Inferring processes underlying B-cell repertoire diversity

@article{Elhanati2015InferringPU,
  title={Inferring processes underlying B-cell repertoire diversity},
  author={Yuval Elhanati and Zachary Sethna and Quentin Marcou and Curtis G Callan and Thierry Mora and Aleksandra M. Walczak},
  journal={Philosophical Transactions of the Royal Society B: Biological Sciences},
  year={2015},
  volume={370}
}
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… 

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References

SHOWING 1-10 OF 52 REFERENCES

Statistical inference of the generation probability of T-cell receptors from sequence repertoires

TLDR
The probabilistic model predicts the generation probability of any specific CDR3 sequence by the primitive recombination process, allowing the potential diversity of the T-cell repertoire and to understand why some sequences are shared between individuals.

Quantifying evolutionary constraints on B-cell affinity maturation

TLDR
It is found that the substitution process is conserved across individuals but varies significantly across gene segments, and a per-residue map of selection is derived, which provides a more nuanced view of the constraints on framework and variable regions.

Reconstructing a B-Cell Clonal Lineage. II. Mutation, Selection, and Affinity Maturation

TLDR
The lineage exhibits a remarkably uniform rate of improvement of the effective affinity to influenza hemagglutinin (HA) over evolutionary time, increasing 1000-fold overall from the unmutated ancestor to the best of the observed antibodies.

Shaping of Human Germline IgH Repertoires Revealed by Deep Sequencing

TLDR
The data suggest that developmental selection removes HCDR3 loops containing patches of hydrophobicity, which are commonly found in some auto-antibodies, and at least 69% of the initial productive IgH rearrangements are removed from the repertoire during B cell development.

Quantifying selection in immune receptor repertoires

TLDR
A significant correlation between biases induced by VDJ recombination and inferred selection factors together with a reduction of diversity during selection suggest that natural selection acting on the recombination process has anticipated the selection pressures experienced during somatic evolution.

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

TLDR
Improved models of SHM targeting and substitution that are based only on synonymous mutations, and are thus independent of selection are produced.

The Inference of Antigen Selection on Ig Genes1

TLDR
Side-by-side application of multinomial and binomial models on 86 previously established Ig sequences disclosed 8 discrepancies, leading to opposite statistical conclusions about Ag selection.

Strong intrinsic biases towards mutation and conservation of bases in human IgVH genes during somatic hypermutation prevent statistical analysis of antigen selection

TLDR
The data suggest that analysis of the distribution of mutations in IgVH genes cannot be used reliably to state whether antigenic selection of the B‐cell carrying the genes occurred, and that intrinsic biases alone may be enough to give the appearance of selection.

Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: clustering, polarity, and specific hot spots.

TLDR
Somatic hypermutation in mice carrying an immunoglobulin kappa transgene exhibits specific base substitution preferences with transitions being favored over transversions and it is proposed that these substitution preferences can be used to discriminate intrinsic from antigen-selected hot spots.
...