 (2001): 928–33.

13. Marks, Jonathan. Human Biodiversity: Genes, Race, and History. New York: Routledge, 2017 

    [originally 2005].

14. Marshall, Eliot. “Drug Firms to Create Public Database of Genetic Mutations.” Science 284 

    (1999): 406–7.

15. Marshall, Eliot. "'Playing Chicken' Over Gene Markers." Science 278 (1997): 2046–8.
16. Marshall, Eliot. "Snipping Away at Genome Patenting." Science 277 (1997): 1752–3.

17. National Human Genome Research Institute. “Human Genome Project Fact Sheet.” National 

    Human Genome Research Institute. https://www.genome.gov/about-genomics/educational-resources/fact-sheets/human-genome-project (Accessed August 7, 2024).

18. National Human Genome Research Institute. “Single Nucleotide Polymorphisms (SNPs).”
19. National Human Genome Research Institute. https://www.genome.gov/genetics-glossary/Single-Nucleotide-Polymorphisms (Accessed August 5, 2024).

20. National Human Genome Research Institute. “The Human Genome Project.” National Human 

    Genome Research Institute. https://www.genome.gov/human-genome-project (Accessed August 7, 2024).

21. Smithsonian National Museum of Natural History. “Homo sapiens.” Smithsonian National 

    Museum of Natural History. https://humanorigins.si.edu/evidence/human-fossils/species/homo-sapiens (Accessed August 7, 2024).

22. Tozatto-Maio, Karina, Robert Girot, Indou Deme Ly, Ana Cristina Silva Pinto, Vanderson 

    Rocha, Francisco Fernandes, Ibrahima, Yahia Benzerara, Carla L. Dinardo, Julia Pavan Soler, Simone Kashima, Itauá Leston Araujo, Chantal Kenzey, Guilherme H. H. Foneca, Evandra S. Rodrigues, Fernanda Volt, Luciana Jarduli, Annalisa Ruggeri, Christina Mariaselvam, Sandra F. M. Gualandro, Hanadi Rafi, Barbara Cappelli, Felipe Melo Nogueira, Graziana Maria Scigliuolo, Renato Luiz Guerino-Cunha, Kelen Cristina Ribeiro Malmegrim, Belinda P. Simões, Eliane Gluckman,Eliane Gluckman, and Ryad Tamouza. “Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease.” Frontiers in Immunology 11 (2020). https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.02041/full (Accessed August 5, 2024).