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Peer-reviewedCC BYCell

Replaying germinal center evolution on a quantified affinity landscape

  • William S. DeWitt1,2,3
  • Ashni A. Vora4
  • Tatsuya Araki4,5
  • Jared Galloway2
  • Tanwee Alkutkar6
  • Juliana Bortolatto7,8,9
  • Tiago B. R. Castro4
  • Will Dumm2
  • Chris Jennings-Shaffer2
  • Tongqiu Jia2
  • Luka Mesin4
  • Gabriel Ozorowski6
9 more authors
  • Juhee Pae4
  • Duncan Ralph2
  • Jesse D. Bloom10,2,3,11
  • Armita Nourmohammad2,12,13,14
  • Yun S. Song15,16
  • Andrew B. Ward6
  • Tyler N. Starr17
  • Frederick A. Matsen IV18,2,3,11
  • Gabriel D. Victora19,8,9
19 affiliations
  1. 1Department of Genome Sciences, University of Washington, Seattle, WA, USA; Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  2. 2Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  3. 3Department of Genome Sciences, University of Washington, Seattle, WA, USA
  4. 4Laboratory of Lymphocyte Dynamics, the Rockefeller University, New York, NY, USA
  5. 5BioMedicine Design, Pfizer, Cambridge, MA, USA
  6. 6Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
  7. 7Laboratory of Lymphocyte Dynamics, the Rockefeller University, New York, NY, USA; Howard Hughes Medical Institute, New York, NY, USA
  8. 8Howard Hughes Medical Institute, New York, NY, USA
  9. 9Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA
  10. 10Department of Genome Sciences, University of Washington, Seattle, WA, USA; Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Howard Hughes Medical Institute, Seattle, WA, USA
  11. 11Howard Hughes Medical Institute, Seattle, WA, USA
  12. 12Department of Applied Mathematics, University of Washington, Seattle, WA, USA
  13. 13Department of Physics, University of Washington, Seattle, WA, USA
  14. 14Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, USA
  15. 15Department of Statistics and Computer Science Division, University of California, Berkeley, Berkeley, CA, USA
  16. 16Department of Statistics, University of California, Berkeley, CA, USA
  17. 17Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
  18. 18Department of Genome Sciences, University of Washington, Seattle, WA, USA; Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Howard Hughes Medical Institute, Seattle, WA, USA; Department of Statistics, University of Washington, Seattle, WA, USA. Electronic address: [email protected]
  19. 19Laboratory of Lymphocyte Dynamics, the Rockefeller University, New York, NY, USA; Howard Hughes Medical Institute, New York, NY, USA. Electronic address: [email protected]
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Abstract

Darwinian evolution of immunoglobulin genes within germinal centers (GCs) underlies the progressive increase in antibody affinity following antigen exposure. Whereas the cellular mechanics of how competition between B cells increases affinity are well established, the evolutionary dynamics of this process are less clear. We developed an experimental evolution model in which we "replay" over one hundred monoclonal GC reactions, assigning affinities to each cell using deep mutational scanning. Our data reveal how GCs achieve predictable outcomes by means of noisy but persistent selection on an affinity landscape whose exploration is heavily constrained by somatic hypermutation biases. We infer a fitness landscape that quantitatively recapitulates the affinity maturation trajectory of our clone and find that apparent features of GC selection, such as permissiveness to low-affinity lineages and rapid plateauing of affinity, are likely artifacts of survivorship biases that distort our view of how B cell affinity progresses over time.

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Cite

BibTeXRIS
BibTeX
@article{dewitt2026replaying,
  title = {{Replaying germinal center evolution on a quantified affinity landscape}},
  author = {William S. DeWitt and Ashni A. Vora and Tatsuya Araki and Jared Galloway and Tanwee Alkutkar and Juliana Bortolatto and Tiago B. R. Castro and Will Dumm and Chris Jennings-Shaffer and Tongqiu Jia and Luka Mesin and Gabriel Ozorowski and Juhee Pae and Duncan Ralph and Jesse D. Bloom and Armita Nourmohammad and Yun S. Song and Andrew B. Ward and Tyler N. Starr and Frederick A. Matsen IV and Gabriel D. Victora},
  journal = {Cell},
  year = {2026},
  month = jun,
  doi = {10.1016/j.cell.2026.05.013},
  url = {https://doi.org/10.1016/j.cell.2026.05.013},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Replaying germinal center evolution on a quantified affinity landscape
AU  - William S. DeWitt
AU  - Ashni A. Vora
AU  - Tatsuya Araki
AU  - Jared Galloway
AU  - Tanwee Alkutkar
AU  - Juliana Bortolatto
AU  - Tiago B. R. Castro
AU  - Will Dumm
AU  - Chris Jennings-Shaffer
AU  - Tongqiu Jia
AU  - Luka Mesin
AU  - Gabriel Ozorowski
AU  - Juhee Pae
AU  - Duncan Ralph
AU  - Jesse D. Bloom
AU  - Armita Nourmohammad
AU  - Yun S. Song
AU  - Andrew B. Ward
AU  - Tyler N. Starr
AU  - Frederick A. Matsen IV
AU  - Gabriel D. Victora
PY  - 2026
DA  - 2026/06/05
JO  - Cell
DO  - 10.1016/j.cell.2026.05.013
UR  - https://doi.org/10.1016/j.cell.2026.05.013
AB  - Darwinian evolution of immunoglobulin genes within germinal centers (GCs) underlies the progressive increase in antibody affinity following antigen exposure. Whereas the cellular mechanics of how competition between B cells increases affinity are well established, the evolutionary dynamics of this process are less clear. We developed an experimental evolution model in which we "replay" over one hundred monoclonal GC reactions, assigning affinities to each cell using deep mutational scanning. Our data reveal how GCs achieve predictable outcomes by means of noisy but persistent selection on an affinity landscape whose exploration is heavily constrained by somatic hypermutation biases. We infer a fitness landscape that quantitatively recapitulates the affinity maturation trajectory of our clone and find that apparent features of GC selection, such as permissiveness to low-affinity lineages and rapid plateauing of affinity, are likely artifacts of survivorship biases that distort our view of how B cell affinity progresses over time.
SN  - 0092-8674
SN  - 1097-4172
ER  -