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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Associate professor Gur Yaari, Yale University, USA
- Second opponent: Postdoctoral Researcher Ivana Mikocziova, University of Turku, Finland
- Third member and chair of the evaluation committee: Professor Ludvig A. Munthe, University of Oslo
Chair of the Defence
Professor Ludvig M. Sollid, University of Oslo
Principal Supervisor
Associate Professor Andreas Lossius, University of Oslo
Summary
Antibodies and B cell receptors are important players in the human immune system. These molecules, collectively called immunoglobulins (Igs), must recognize a wide range of pathogens with very high accuracy. This broad recognition capacity is achieved through recombinatorial and mutational processes in the DNA that encodes Igs. The locus for the Ig heavy chain (IGH) encodes the largest part of the molecule, which forms the structural backbone, provides effector functions and contributes to target binding.
The IGH locus is genetically complex due to repeated sequences and other structural variants and therefore has only been fully resolved twice. Consequently, global genetic variation is poorly characterized.
The inherited germline IGH influences the immune response during infection and vaccination. Our limited knowledge of IGH diversity hampers our ability to study such inherited effects. Closing this knowledge gap is therefore an important step forward in immunogenetics.
In this thesis, a new method for sequencing the IGH locus with ultra-long sequencing is presented, which enables the generation of complete haplotypes. By applying this method to 16 donors, 31 new IGH haplotypes were resolved. Many new alleles, copy number variations, and structural variants were uncovered, many of which may have functional significance.
The thesis also presents a new tool for analyzing immunoglobulin expression. Current Ig-repertoire analyses mainly concern the variable sequence, and allelic variation in constant region is ignored. To address this, we developed a tool to reconstruct and analyze scRNA-seq Ig sequences, enabling recovery of full-length paired heavy and light chains, even in cells with low transcript abundance.
Taken together, this work expands our understanding of genetic variation in IGH and introduces two methods that make it possible to study IGH genetics at higher resolution, and that can be used to link immunity to genetic background.
Additional information
Contact the research support staff.