Inferring processes underlying B-cell repertoire diversity

Abstract

We quantify the VDJ recombination and somatic hypermutation processes in human B cells using probabilistic inference methods on high-throughput DNA sequence repertoires of human B-cell receptor heavy chains. Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then after selection for functionality. We also infer statistical properties of the somatic hypermutation machinery (exclusive of subsequent effects of selection). Our main results are the following: the B-cell repertoire is substantially more diverse than T-cell repertoires, owing to longer junctional insertions; sequences that pass initial selection are distinguished by having a higher probability of being generated in a VDJ recombination event; somatic hypermutations have a non-uniform distribution along the V gene that is well explained by an independent site model for the sequence context around the hypermutation site.

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References 34

1. 1.

   Teng G Papavasiliou FN 2007 Immunoglobulin somatic hypermutation. Annu. Rev. Genet. 41, 107–120. ()

   Not in our library10.1146/annurev.genet.41.110306.130340

2. 2.

   Janeway C Murphy KP Travers P Walport M 2008 Janeway‘s immunobiology. New York, NY: Garland Science.

   Not in our library

3. 3.
   The Past, Present, and Future of Immune Repertoire Biology – The Rise of Next-Generation Repertoire Analysis · 2013

   No notice
4. 4.

   Robins H 2013 Immunosequencing: applications of immune repertoire deep sequencing. Curr. Opin. Immunol. 25, 646–652. ()

   Not in our library10.1016/j.coi.2013.09.017

5. 5.

   Murugan A Mora T Walczak AM Callan CG 2012 Statistical inference of the generation probability of T-cell receptors from sequence repertoires. Proc. Natl Acad. Sci. USA 109, 16 161–16 166. ()

   Not in our library10.1073/pnas.1212755109

6. 6.

   Elhanati Y Murugan A Callan CG Mora T Walczak AM 2014 Quantifying selection in immune receptor repertoires. Proc. Natl Acad. Sci. USA 111, 9875–9880. ()

   Not in our library10.1073/pnas.1409572111

7. 7.

   Lim A Lemercier B Wertz X Pottier SL Huetz F Kourilsky P 2008 Many human peripheral VH5-expressing IgM+ B cells display a unique heavy-chain rearrangement. Int. Immunol. 20, 105–116. ()

   Not in our library10.1093/intimm/dxm125

8. 8.

   Foreman AL 2008 VH gene usage and CDR3 analysis of B cell receptor in the peripheral blood of patients with PBC. Autoimmunity 41, 80–86. ()

   Not in our library10.1080/08916930701619656

9. 9.

   Brezinschek HP Foster SJ Brezinschek RI Dörner T Domiati-Saad R Lipsky PE 1997 Analysis of the human VH gene repertoire. differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM+ and CD5(−)/IgM+ B cells. J. Clin. Investig. 99, 2488–2501. ()

   Not in our library10.1172/jci119433

10. 10.

    Rock EP Sibbald PR Davis MM Chien YH 1994 CDR3 length in antigen-specific immune receptors. J. Exp. Med. 179, 323–328. ()

    Not in our library10.1084/jem.179.1.323

11. 11.

    Wu TT Johnson G Kabat EA 1993 Length distribution of CDRH3 in antibodies. Proteins Struct. Funct. Bioinform. 16, 1–7. ()

    Not in our library10.1002/prot.340160102

12. 12.

    Shiokawa S Mortari F Lima JO Nuñez C Bertrand FE III Kirkham PM Zhu S Dasanayake AP Schroeder HW Jr 1999 IgM heavy chain complementarity-determining region 3 diversity is constrained by genetic and somatic mechanisms until two months after birth. J. Immunol. 162, 6060–6070.

    Not in our library

13. 13.

    Ivanov II Schelonka RL Zhuang Y Gartland GL Zemlin M Schroeder HW 2005 Development of the expressed Ig CDR-H3 repertoire is marked by focusing of constraints in length, amino acid use, and charge that are first established in early B cell progenitors. J. Immunol. 174, 7773–7780. ()

    Not in our library10.4049/jimmunol.174.12.7773

14. 14.

    Wardemann H Yurasov S Schaefer A Young JW Meffre E Nussenzweig MC 2003 Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377. ()

    Not in our library10.1126/science.1086907

15. 15.

    Uduman M Yaari G Hershberg U Stern JA Shlomchik MJ Kleinstein SH 2011 Detecting selection in immunoglobulin sequences. Nucleic Acids Res. 39, W499–W504. ()

    Not in our library10.1093/nar/gkr413

16. 16.

    Larimore K McCormick MW Robins HS Greenberg PD 2012 Shaping of human germline IgH repertoires revealed by deep sequencing. J. Immunol. 189, 3221–3230. ()

    Not in our library10.4049/jimmunol.1201303

17. 17.

    Raaphorst FM Raman CS Tami J Fischbach M Sanz I 1997 Human Ig heavy chain CDR3 regions in adult bone marrow pre-B cells display an adult phenotype of diversity: evidence for structural selection of DH amino acid sequences. Int. Immunol. 9, 1503–1515. ()

    Not in our library10.1093/intimm/9.10.1503

18. 18.

    Meffre E Milili M Blanco-Betancourt C Antunes H Nussenzweig MC Schiff C 2001 Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development. J. Clin. Investig. 108, 879–886. ()

    Not in our library10.1172/jci13051

19. 19.

    McCoy CO Bedford T Minin VN Bradley P Robins H Matsen FA 2014 Quantifying evolutionary constraints on B cell affinity maturation. arXiv 1403.3066v3 [q-bio.PE].

    Not in our library10.1098/rstb.2014.0244

20. 20.
    Models of Somatic Hypermutation Targeting and Substitution Based on Synonymous Mutations from High-Throughput Immunoglobulin Sequencing Data · 2013

    No notice
21. 21.

    Shapiro GS Aviszus K Ikle D Wysocki LJ 1999 Predicting regional mutability in antibody V genes based solely on di- and trinucleotide sequence composition. J. Immunol. 163, 259–268.

    Not in our library

22. 22.

    Betz AG Rada C Pannell R Milstein C Neuberger MS 1993 Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: clustering, polarity, and specific hot spots. Proc. Natl Acad. Sci. USA 90, 2385–2388. ()

    Not in our library10.1073/pnas.90.6.2385

23. 23.

    Cowell LG Kepler TB 2000 The nucleotide-replacement spectrum under somatic hypermutation exhibits microsequence dependence that is strand-symmetric and distinct from that under germline mutation. J. Immunol. 164, 1971–1976. ()

    Not in our library10.4049/jimmunol.164.4.1971

24. 24.

    Kepler TB 2014 Reconstructing a B-cell clonal lineage. II. Mutation, selection, and affinity maturation. Front. Immunol. 5, 170 ()

    Not in our library10.3389/fimmu.2014.00170

25. 25.

    Lossos IS Tibshirani R Narasimhan B Levy R 2000 The inference of antigen selection on Ig genes. J. Immunol. 165, 5122–5126. ()

    Not in our library10.4049/jimmunol.165.9.5122

26. 26.

    Dunn-Walters DK Dogan A Boursier L MacDonald CM Spencer J 1998 Base-specific sequences that bias somatic hypermutation deduced by analysis of out-of-frame human IgVH genes. J. Immunol. 160, 2360–2364.

    Not in our library

27. 27.

    Steiman-Shimony A 2006 Lineage tree analysis of immunoglobulin variable-region gene mutations in autoimmune diseases: chronic activation, normal selection. Cell. Immunol. 244, 130–136. ()

    Not in our library10.1016/j.cellimm.2007.01.009

28. 28.

    Giudicelli V Chaume D Lefranc MP 2005 IMGT/GENE-DB: a comprehensive database for human and mouse immunoglobulin and T cell receptor genes. Nucleic Acids Res. 33, D256–D261. ()

    Not in our library10.1093/nar/gki010

29. 29.

    Stryer L Berg JM Tymoczko JL 2002 Biochemistry, 5th edn New York, NY: W.H. Freeman & Co Ltd.

    Not in our library

30. 30.

    Martin J Lavery R 2012 Arbitrary protein–protein docking targets biologically relevant interfaces. BMC Biophys. 1, 7 ()

    Not in our library10.1186/2046-1682-5-7

31. 31.

    Berg OG von Hippel PH 1987 Selection of DNA binding sites by regulatory proteins: statistical–mechanical theory and application to operators and promoters. J. Mol. Biol. 193, 723–743. ()

    Not in our library10.1016/0022-2836(87)90354-8

32. 32.

    Dunn-Walters DK Spencer J 1998 Strong intrinsic biases towards mutation and conservation of bases in human IgVH genes during somatic hypermutation prevent statistical analysis of antigen selection. Immunology 95, 339–345. ()

    Not in our library10.1046/j.1365-2567.1998.00607.x

33. 33.

    Oprea M Cowell LG Kepler TB 2001 The targeting of somatic hypermutation closely resembles that of meiotic mutation. J. Immunol. 166, 892–899. ()

    Not in our library10.4049/jimmunol.166.2.892

34. 34.

    Spencer J Dunn-Walters DK 2005 Hypermutation at A-T base pairs: the A nucleotide replacement spectrum is affected by adjacent nucleotides and there is no reverse complementarity of sequences flanking mutated A and T nucleotides. J. Immunol. 175, 5170–5177. ()

    Not in our library10.4049/jimmunol.175.8.5170

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