Population matched (PM) germline allelic variants of immunoglobulin (IG) loci: New pmIG database to better understandIGrepertoire and selection processes in disease and vaccination

Abstract

At the population level, immunoglobulin (IG) loci harbor inter-individual allelic variants in the many different germline IG variable (V), Diversity (D) and Joining (J) genes of the IG heavy (IGH), IG kappa (IGK) and IG lambda (IGL) loci, which together form the genetic basis of the highly diverse antigen-specific B-cell receptors. These inter-individual allelic variants can be shared between or be specific to human populations. The current IG databases IMGT, VBASE2 and IgPdb hold information about germline alleles, most of which are partial sequences, obtained from a mixture of human (B-cell) samples, many with sequence errors and/or acquired (non-germline) IG variations, induced by somatic hypermutation (SHM) during antigen-specific B-cell responses. We systematically identified true germline alleles (without SHM) from 26 different human populations around the world, profiled by the “1000 Genomes data”. Our resource is uniquely enriched with complete IG allele sequences and their frequencies across human populations. We identified 409 IGHV, 179 IGKV, and 199 IGLV germline alleles supported by at least seven haplotypes (= minimum of four individuals), after removal of potential false-positives, based on using other genomic databases, i.e. ENSEMBL, TopMed, ExAC, ProjectMine. Remarkably, the positions of the identified variant nucleotides of the different alleles are not at random (as observed in case of SHM), but show striking patterns, restricted to limited nucleotide positions, the same as found in other IG data bases, suggesting over-time evolutionary selection processes. The identification of these specific patterns provides extra evidence that the identified variant nucleotides are not sequencing errors, but genuine allelic variants. The diversity of germline allelic variants in IGH and IGL loci is the highest in Africans, while the IGK locus is most diverse in Europeans. We also report on the presence of recombination signal sequences (RSS) in V pseudogenes, explaining their usage in V(D)J rearrangements. We propose that this new set of genuine germline IG sequences can serve as a new population-matched IG (pmIG) database for better understanding B-cell repertoire and B-cell receptor selection processes in disease and vaccination within and between different human populations. The database in format of fasta is available via GitHub (https://github.com/InduKhatri/pmIG). Contribution to the Field Statement We present a catalogue of immunoglobulin (IG) germline-alleles of unprecedented completeness and accuracy from 26 different human populations belonging to five different large ethnicities (Source: 1000 Genomes). We identified the population distribution of several known germline alleles and identified multiple new alleles, especially in African populations, indicative of high allelic diversity of IG genes in Africa. Strikingly, the identified variant nucleotides of the different alleles are not at random, but show striking patterns, restricted to limited nucleotide positions, the same as found in ot...

A novel framework for characterizing genomic haplotype diversity in the human immunoglobulin heavy chain locus

“…Notably, the novel alleles described in NA19240 represent the largest contribution to the IMGT database from a single individual. Related to this point, we also observed high numbers of false-positive/negative IGHV SNVs in 1KGP datasets, reinforcing that efforts to identify IG alleles from 1KGP data should be done with extreme caution 58,64,65 . An added advantage of our approach is the ability to capture variation outside of IG coding segments and more fully characterize SVs.…”

A Novel Framework for Characterizing Genomic Haplotype Diversity in the Human Immunoglobulin Heavy Chain Locus

“…Notably, the novel alleles described in NA19240 represent the largest contribution to the IMGT database from a single individual. Related to this point, we also observed high numbers of false-positive/negative IGHV SNVs in 1KGP datasets, reinforcing that efforts to identify IG alleles from 1KGP data should be done with extreme caution ( 59 , 66 , 67 ). An added advantage of our approach is the ability to capture variation outside of IG coding segments and more fully characterize SVs.…”

pmTR database: population matched (PM) germline allelic variants of T-cell receptor (TR) loci

“…Interestingly, in all the TR loci, an early separation of Mexicans (MXL) and Peruvians (PEL) populations is observed ( Figure 4B). Similar to the population structure in TRG loci, the relatedness of the PEL population was also observed in the IG loci [13].…”

“…The heptamers and nonamers in the RSS sequence turned out not to be conserved for most TR genes resulting in lower recombinant frequencies for those genes [22]. Similar to IG pseudogenes [13], we also identified conserved heptamers for TR pseudogenes suggesting the role of RSS in recombination of pseudogenes in T-cell repertoire [23] ( Table S6).…”

“…Till date, there is, however, only one database that reports all the alleles for the TR locus: the International ImMunoGeneTics information system (IMGT) [11,12]. But, this database does not report allelic frequencies or population statistics and, moreover, reported alleles are mostly profiled from Caucasian populations [13,14].…”