Mari Bergstøl Gornitzka

• Seyedraoufi, Seyedmojtaba; Gornitzka, Mari Bergstøl & Lossius, Andreas (2026). GATHeR: graph-based accurate tool for immunoglobulin heavy- and light-chain reconstruction. Nature Communications. doi: 10.1038/s41467-026-74272-w. Full text in Research Archive Show summary

  Abstract Recovering full-length, paired B-cell receptor (BCR) sequences from scRNA-seq reads remains difficult, especially in naive and memory B cells where immunoglobulin transcripts are sparse. Incomplete constant-region coverage in current methods limits isoform, subclass, and allele resolution. Here we present GATHeR, an open-source tool that assembles and annotates paired heavy- and light-chain BCR sequences and extends assembled sequences into constant regions. This enables confident subclass and allele assignment and recovery of membrane-bound isoforms, including the transmembrane segment and cytoplasmic tail, thereby distinguishing surface BCRs from secreted antibodies. GATHeR supports Smart-seq2/3 and 10x Genomics libraries and outperforms existing methods across benchmarks, with the largest gains in naive and memory B cells. Notably, in these populations the constant-region extension also enables detection of splice variation, including intron-containing heavy-chain transcripts with read-level support. By delivering high-fidelity receptor, isoform, and clonal lineage information, GATHeR broadens the analytical reach of scRNA-seq for B-cell immunology.

• Gornitzka, Mari B.; Røsjø, Egil Rørvik; Jana, Uddalok; Ford, Easton E.; Tourancheau, Alan & Lees, William D. [Show all 10 contributors for this article] (2025). Ultra-long sequencing for contiguous haplotype resolution of the human immunoglobulin heavy-chain locus. Genome Research. ISSN 1088-9051. 35(10), p. 2240–2251. doi: 10.1101/gr.280400.125. Full text in Research Archive Show summary

  Genetic diversity within the human immunoglobulin heavy-chain (IGH) locus influences the expressed antibody repertoire and susceptibility to infectious and autoimmune diseases. However, repetitive sequences and complex structural variation pose significant challenges for large-scale characterization. Here, we introduce a method that combines Oxford Nanopore Technologies ultra-long sequencing and adaptive sampling with a bioinformatic pipeline to produce haplotype-resolved, annotated IGH assemblies. Notably, our strategy overcomes prior limitations in phasing resolution, enabling single-contig haplotype assemblies that span the entire IGH locus. We apply this method to four individuals and validate the accuracy of the IGH assemblies using Pacific Biosciences HiFi reads, demonstrating near-complete sequence congruence, with only some residual indel errors. Moreover, when applied to the reference material HG002, our pipeline reveals no base differences and a limited number of indels compared with the telomere-to-telomere genome benchmark across the IGH region. Importantly, in the four individuals, our approach uncovers 28 novel alleles and previously uncharacterized large structural variants, including a 120 kb duplication spanning IGHE to IGHA1 within the IGH constant region (IGHC) and, within the IGHV region, an expanded seven-copy IGHV3-23 gene haplotype. These findings underscore the power of our method to resolve the full complexity of the IGH locus and uncover previously unrecognized variants that may affect immune function and disease susceptibility. Thus, our method provides a strong basis for future immunological research and translational applications.

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• Gornitzka, Mari Bergstøl; Lossius, Andreas; Røsjø, Egil Rørvik & Vartdal, Frode (2026). Resolving the Immunoglobulin Heavy Chain Locus Methodological advances, genetic diversity, and constant region bias in multiple sclerosis. Universitetet i Oslo. ISSN 9788234808791. Full text in Research Archive Show summary

  Antibodies and B-cell receptors are central components of the human adaptive immune system. These molecules, collectively termed immunoglobulins, can bind a wide range of pathogens with remarkable specificity. This breadth of recognition is achieved through somatic recombination and hypermutation of the loci that encode immunoglobulins. The immunoglobulin heavy chain (IGH) locus encodes the largest subunit of this molecule, which forms the central scaffold, contributes to antigen binding, and mediates effector functions. The IGH locus is genetically complex due to extensive repetitive sequences, segmental duplications, and structural variation, which has limited comprehensive characterization; to date, the locus has been fully resolved only twice. The IGH locus displays considerable genetic variation between individuals, yet much of this diversity is still unmapped. Because germline IGH variation shapes the expressed antibody repertoire and influences immune responses to infection and vaccination, gaps in our understanding of IGH diversity impede efforts to study these germline effects. Closing this gap is therefore essential for advancing immunogenetics. A novel method for characterizing the IGH locus is presented in this thesis. We demonstrate that this method generates single-contig complete haplotypes with very few errors and employ it to 16 donors, completely resolving 31 new IGH haplotypes. Across these assemblies, we identify novel alleles, copy number variations and structural variants, which are likely to have biologically meaningful effects. The motivation for IGH locus characterization was to investigate haplotypes carrying different IGH constant gene polymorphisms. In particular, the G1m1 allotype of IgG1, which has a heavily biased expression pattern in multiple sclerosis. Using our method on a cohort of Norwegian patients, we mapped the genetic architecture of their IGH to reveal differences between G1m1 and non-G1m1-containing haplotypes. In the second part of this thesis, the emphasis turns from IGH germline genetics to expression of IGH transcripts. Immunoglobulin repertoires are frequently analyzed in the context of vaccination, infection, and autoimmunity, where selective usage of specific variable genes can shape functional outcomes. However, analyses of IGH constant-gene usage typically stop at the isotype level, overlooking the potential relevance of allelic variation in constant regions. To address this gap, we developed a tool for reconstructing and analyzing immunoglobulin sequences from single-cell RNA-seq data. This enables robust recovery of full-length paired heavy and light chains, even from cells with low transcript abundance. Overall, this thesis broadens our understanding of IGH genetic diversity and introduces two methodological approaches that make it possible to study immunogenetic variation with far greater resolution. These tools lay the groundwork for future efforts to link germline architecture with the behavior of expressed antibody repertoires.

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