Journal of the History of Biology

, Volume 51, Issue 4, pp 841–873 | Cite as

Variations on a Chip: Technologies of Difference in Human Genetics Research

  • Ramya M. RajagopalanEmail author
  • Joan H. Fujimura
Open Access


In this article we examine the history of the production of microarray technologies and their role in constructing and operationalizing views of human genetic difference in contemporary genomics. Rather than the “turn to difference” emerging as a post-Human Genome Project (HGP) phenomenon, interest in individual and group differences was a central, motivating concept in human genetics throughout the twentieth century. This interest was entwined with efforts to develop polymorphic “genetic markers” for studying human traits and diseases. We trace the technological, methodological and conceptual strategies in the late twentieth century that established single nucleotide polymorphisms (SNPs) as key focal points for locating difference in the genome. By embedding SNPs in microarrays, researchers created a technology that they used to catalog and assess human genetic variation. In the process of making genetic markers and array-based technologies to track variation, scientists also made commitments to ways of describing, cataloging and “knowing” human genetic differences that refracted difference through a continental geographic lens. We show how difference came to matter in both senses of the term: difference was made salient to, and inscribed on, genetic matter(s), as a result of the decisions, assessments and choices of collaborative and hybrid research collectives in medical genomics research.


Sociotechnical practice Biomedical genomics Human genetic variation Single nucleotide polymorphisms (SNPs) Population Difference DNA microarray SNP chip Haplotype map Public–private research partnerships Genomics consortia 



We gratefully thank respondents at our field sites who generously shared their time and allowed us to observe their work. We also thank Christopher Donohue and the staff at the NHGRI History of Genomics Program for facilitating access to the NHGRI Archival Resource, and for organizing the workshop ‘‘Capturing the History of Genomics,’’ where an early version of this article was presented. The article also benefited from questions and comments at presentations in Australia, Denmark, France, Norway, Taiwan, the U.S. and Wales. We thank the two anonymous reviewers who offered valuable feedback to strengthen the manuscript. RMR acknowledges research support from the Life Sciences Foundation (now the Science History Institute). JHF acknowledges research support from the Russell Sage Foundation and the Center for Advanced Study in the Behavioral Sciences. This work was supported by NSF grant 0621022, NIH/NHGRI Grant R03HG005030, NIH/NHGRI Grant R03HG006571, a University of Wisconsin-Madison Vilas Life Cycle Professorship Award, and grants from the University of Wisconsin Institute for Race and Ethnicity and the University of Wisconsin Graduate School


  1. Altshuler, D., Pollara, V.J., Cowles, C.R., Van Etten, W.J., Baldwin, J., Linton, L. and Lander, E.S. 2000. “A SNP Map of the Human Genome Generated by Reduced Representation Shotgun Sequencing.” Nature 407(6803): 513–516.CrossRefGoogle Scholar
  2. Bangham, J. 2014. “Blood Groups and Human Groups: Collecting and Calibrating Genetic data After World War Two.” Studies in the History and Philosophy of Biological and Biomedical Sciences, Part A 47: 74–86.CrossRefGoogle Scholar
  3. Bien, S.A., Wojcik, G.L., Zubair, N., Gignoux, C.R., Martin, A.R., Kocarnik, J.M., Martin, L.W., et al. 2016. “Strategies for Enriching Variant Coverage in Candidate Disease Loci on a Multiethnic Genotyping Array.” PLoS ONE 11(12): e0167758.CrossRefGoogle Scholar
  4. Botstein, D., White, R.L., Skolnick, M. and Davis, R.W. 1980. “Construction of a Genetic Linkage Map in Man Using Restriction Fragment Length Polymorphisms.” American Journal of Human Genetics. 32(3): 314–331.Google Scholar
  5. Brooks, L.D. 2003. “SNPs: Why Do We Care?” P.-Y. Kwok (ed.), Single Nucleotide Polymorphisms: Methods and Protocols. Totowa: Humana Press, pp. 1–14.Google Scholar
  6. Brown, P. 2003. “Why we Developed the Microarray.” DNA Interactive Video Interview 15036, DNA Learning Center at Cold Spring Harbor Laboratory.
  7. Cargill, M., Altshuler, D., Ireland, J., Sklar, P., Ardlie, K., Patil, N., Shaw, N., et al. 1999. “Characterization of Single-Nucleotide Polymorphisms in Coding Regions of Human Genes.” Nature Genetics 22: 231–238.CrossRefGoogle Scholar
  8. Cavalli-Sforza, L.L., Menozzi, P. and Piazza, A. 1994. The History and Geography of Human Genes. Princeton, NJ: Princeton University Press.Google Scholar
  9. Collins, A., Lonjou, C., Morton, N.E. 1999. “Genetic Epidemiology of Single-Nucleotide Polymorphisms.” Proceedings of the National Academy of Sciences of United States of America 96(26): 15173–15177.CrossRefGoogle Scholar
  10. Collins, F.C. 1991. “Of Needles and Haystacks: Finding Human Disease Genes by Positional Cloning.” Clinical Research 39(4): 615–623.Google Scholar
  11. Collins, F.C. and Galas, D. 1993. “A New Five-Year Plan for the U.S. Human Genome Project.” Science 262(5130): 43–46.CrossRefGoogle Scholar
  12. Collins, F.C., Guyer, M.S. and Chakravarti, A. 1997. “Variations on a Theme: Cataloging Human DNA Sequence Variation.” Science 278: 1580–1581.CrossRefGoogle Scholar
  13. Cronin, M.T., Fucini, R.V., Kim, S.M., Masino, R.S., Wespi, R.M. and Miyada, C.G. 1996. “Cystic Fibrosis Mutation Detection by Hybridization to Light-Generated DNA Probe Arrays.” Human Mutation 7(3): 244–255.CrossRefGoogle Scholar
  14. Daly, M.J., Rioux, J.D., Schaffner, S.F., Hudson, T.J. and Lander, E.S. 2001. “High-Resolution Haplotype Structure in the Human Genome.” Nature Genetics 29(2): 229–232.CrossRefGoogle Scholar
  15. de Chadarevian, S. 2014. “Chromosome Surveys of Human Populations: Between Epidemiology and Anthropology.” Studies in the History and Philosophy of Biological and Biomedical Sciences Part A 47: 87–96.CrossRefGoogle Scholar
  16. Delahunty, C., Ankener, W., Deng, Q., Eng, J. and Nickerson, D.A. 1996. “Testing the Feasibility of DNA Typing for Human Identification by PCR and an Oligonucleotide Ligation Assay.” American Journal of Human Genetics. 58(6): 1239–1246.Google Scholar
  17. De La Vega, F.M., Dailey, D., Ziegle, J., Williams, J., Madden, D. and Gilbert, D.A. 2002. “New Generation Pharmacogenomic Tools: A SNP Linkage Disequilibrium Map, Validated SNP Assay Resource, and High-Throughput Instrumentation System for Large-Scale Genetic Studies.” Biotechniques 32: S48–S54.CrossRefGoogle Scholar
  18. Doel, R.E. and Söderqvist, T. 2006. The Historiography of Contemporary Science, Technology, and Medicine: Writing Recent Science. New York: Routledge.CrossRefGoogle Scholar
  19. Fodor, S.P., Read, J.L., Pirrung, M.C., Stryer, L., Lu, A.T. and Solas, D. 1991. “Light-Directed, Spatially Addressable Parallel Chemical Synthesis.” Science 251(4995): 767–773.CrossRefGoogle Scholar
  20. Fujimura, J.H. and Rajagopalan, R. 2011. “Different Differences: The Use of Ancestry Versus Race in Biomedical Human Genetic Research.” Social Studies of Science 41(1): 5–30.CrossRefGoogle Scholar
  21. Fullwiley, D. 2008. “The Biologistical Construction of Race: ‘Admixture’ Technology and the New Genetic Medicine.” Social Studies of Science 38(5): 695–735.CrossRefGoogle Scholar
  22. Gabriel, S.B., Schaffner, S.F., Nguyen, H., Moore, J.M., Roy, J., Blumenstiel, B., Higgins, J., et al. 2002. “The Structure of Haplotype Blocks in the Human Genome.” Science 296(5576): 2225–2229.CrossRefGoogle Scholar
  23. Gannett, L. 2001. “Racism and Human Genome Diversity Research: The Ethical Limits of ‘Population Thinking’.” Philosophy of Science 68(3): S479–S492.CrossRefGoogle Scholar
  24. Gannett, L. and Griesemer, J. 2004. “The ABO Blood Groups: Mapping the History and Geography of Genes in Homo sapiens.” J.-P. Gaudillière and H.-J. Rheinberger (eds.), Classical Genetic Research and Its Legacy: The Mapping Cultures of Twentieth-Century Genetics. New York: Routledge.Google Scholar
  25. Gaudillière, J.-P. and Rheinberger, H.-J. (eds.). 2004. From Molecular Genetics to Genomics: The Mapping Cultures of Twentieth-Century Genetics. New York: Routledge.Google Scholar
  26. Gudmundsson, J., Sulem, P., Manolescu, A., Amundadottir, L.T., Gudbjartsson, D., Helgason, A., Rafnar, T., et al. 2007. “Genome-Wide Association Study Identifies a Second Prostate Cancer Susceptibility Variant at 8q24.” Nature Genetics 39(5): 631–637.CrossRefGoogle Scholar
  27. Guo, Z., Guilfoyle, R.A., Thiel, A.J., Wang, R. and Smith, L.M. 1994. “Direct Fluorescence Analysis of Genetic Polymorphisms by Hybridization with Oligonucleotide Arrays on Glass Supports.” Nucleic Acids Research 22(24): 5456–5465.CrossRefGoogle Scholar
  28. Hacia, J.G., Brody, L.C., Chee, M.S., Fodor, S.P. and Collins, F.S. 1996. “Detection of Heterozygous Mutations in BRCA1 Using High Density Oligonucleotide Arrays and Two-Colour Fluorescence Analysis.” Nature Genetics 14(4): 441–447.CrossRefGoogle Scholar
  29. Hacia, J.G. and Collins, F.C. 1999. “Mutational Analysis Using Oligonucleotide Microarrays.” Journal of Medical Genetics 36: 730–736.CrossRefGoogle Scholar
  30. Halushka, M.K., Fan, J.B., Bentley, K., Hsie, L., Shen, N., Weder, A., Cooper, R., et al. 1999. “Patterns of Single-Nucleotide Polymorphisms in Candidate Genes for Blood-Pressure Homeostasis.” Nature Genetics 22(3): 239–247.CrossRefGoogle Scholar
  31. Hoffmann, T.J., Kvale, M.N., Hesselson, S.E., Zhan, Y., Aquino, C., Cao, Y., Cawley, S., et al. 2011a. “Next Generation Genome-Wide Association Tool: Design and Coverage of a High-Throughput European-Optimized SNP Array.” Genomics 98(2): 79–89.CrossRefGoogle Scholar
  32. Hoffmann, T.J., Zhan, Y., Kvale, M.N., Hesselson, S.E., Gollub, J., Iribarren, C., Lu, Y., et al. 2011b. “Design and Coverage of High Throughput Genotyping Arrays Optimized for Individuals of East Asian, African American, and Latino Race/Ethnicity Using Imputation and a Novel Hybrid SNP Selection Algorithm.” Genomics 98(6): 422–430.CrossRefGoogle Scholar
  33. Holden, A.L. 2002. “The SNP Consortium: Summary of a Private Consortium Effort to Develop an Applied Map of the Human Genome.” BioTechniques 32: S22–S26.CrossRefGoogle Scholar
  34. International HapMap 3 Consortium. 2010. “Integrating common and rare genetic variation in diverse human populations.” Nature 467(7311): 52–58.CrossRefGoogle Scholar
  35. International SNP Map Working Group. 2001. “A Map of Human Genome Sequence Variation Containing 1.42 Million Single Nucleotide Polymorphisms.” Nature 409(6822): 928–933.CrossRefGoogle Scholar
  36. Kawai, Y., Mimori, T., Kojima, K., Nariai, N., Danjoh, I., Saito, R., Yusada, J., et al. 2015. “Japonica Array: Improved Genotype Imputation by Designing a Population-Specific SNP Array with 1070 Japanese Individuals.” Journal of Human Genetics. 60(10): 581–587.CrossRefGoogle Scholar
  37. Klein, R.J., Zeiss, C., Chew, E.Y., Tsai, J.-Y., Sackler, R.S., Haynes, C., Henning, A.K., et al. 2005. “Complement Factor H Polymorphism in Age-Related Macular Degeneration.” Science 308(5720): 385–389.CrossRefGoogle Scholar
  38. Kruglyak, L. 1997. The Use of a Genetic Map of Biallelic Markers in Linkage Studies. Nature Genetics 17: 21–24.Google Scholar
  39. Kruglyak, L. 1999. “Prospects for Whole-Genome Linkage Disequilibrium Mapping of Common Disease Genes.” Nature Genetics 22: 139–144.CrossRefGoogle Scholar
  40. Kruglyak, L. and Nickerson, D. 2001. “Variation is the Spice of Life.” Nature Genetics 27: 234–236.CrossRefGoogle Scholar
  41. Lander, E.S. 1996. “The New Genomics: Global Views of Biology.” Science. 274(5287): 536–539.CrossRefGoogle Scholar
  42. Lander, E.S. and Botstein, D. 1986. “Strategies for Studying Heterogeneous Genetic Traits in Humans by Using a Linkage Map of Restriction Fragment Length Polymorphisms.” Proceedings of the National Academy of Sciences of United States of America 83: 7353–7357.CrossRefGoogle Scholar
  43. Lipphardt, V. 2014. “Geographical Distribution Patterns of Various Genes: Genetic Studies of Human Variation After 1945.” Studies in History and Philosophy of Biological and Biomedical Sciences, Part A 47: 50–61.CrossRefGoogle Scholar
  44. Lipshutz, R.J., Fodor, S.P.A., Gingeras, T.R. and Lockhart, D.J. 1999. “High Density Synthetic Oligonucleotide Arrays.” Nature Genetics 21: 20–24.CrossRefGoogle Scholar
  45. Marks, J. 2012. “The Origins of Anthropological Genetics.” Current Anthropology 53(S5): S161–S172.CrossRefGoogle Scholar
  46. Marshall, E. 1997. “‘Playing Chicken’ over Genetic Markers.” Science 278(5346): 2046–2048.CrossRefGoogle Scholar
  47. Matson, R., Rampal, J., Pentoney, S.L., Anderson, P.D. and Coassin, P. 1995. “Biopolymer Synthesis on Polypropylene Supports: Oligonucleotide Arrays.” Analytical Biochemistry 224(1): 110–116.CrossRefGoogle Scholar
  48. McCusick, V. 1992. Mendelian Inheritance in Man: Catalogs of Autosomal Dominant, Autosomal Recessive and X-Linked Phenotypes, 10th ed. Baltimore: Johns Hopkins University Press.Google Scholar
  49. M’charek, A. 2005. The Human Genome Diversity Project: An Ethnography of Scientific Practice. Cambridge: Cambridge University Press.CrossRefGoogle Scholar
  50. Michael, K.L., Taylor, L.C., Schultz, S.L. and Walt, D.R. 1998. “Randomly Ordered Addressable High-Density Optical Sensor Arrays.” Analytical Chemistry 7: 1242–1248.CrossRefGoogle Scholar
  51. Mukharji, P.B. 2014. “From Serosocial to Sanguinary Identities: Caste, Transnational Race Science and the Shifting Metonymies of Blood Group B, India c. 1918–1960.” Indian Economic and Social History Review 51(2): 143–176.CrossRefGoogle Scholar
  52. Nickerson, D.A., Kaiser, R., Lappin, S., Stewart, J., Hood, L. and Landegren, U. 1990. “Automated DNA Diagnostics Using An ELISA-based Oligonucleotide Ligation Assay. ” Proceedings of the National Academy of Sciences of United States of America 87: 8923–8927.Google Scholar
  53. Nikiforov, T.T., Rendle, R.B., Goelet, P., Rogers, Y.H., Kotewicz, M.L., Anderson, S., Trainor, G.L., et al. 1994. “Genetic Bit Analysis: A Solid Phase Method for Typing Single Nucleotide Polymorphisms.” Nucleic Acids Research 22(20): 4167–4175.CrossRefGoogle Scholar
  54. Oliphant, A., Barker, D.L., Stuelpnagel, J.R. and Chee, M.S. 2002. “BeadArray Technology: Enabling an Accurate, Cost-Effective Approach to High-Throughput Genotyping.” Biotechniques 32: S56–S61.CrossRefGoogle Scholar
  55. Patil, N., Berno, A.J., Hinds, D.A., Barrett, W.A., Doshi, J.M., Hacker, C.R., Kautzer, C.R., et al. 2001. “Blocks of Limited Haplotype Diversity Revealed by High-Resolution Scanning of Human Chromosome 21.” Science 294(5547): 1719–1723.CrossRefGoogle Scholar
  56. Peacock, E. and Whiteley, P. 2005. “Perlegen Sciences, Inc.” Pharmacogenomics 6(4): 439–442.CrossRefGoogle Scholar
  57. Pe’er, I., de Bakker, P.I., Maller, J., Yelensky, R., Altshuler, D. and Daly, M.J. 2006. “Evaluating and Improving Power in Whole-Genome Association Studies Using Fixed Marker Sets.” Nature Genetics 38(6): 663–667.CrossRefGoogle Scholar
  58. Rajagopalan, R. and Fujimura, J.H. 2012. “Making History Via DNA, Making DNA from History: Deconstructing the Race-Disease Connection in Admixture Mapping.” K Wailoo, C Lee, A Nelson (eds.), Genetics and the Unsettled Past: The Collision between DNA, Race and History. New Brunswick: Rutgers University Press.Google Scholar
  59. Reardon, J. 2005. Race to the Finish: Identity and Governance in an Age of Genomics. Princeton: Princeton University Press.Google Scholar
  60. Reich, D.E., Cargill, M., Bolk, S., Ireland, J., Sabeti, P.C., Richter, D.C., Lavery, T., et al. 2001. “Linkage Disequilibrium in the Human Genome.” Nature 411(6834): 199–204.CrossRefGoogle Scholar
  61. Risch, N. and Merikangas, K. 1996. “The Future of Genetic Studies of Complex Human Diseases.” Science 273(5281): 1516–1517.CrossRefGoogle Scholar
  62. Rogers, S. and Cambrosio, A. 2007. “Making a New Technology Work: The Standardization and Regulation of Microarrays.” Yale Journal of Biology and Medicine 80: 165–178.Google Scholar
  63. Saxena, R., Voight, B.F., Lyssenko, V., Burtt, N.P., de Bakker, P.I., Chen, H., Roix, J.J., et al. 2007. “Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels.” Science 316(5829): 1331–1336.CrossRefGoogle Scholar
  64. Schena, M., Shalon, D., Davis, R.W. and Brown, P.O. 1995. “Quantitative Monitoring of Gene Expression Patterns with a Complementary DNA Microarray.” Science 270(5235): 467–470.CrossRefGoogle Scholar
  65. Shostak, S. 2005. “The Emergence of Toxicogenomics: A Case Study of Molecularization.” Social Studies of Science 35(3): 367–403.CrossRefGoogle Scholar
  66. Southern, E.M., Maskos, U. and Elder, J.K. 1992. Analyzing and Comparing Nucleic Acid Sequences by Hybridization to Arrays of Oligonucleotides: Evaluation Using Experimental Models. Genomics 13(4): 1008–1017.Google Scholar
  67. Suárez-Diáz, E. 2014. “Indigenous Populations in Mexico: Medical Anthropology in the Work of Ruben Lisker in the 1960s.” Studies in History and Philosophy of Biological and Biomedical Sciences 47: 108–117.CrossRefGoogle Scholar
  68. The 1000 Genomes Project Consortium. 2015. “A Global Reference for Human Genetic Variation.” Nature 526(7571): 68–74.Google Scholar
  69. U.S. Congress Office of Technology Assessment. 1988. Mapping Our Genes. The Genome Projects: How Big, How Fast?. Washington: U.S. Government Printing Office.Google Scholar
  70. Wang, D., Sapolsky, R., Spencer, J., Rioux, J., Kruglyak, L., Hubbell, E., Ghandour, G., et al. 1996. “Toward a Third Generation Genetic Map of the Human Genome Based on Biallelic Polymorphisms.” American Journal of Human Genetics 59: A3.Google Scholar
  71. Wang, D.G., Fan, J.B., Siao, C.J., Berno, A., Young, P., Sapolsky, R., Ghandour, G., et al. 1998. “Large-Scale Identification, Mapping, and Genotyping of Single-Nucleotide Polymorphisms in the Human Genome.” Science 280(5366): 1077–1082.CrossRefGoogle Scholar
  72. Weber, J.L. and May, P.E. 1989. “Abundant Class of Human DNA Polymorphisms Which can be Typed Using the Polymerase Chain Reaction.” American Journal of Human Genetics. 44(3): 388–396.Google Scholar
  73. Weber, J.L. 1990. “Human DNA Polymorphisms and Methods of Analysis.” Current Opinion in Biotechnology 1(2): 166–171.CrossRefGoogle Scholar
  74. Weissenbach, J. 1993. “Microsatellite Polymorphisms and the Genetic Linkage Map of the Human Genome.” Current Opinion in Genetics and Development 3(3): 414–417.CrossRefGoogle Scholar
  75. Weiss, K.M. 1998. “In Search of Human Variation.” Genome Research 8(7): 691–697.CrossRefGoogle Scholar
  76. Wellcome Trust Case Control Consortium. 2007. “Genome-Wide Association Study of 14,000 Cases of Seven Common Diseases and 3,000 Shared Controls.” Nature 447(7145): 661–678.CrossRefGoogle Scholar
  77. Widmer, A. 2014. “Making Blood ‘Melanesian’: Fieldwork and Isolating Techniques in Genetic Epidemiology (1963–1976).” Studies in the History and Philosophy of Biological and Biomedical Sciences, Part A 47: 118–129.CrossRefGoogle Scholar
  78. Zietkiewicz, E., Yotova, V., Jarnik, M., Korab-Laskowska, M., Kidd, K.K., Modiano, D., Scozzari, R., et al. 1997. “Nuclear DNA Diversity in Worldwide Distributed Human Populations.” Gene 205(1–2): 161–171.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2018
corrected publication 2019

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.Institute for Practical EthicsUniversity of California, San DiegoSan DiegoUSA
  2. 2.Department of Sociology and Holtz Center for Science and Technology StudiesUniversity of Wisconsin-MadisonMadisonUSA

Personalised recommendations