Signatures of selection in the human antibody repertoire: Selective sweeps, competing subclones, and neutral drift
Felix Horns, Christopher Vollmers, Cornelia L Dekker, Stephen R Quake, Felix Horns, Christopher Vollmers, Cornelia L Dekker, Stephen R Quake
Abstract
Antibodies are created and refined by somatic evolution in B cell populations, which endows the human immune system with the ability to recognize and eliminate diverse pathogens. However, the evolutionary processes that sculpt antibody repertoires remain poorly understood. Here, using an unbiased repertoire-scale approach, we show that the population genetic signatures of evolution are evident in human B cell lineages and reveal how antibodies evolve somatically. We measured the dynamics and genetic diversity of B cell responses in five adults longitudinally before and after influenza vaccination using high-throughput antibody repertoire sequencing. We identified vaccine-responsive B cell lineages that carry signatures of selective sweeps driven by positive selection, and discovered that they often display evidence for selective sweeps favoring multiple subclones. We also found persistent B cell lineages that exhibit stable population dynamics and carry signatures of neutral drift. By exploiting the relationship between B cell fitness and antibody binding affinity, we demonstrate the potential for using phylogenetic approaches to identify antibodies with high binding affinity. This quantitative characterization reveals that antibody repertoires are shaped by an unexpectedly broad spectrum of evolutionary processes and shows how signatures of evolutionary history can be harnessed for antibody discovery and engineering.
Trial registration: ClinicalTrials.gov NCT02987374.
Keywords: Adaptive immunity; Population genetics; Somatic evolution.
Conflict of interest statement
The authors declare no conflict of interest.
Copyright © 2019 the Author(s). Published by PNAS.
Figures
References
- Burnet FM. A modification of Jerne’s theory of antibody production using the concept of clonal selection. Aust J Sci. 1957;20:67–69.
- Eisen HN. Affinity enhancement of antibodies: How low-affinity antibodies produced early in immune responses are followed by high-affinity antibodies later and in memory B-cell responses. Cancer Immunol Res. 2014;2:381–392.
- Tarlinton DM. Evolution in miniature: Selection, survival and distribution of antigen reactive cells in the germinal centre. Immunol Cell Biol. 2008;86:133–138.
- Victora GD, Wilson PC. Germinal center selection and the antibody response to influenza. Cell. 2015;163:545–548.
- Eisen HN, Siskind GW. Variations in affinities of antibodies during the immune response. Biochemistry. 1964;3:996–1008.
- Kuraoka M, et al. Complex antigens drive permissive clonal selection in germinal centers. Immunity. 2016;44:542–552.
- Allen CDC, Okada T, Cyster JG. Germinal-center organization and cellular dynamics. Immunity. 2007;27:190–202.
- Victora GD, Mesin L. Clonal and cellular dynamics in germinal centers. Curr Opin Immunol. 2014;28:90–96.
- Victora GD, et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell. 2010;143:592–605.
- Gitlin AD, Shulman Z, Nussenzweig MC. Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature. 2014;509:637–640.
- Gitlin AD, et al. HUMORAL IMMUNITY. T cell help controls the speed of the cell cycle in germinal center B cells. Science. 2015;349:643–646.
- Shulman Z, et al. T follicular helper cell dynamics in germinal centers. Science. 2013;341:673–677.
- Tas JMJ, et al. Visualizing antibody affinity maturation in germinal centers. Science. 2016;351:1048–1054.
- Yaari G, Uduman M, Kleinstein SH. Quantifying selection in high-throughput immunoglobulin sequencing data sets. Nucleic Acids Res. 2012;40:e134.
- McCoy CO, et al. Quantifying evolutionary constraints on B-cell affinity maturation. Philos Trans R Soc Lond B Biol Sci. 2015;370:20140244.
- Lossos IS, Tibshirani R, Narasimhan B, Levy R. The inference of antigen selection on Ig genes. J Immunol. 2000;165:5122–5126.
- Vollmers C, Sit RV, Weinstein JA, Dekker CL, Quake SR. Genetic measurement of memory B-cell recall using antibody repertoire sequencing. Proc Natl Acad Sci USA. 2013;110:13463–13468.
- Horns F, et al. Lineage tracing of human B cells reveals the in vivo landscape of human antibody class switching. eLife. 2016;5:e16578.
- Gupta NT, et al. Hierarchical clustering can identify B cell clones with high confidence in Ig repertoire sequencing data. J Immunol. 2017;198:2489–2499.
- Bedford T, Cobey S, Pascual M. Strength and tempo of selection revealed in viral gene genealogies. BMC Evol Biol. 2011;11:220.
- Zanini F, et al. Population genomics of intrapatient HIV-1 evolution. eLife. 2015;4:e11282.
- Neher RA, Hallatschek O. Genealogies of rapidly adapting populations. Proc Natl Acad Sci USA. 2013;110:437–442.
- Kingman JFC. The coalescent. Stochastic Processes Appl. 1982;13:235–248.
- Bolthausen E, Sznitman A-S. On Ruelle’s probability cascades and an abstract cavity method. Commun Math Phys. 1998;197:247–276.
- Zeng K, Fu Y-X, Shi S, Wu C-I. Statistical tests for detecting positive selection by utilizing high-frequency variants. Genetics. 2006;174:1431–1439.
- Kindt TJ, Goldsby RA, Osborne BA, Kuby J. Kuby Immunology. W. H. Freeman; New York: 2007.
- Fay JC, Wu C-I. Hitchhiking under positive Darwinian selection. Genetics. 2000;155:1405–1413.
- Förster I, Rajewsky K. Expansion and functional activity of Ly-1+ B cells upon transfer of peritoneal cells into allotype-congenic, newborn mice. Eur J Immunol. 1987;17:521–528.
- Kroese FG, Ammerlaan WA, Kantor AB. Evidence that intestinal IgA plasma cells in mu, kappa transgenic mice are derived from B-1 (Ly-1 B) cells. Int Immunol. 1993;5:1317–1327.
- Rothstein TL, Griffin DO, Holodick NE, Quach TD, Kaku H. Human B-1 cells take the stage. Ann N Y Acad Sci. 2013;1285:97–114.
- Baumgarth N. The double life of a B-1 cell: Self-reactivity selects for protective effector functions. Nat Rev Immunol. 2011;11:34–46.
- Quách TD, et al. Distinctions among circulating antibody-secreting cell populations, including B-1 cells, in human adult peripheral blood. J Immunol. 2016;196:1060–1069.
- Muller HJ. Some genetic aspects of sex. Am Nat. 1932;66:118–138.
- Neher RA, Russell CA, Shraiman BI. Predicting evolution from the shape of genealogical trees. eLife. 2014;3:e03568.
- Padlan EA, et al. Structure of an antibody-antigen complex: Crystal structure of the HyHEL-10 Fab-lysozyme complex. Proc Natl Acad Sci USA. 1989;86:5938–5942.
- MacCallum RM, Martin ACR, Thornton JM. Antibody-antigen interactions: Contact analysis and binding site topography. J Mol Biol. 1996;262:732–745.
- Xu JL, Davis MM. Diversity in the CDR3 region of V(H) is sufficient for most antibody specificities. Immunity. 2000;13:37–45.
- Jiang N, et al. Lineage structure of the human antibody repertoire in response to influenza vaccination. Sci Transl Med. 2013;5:171ra19.
- Laserson U, et al. High-resolution antibody dynamics of vaccine-induced immune responses. Proc Natl Acad Sci USA. 2014;111:4928–4933.
- Schmidt AG, et al. Immunogenic stimulus for germline precursors of antibodies that engage the influenza hemagglutinin receptor-binding site. Cell Rep. 2015;13:2842–2850.
- Raymond DD, et al. Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain. Nat Med. 2016;22:1465–1469.
- Ye J, Ma N, Madden TL, Ostell JM. IgBLAST: An immunoglobulin variable domain sequence analysis tool. Nucleic Acids Res. 2013;41:W34–W40.
- Neher RA, Kessinger TA, Shraiman BI. Coalescence and genetic diversity in sexual populations under selection. Proc Natl Acad Sci USA. 2013;110:15836–15841.
- Edgar RC. MUSCLE: Multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004;32:1792–1797.
- Price MN, Dehal PS, Arkin AP. FastTree 2–Approximately maximum-likelihood trees for large alignments. PLoS One. 2010;5:e9490.
Source: PubMed