Inter- and intraspecies comparison of phylogenetic fingerprints and sequence diversity of immunoglobulin variable genes

Abstract

Protection and neutralization of a vast array of pathogens is accomplished by the tremendous diversity of the B cell receptor (BCR) repertoire. For jawed vertebrates, this diversity is initiated via the somatic recombination of immunoglobulin (Ig) germline elements. While it is clear that the number of these germline segments differs from species to species, the extent of cross-species sequence diversity remains largely uncharacterized. Here we use extensive computational and statistical methods to investigate the sequence diversity and evolutionary relationship between Ig variable (V), diversity (D), and joining (J) germline segments across nine commonly studied species ranging from zebrafish to human. Metrics such as guanine-cytosine (GC) content showed low redundancy across Ig germline genes within a given species. Other comparisons, including amino acid motifs, evolutionary selection, and sequence diversity, revealed species-specific properties. Additionally, we showed that the germline-encoded diversity differs across antibody (recombined V-D-J) repertoires of various B cell subsets. To facilitate future comparative immunogenomics analysis, we created VDJgermlines, an R package that contains the germline sequences from multiple species. Our study informs strategies for the humanization and engineering of therapeutic antibodies.

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Correspondence to Alexander Yermanos or Sai T. Reddy.

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Figure S1

Number and properties of the germline genes included in this study. (A) The number of IgH D, IgH J, IgK V, and IgL V genes for each species. Allelic germlines were only included for human IgH V genes. (B) Nucleotide sequence length of the IgH V genes. (C) Amino acid sequence length of the variable light chain genes. (D) Distributions of GC content for IgH V genes annotated either as pseudogenes or as functional alleles from human*01. (E) Distributions of protein instability indices for all IgH V genes and (F) IgK V genes. Dashed and solid lines indicate the median and quartiles, respectively. (PDF 665 kb)

Figure S2

Amino acid motifs improve species-separation of variable light chain genes. Mean amino acid frequencies for variable heavy, kappa, and lambda germline segments. The intensity corresponds to the mean occurrence (%) of a given amino acid across all variable gene segments for each species. (B) t-SNE plot projecting the amino acid frequencies for the individual variable heavy segments into two dimensions. Each triangle represents a single variable kappa chain and diamonds represent variable lambda chain. No allelic variants for human_02 were included in the analysis. (C) t-SNE plot projecting the k-mers (k=2,3,4) composition of each variable chain into two dimensions as in B. (PDF 62 kb)

Figure S3

Interspecies comparison between variable kappa and lambda chains. (A-B) The normalized Colless number, normalized Sackin index, normalized ladder size, and maximum distance from root were calculated for each inferred phylogenetic tree composed of all IgK V and IgL V genes per each species, respectively. (PDF 43 kb)

Figure S4

Clustering based on Laplacian spectra across variable heavy, kappa, and lambda chains. Heatmap displaying the pairwise Jensen Shannon index based on the Laplacian spectra from each variable gene phylogenetic tree. (PDF 36 kb)

Figure S5

Cross-species phylogenetic tree of variable heavy genes from human, macaque, platypus, and zebrafish. Sequences from each species are labeled with “H” (blue tip labels), “M” (red tip labels), “P” (black tip labels), and “Z” (green tip labels), respectively. (PDF 41 kb)

Figure S6

Pairwise distance from the variable kappa and lambda chains between species normalized by sequence length. (PDF 554 kb)

Table S1

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Table S2

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Yermanos, A., Dounas, A., Greiff, V. et al. Inter- and intraspecies comparison of phylogenetic fingerprints and sequence diversity of immunoglobulin variable genes. Immunogenetics 72, 279–294 (2020). https://doi.org/10.1007/s00251-020-01164-8

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Keywords

  • Antibody
  • Germline
  • V-D-J recombination
  • Phylogenetics
  • Bioinformatics
  • R package