Genetic diversity at human immunoglobulin loci and implications for human disease

Date created: 
Structural variation
Single nucleotide polymorphism
Linkage disequilibrium
Human disease

B cells are primary components of the immune system, with important roles in both innate and adaptive immunity. Immunoglobulins (IGs), which can be expressed as either membrane-bound receptors on B cells or secreted as antibodies, are essential to the function of these cells. Most notably, IGs facilitate the recognition of a diverse range of pathogen-associated antigens by the immune system. IGs are formed by two pairs of identical “heavy” and “light” protein chains, encoded by genes located at three primary loci in the human genome: the IG heavy chain (IGH) genes at 14q32.33, and the IG light chains, lambda (IGL) and kappa (IGK), at 22q11.2 and 2p11.2. The importance of their function in pathogen recognition is evidenced by the diversity and number of IG genes present within a given genome, as well as allelic variation observed at the population level. In addition, IG loci are also characterized by the occurrence of structural variants (SVs), resulting in haplotypes harboring variable numbers of functional IG genes, with known impacts on antibody expression. Importantly, however, the full extent and distribution of IG genetic diversity is not known, likely due to limited sampling. Given their role in B cell function and immunity, IG genes are candidates for autoimmune and infectious disease susceptibility, but despite the large number of disease association studies conducted, few disease links have been robustly established. However, the apparent lack of disease associations, particularly with respect to IGH polymorphisms, may in part result from incomplete genetic data in IG loci. As a first step toward addressing such issues, I present the largest genomic resequencing effort in IG loci to date. Included in these data is the first genomic description of IGH, IGL, and IGK loci from a single haploid genome, the identification of novel IG gene alleles and SVs, and 222 kbp of novel inserted sequence in IGH. Furthermore, extensions of these data provide novel insight into IG population and disease genetics. The primary contribution of this work is that these data will serve as a useful reference for future investigations of IG genetic polymorphisms, antibody expression, and human disease.

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Senior supervisor: 
Felix Breden
Science: Biological Sciences Department
Thesis type: 
(Thesis) Ph.D.