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Software Availability

The methods described herein have been implemented in software and are available as a Microsoft Windows installer at computationalimmunology/research/software.

Source code is available at Codeplex, at


This work was supported by the National Institute of Immunology, Allergy, and Transplantation under cooperative agreement 1 U19 AI117892-01.


  • 1. J. A. Weinstein, N. Jiang, R. A. White, D. S. Fisher, and S. R. Quake. High- throughput sequencing of the zebrafish antibody repertoire. Science 324, 807810 (2009).
  • 2. J. Glanville, W. Zhai, J. Berka, D. Telman, G. Huerta, G. R. Mehta, I. Ni, et al. Precise determination of the diversity of a combinatorial antibody library gives insight into the human immunoglobulin repertoire. Proceedings of the National Academy of Sciences 106, 20216-20221 (2009).
  • 3. J. A. Finn, and J. E. Crowe, Jr. Impact of new sequencing technologies on studies of the human B cell repertoire. Current Opinion in Immunology 25, 613-618 (2013).
  • 4. H. Robins. Immunosequencing: Applications of immune repertoire deep sequencing. Current Opinion in Immunology 25, 646-652 (2013).
  • 5. P. Mathonet, and C. Ullman. The application of next generation sequencing to the understanding of antibody repertoires. Frontiers in Immunology 4, 265 (2013).
  • 6. G. Georgiou, G. C. Ippolito, J. Beausang, C. E. Busse, H. Wardemann, and S. R. Quake. The promise and challenge of high-throughput sequencing of the antibody repertoire. Nature Biotechnology 32, 158-168 (2014).
  • 7. S. D. Boyd, Y. Liu, C. Wang, V. Martin, and D. K. Dunn-Walters. Human lymphocyte repertoires in ageing. Current Opinion in Immunology 25, 511515 (2013).
  • 8. W. H. Robinson. Sequencing the functional antibody repertoire—Diagnostic and therapeutic discovery. Nature Reviews Rheumatology 11, 171-182 (2015).
  • 9. A. C. Logan, H. Gao, C. Wang, B. Sahaf, C. D. Jones, E. L. Marshall, I. Buno, et al. High-throughput VDJ sequencing for quantification of minimal residual disease in chronic lymphocytic leukemia and immune reconstitution assessment. Proceedings of the National Academy of Sciences 108, 21194-21199 (2011).
  • 10. N. Jiang, J. He, J. A. Weinstein, L. Penland, S. Sasaki, X.-S. He, C. L. Dekker, et al. Lineage structure of the human antibody repertoire in response to influenza vaccination. Science Translational Medicine 5, 171ra119 (2013).
  • 11. J. D. Galson, A. J. Pollard, J. Truck, D. F. Kelly. Studying the antibody repertoire after vaccination: Practical applications. Trends in Immunology 35, 319-331 (2014).
  • 12. X. Wu, T. Zhou, J. Zhu, B. Zhang, I. Georgiev, C. Wang, X. Chen, et al. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 333, 1593-1602 (2011).
  • 13. H. X. Liao, R. Lynch, T. Zhou, F. Gao, S. M. Alam, S. D. Boyd, A. Z. Fire, et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496, 469-476 (2013).
  • 14. G. M. Edelman. Antibody structure and molecular immunology. Science 180, 830-840 (1973).
  • 15. F. Trepel. Number and distribution of lymphocytes in man. A critical analysis. Klinische Wochenschrift 52, 511-515 (1974).
  • 16. R. Somasundaram, M. A. Prasad, J. Ungerback, and M. Sigvardsson. Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia. Blood 126, 144-152 (2015).
  • 17. E. ten Boekel, F. Melchers, and A. Rolink. The status of Ig loci rearrangements in single cells from different stages of B cell development. Internal Immunology 7, 1013-1019 (1995).
  • 18. E. Meffre, and M. C. Nussenzweig. Deletion of immunoglobulin beta in developing B cells leads to cell death. Proceedings of the National Academy of Sciences of the United States of America 99, 11334-11339 (2002).
  • 19. M. S. Naradikian, J. L. Scholz, M. A. Oropallo, and M. P. Cancro. Drugs Targeting B-Cells in Autoimmune Diseases. (Springer, New York, 2014), pp. 11-35.
  • 20. D. Gay, T. Saunders, S. Camper, and M. Weigert. Receptor editing: An approach by autoreactive B cells to escape tolerance. Journal of Experimental Medicine 177, 999-1008 (1993).
  • 21. H. Wardemann, S. Yurasov, A. Schaefer, J. Young, E. Meffre, and M. Nussenzweig. Predominant autoantibody production by early human B cell precursors. Science 301, 1374-1377 (2003).
  • 22. E. Gaudin, Y. Hao, M. M. Rosado, R. Chaby, R. Girard, and A. A. Freitas. Positive selection of B cells expressing low densities of self-reactive BCRs. Journal of Experimental Medicine 199, 843-853 (2004).
  • 23. A. G. Rolink, J. Tschopp, P. Schneider, and F. Melchers. BAFF is a survival and maturation factor for mouse B cells. European Journal of Immunology 32, 20042010 (2002).
  • 24. Y. X. Fu, and D. D. Chaplin. Development and maturation of secondary lymphoid tissues. Annual Review of Immunology 17, 399-433 (1999).
  • 25. M. Nishana, and S. C. Raghavan. Role of recombination activating genes in the generation of antigen receptor diversity and beyond. Immunology 137, 271-281 (2012).
  • 26. D. G. Schatz, and Y. Ji. Recombination centres and the orchestration of V(D)J recombination. Nature Reviews Immunology 11, 251-263 (2011).
  • 27. J. M. den Haan, R. Arens, and M. C. van Zelm. The activation of the adaptive immune system: Cross-talk between antigen-presenting cells, T cells and B cells. Immunology Letters 162, 103-112 (2014).
  • 28. C. A. Janeway, Jr., P. Travers, M. Walport, and M. Schlomchik. Immunobiology: The Immune System in Health and Disease. 6th edn. (Garland Science, New York, 2005), pp. 369-383.
  • 29. N. S. De Silva, and U. Klein. Dynamics of B cells in germinal centres. Nature Reviews Immunology 15, 137-148 (2015).
  • 30. G. D. Victora, and M. C. Nussenzweig. Germinal centers. Annual Review of Immunology 30, 429-457 (2012).
  • 31. A. Tanaka, H. M. Shen, S. Ratnam, P. Kodgire, and U. Storb. Attracting AID to targets of somatic hypermutation. Journal of Experimental Medicine 207,405-415 (2010).
  • 32. S. D. Wagner, C. Milstein, and M. S. Neuberger. Codon bias targets mutation. Nature 376, 732-732 (1995).
  • 33. T. B. Kepler. Codon bias and plasticity in immunoglobulins. Molecular Biology and Evolution Society 14, 637-643 (1997).
  • 34. J. Tan, K. Pieper, L. Piccoli, A. Abdi, M. Foglierini, R. Geiger, C. M. Tully, et al. A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens. Nature 529, 105-109 (2016).
  • 35. M. Seifert, M. Przekopowitz, S. Taudien, A. Lollies, V. Ronge, B. Drees, M. Lindemann, et al. Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions. Proceedings of the National Academy of Sciences of the United States of America 112, E546-555 (2015).
  • 36. L. J. Mcheyzer-Williams, P. J. Milpied, S. L. Okitsu, and M. G. Mcheyzer- Williams. Class-switched memory B cells remodel BCRs within secondary germinal centers. Nature Immunology 16, 296-305 (2015).
  • 37. H. Morbach, E. M. Eichhorn, J. G. Liese, and H. J. Girschick. Reference values for B cell subpopulations from infancy to adulthood. Clinical & Experimental Immunology 162, 271-279 (2010).
  • 38. M. P. Cancro. The persistence of memory: A unique niche for IgG memory B cells. Proceedings of the National Academy of Sciences of the United States of America 107, 12737-12738 (2010).
  • 39. R. A. Manz, A. Thiel, and A. Radbruch. Lifetime of plasma cells in the bone marrow. Nature 388, 133-134 (1997).
  • 40 . X . Yu, T . Tsibane, P . A . McGraw, F . S. House, C . J . Keefer, M . D . Hicar, T . M. Tumpey, et al. Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors. Nature 455, 532-536 (2008).
  • 41. M. K. Slifka, R. Ahmed. Long-lived plasma cells: A mechanism for maintaining persistent antibody production. Current Opinion in Immunology 10, 252-258 (1998).
  • 42. J. A. Weinstein, X. Zeng, Y. H. Chien, and S. R. Quake. Correlation of gene expression and genome mutation in single B-cells. PLoS One 8, e67624 (2013).
  • 43. C. E. Busse, I. Czogiel, P. Braun, P. F. Arndt, and H. Wardemann. Single-cell based high-throughput sequencing of full-length immunoglobulin heavy and light chain genes. European Journal of Immunology 44, 597-603 (2014).
  • 44. B. J. DeKosky, G. C. Ippolito, R. P. Deschner, J. J. Lavinder, Y. Wine, B. M. Rawlings, N. Varadarajan, et al. High-throughput sequencing of the paired human immunoglobulin heavy and light chain repertoire. Nature Biotechnology 31, 166-169 (2013).
  • 45. J. L. Duke, C. Lind, K. Mackiewicz, D. Ferriola, A. Papazoglou, O. Derbeneva, D. Wallace, and D. S. Monos. Towards allele-level human leucocyte antigens genotyping—Assessing two next-generation sequencing platforms: Ion Torrent Personal Genome Machine and Illumina MiSeq. International Journal of Immunogenetics 42, 346-358 (2015).
  • 46. M. Schirmer, U. Z. Ijaz, R. D'Amore, N. Hall, W. T. Sloan, and C. Quince. Insight into biases and sequencing errors for amplicon sequencing with the Illumina MiSeq platform. Nucleic Acids Research 43, e37 (2015).
  • 47. J. J. Kozich, S. L. Westcott, N. T. Baxter, S. K. Highlander, and P. D. Schloss. Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Applied and Environmental Microbiology 79, 5112-5120 (2013).
  • 48. M. Quail, M. E. Smith, P. Coupland, T. D. Otto, S. R. Harris, T. R. Connor, A. Bertoni, H. P. Swerdlow, and Y. Gu. A tale of three next generation sequencing platforms: Comparison of Ion torrent, Pacific Biosciences and Illumina MiSeq sequencers. BMC Genomics 13, 1 (2012).
  • 49. M. Jain, I. T. Fiddes, K. H. Miga, H. E. Olsen, B. Paten, and M. Akeson. Improved data analysis for the MinION nanopore sequencer. Nature Methods 12, 351-356 (2015).
  • 50. World Health Organization. (2016, November) HIV/AIDS [Fact Sheet]. Retrieved from
  • 51. L. M. Mansky, and H. M. Temin. Lower in-vivo mutation-rate of human- immunodeficiency-virus type-1 than that predicted from the fidelity of purified reverse-transcriptase. Journal of Virology 69, 5087-5094 (1995).
  • 52. J. F. Koellhoffer, C. D. Higgins, and J. R. Lai. Protein engineering strategies for the development of viral vaccines and immunotherapeutics. FEBS Letters 588, 298-307 (2013).
  • 53. D. R. Burton, R. Ahmed, D. H. Barouch, S. T. Butera, S. Crotty, A. Godzik, D. E. Kaufmann, et al. A blueprint for HIV vaccine discovery. Cell Host and Microbe 12, 396-407 (2012).
  • 54. N. A. Doria-Rose, R. M. Klein, M. G. Daniels, S. O'Dell, M. Nason, A. Lapedes, T. Bhattacharya, et al. Breadth of human immunodeficiency virus-specific neutralizing activity in sera: Clustering analysis and association with clinical variables. Journal of Virology 84, 1631-1636 (2010).
  • 55. L. M. Walker, M. D. Simek, F. Priddy, J. S. Gach, D. Wagner, M. B. Zwick, S. K. Phogat, P. Poignard, and D. R.Burton. A limited number of antibody specificities mediate broad and potent serum neutralization in selected HIV-1 infected individuals. PLoS Pathogens 6, e1001028 (2010).
  • 56. M. D. Simek, W. Rida, F. H. Priddy, P. Pung, E. Carrow, D. S. Laufer, J. K. Lehman, et al. Human immunodeficiency virus type 1 elite neutralizers: Individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm. Journal of Virology 83, 7337-7348 (2009).
  • 57. J. R. Mascola, and B. F. Haynes. HIV-1 neutralizing antibodies: Understanding nature's pathways. Immunological Reviews 254, 225-244 (2013).
  • 58. A. J. Hessell, P. Poignard, M. Hunter, L. Hangartner, D. M. Tehrani, W. K. Bleeker, P. W. Parren, P. A. Marx, and D. R. Burton. Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nature Medicine 15, 951-954 (2009).
  • 59. A. J. Hessell, E. G. Rakasz, P. Poignard, L. Hangartner, G. Landucci, D. N. Forthal, W. C. Koff, D. I. Watkins, and D. R. Burton. Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathogens 5, e1000433 (2009).
  • 60. B. F. Haynes, J. Fleming, E. W. St Clair, H. Katinger, G. Stiegler, R. Kunert, J. Robinson, et al. Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308, 1906-1908 (2005).
  • 61. R. Diskin, J. F. Scheid, P. M. Marcovecchio, A. P. West, F. Klein, H. Gao, P. N. P. Gnanapragasam, et al. Increasing the potency and breadth of an HIV antibody by using structure-based rational design. Science 334, 1289-1293 (2011).
  • 62. J. Zhu, G. Ofek, Y. Yang, B. Zhang, M. K. Louder, G. Lu, K. McKee, et al. Mining the antibodyome for HIV-1-neutralizing antibodies with next-generation sequencing and phylogenetic pairing of heavy/light chains. Proceedings of the National Academy of Sciences of the United States of America 110, 6470-6475 (2013).
  • 63. J. Zhu, X. Wu, B. Zhang, K. McKee, S. O'Dell, C. Soto, T. Zhou, et al. De novo identification of VRC01 class HIV-1-neutralizing antibodies by next-generation sequencing of B-cell transcripts. Proceedings of the National Academy of Sciences of the United States of America 110, E4088-4097 (2013).
  • 64. J. Zhu, S. O'Dell, G. Ofek, M. Pancera, X. Wu, B. Zhang, Z. Zhang, et al. Somatic populations of PGT135-137 HIV-1-neutralizing antibodies identified by 454 pyrosequencing and bioinformatics. Frontiers in Microbiology 3, 315 (2012).
  • 65. B. F. Haynes, G. Kelsoe, S. C. Harrison, and T. B. Kepler. B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study. Nature Biotechnology 30, 423-433 (2012).
  • 66. A. Escolano, J. M. Steichen, P. Dosenovic, D. W. Kulp, J. Golijanin, D. Sok, N. T. Freund, et al. Sequential immunization elicits broadly neutralizing anti-HIV-1 antibodies in Ig knockin mice. Cell 166, 1445-1458. e12 (2016).
  • 67. Z. Yang. Molecular Evolution: A Statistical Approach. (Oxford University Press, Oxford, UK, 2014).
  • 68. M. Kimura. Estimation of evolutionary distances between homologous nucleotide sequences. Proceedings of the National Academy of Sciences 78, 454-458 (1981).
  • 69. Ramesh A. Immunogenetics of the Rhesus Macaque, an Animal Model for HIV Vaccine Development (Doctoral dissertation, Boston University School of Medicine), (2017).
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