Date on Master's Thesis/Doctoral Dissertation
12-2024
Document Type
Doctoral Dissertation
Degree Name
Ph. D.
Department
Biochemistry and Molecular Biology
Degree Program
Biochemistry and Molecular Biology, PhD
Committee Chair
Watson, Corey
Committee Member
Mitchell, Thomas
Committee Member
Rouchka, Eric
Committee Member
Smith, Melissa
Committee Member
Yaddanapudi, Kavitha
Author's Keywords
Immunogenetics
Abstract
B cells produce immunoglobulins (IGs; antibodies), which are critical protein components of the immune system. Human IGs are composed of two pairs of identical ‘heavy’ chains and ‘light’ kappa or lambda chains, encoded by genes located at three loci in the genome: the IG heavy chain locus (IGH, chromosome 14), and the IG lambda (IGL, chromosome 22) and kappa (IGK, chromosome 2) loci. Each locus spans ~920-100 kilobase pairs (Kbp) of DNA and harbors families of gene segments that are somatically rearranged during B cell development. The IG loci collectively harbor >180 functional genes, many of which are part of segmental duplications, and are among the most polymorphic and least mappable regions of the human genome. The complex nature of IG loci limits effectiveness of short-read and short-oligo genotyping approaches, leaving genetic variation in these regions largely unexplored. Therefore, until recently, we have lacked characterizations of haplotype variation in IG loci at population-scale. This has been a critical knowledge gap in pursuit of genetic associations with human traits, because genomic regions which encode antibodies have not been accurately accounted for. In this work, we describe haplotype variation in the IGK locus at population-scale for the first time. In addition, we provide the second population-scale description of haplotype variation in the IGL locus. We report novel structural variants in the IGK locus, including a gene deletion, a large inversion, and we confirm that that are two distinct haplotype structures in a portion of the IGK locus that includes the genes IGKV1D-13 and IGKV1D-12. We characterize >250 allelic variants of IGK and IGL genes that were not previously curated, and these alleles are undergoing submission to the publicly available germline allele database called “VDJbase”. We demonstrate that usage of light chain V and J genes in peripheral antibody repertoires is associated with common genetic variants in cis. Such associations, termed gene usage quantitative trait loci (guQTL), were identified for over half of IGKV genes and >70% of IGLV genes. These data are critical to refine our understanding of factors that explain inter-individual variation in antibody-related phenotypes. Finally, we show that long-read chromatin profiling tools will be needed to determine mechanistic regulation of non-coding variants which impact IGH V(D)J recombination at haplotype-resolution.
Recommended Citation
Engelbrecht, Eric, "Impact of human immunoglobulin genetic variants on the expressed antibody repertoire." (2024). Electronic Theses and Dissertations. Paper 4464.
Retrieved from https://ir.library.louisville.edu/etd/4464
