title: The Number of Overlapping AID Hotspots in Germline IGHV Genes Is Inversely Correlated with Mutation Frequency in Chronic Lymphocytic Leukemia.
abstract: The targeting of mutations by Activation-Induced Deaminase (AID) is a key step in generating antibody diversity at the Immunoglobulin (Ig) loci but is also implicated in B-cell malignancies such as chronic lymphocytic leukemia (CLL). AID has previously been shown to preferentially deaminate WRC (W = A/T, R = A/G) hotspots. WGCW sites, which contain an overlapping WRC hotspot on both DNA strands, mutate at much higher frequency than single hotspots. Human Ig heavy chain (IGHV) genes differ in terms of WGCW numbers, ranging from 4 for IGHV3-48*03 to as many as 12 in IGHV1-69*01. An absence of V-region mutations in CLL patients ("IGHV unmutated", or U-CLL) is associated with a poorer prognosis compared to "IGHV mutated" (M-CLL) patients. The reasons for this difference are still unclear, but it has been noted that particular IGHV genes associate with U-CLL vs M-CLL. For example, patients with IGHV1-69 clones tend to be U-CLL with a poor prognosis, whereas patients with IGHV3-30 tend to be M-CLL and have a better prognosis. Another distinctive feature of CLL is that ~30% of (mostly poor prognosis) patients can be classified into "stereotyped" subsets, each defined by HCDR3 similarity, suggesting selection, possibly for a self-antigen. We analyzed >1000 IGHV genes from CLL patients and found a highly significant statistical relationship between the number of WGCW hotspots in the germline V-region and the observed mutation frequency in patients. However, paradoxically, this correlation was inverse, with V-regions with more WGCW hotspots being less likely to be mutated, i.e., more likely to be U-CLL. The number of WGCW hotspots in particular, are more strongly correlated with mutation frequency than either non-overlapping (WRC) hotspots or more general models of mutability derived from somatic hypermutation data. Furthermore, this correlation is not observed in sequences from the B cell repertoires of normal individuals and those with autoimmune diseases.
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, NY, United States of America.
authors.forename: Chaohui
authors.initials: C
authors.lastname: Yuan
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States of America.|Departments of Medicine and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, United States of America.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chu
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States of America.
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yan
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States of America.
authors.forename: Davide
authors.initials: D
authors.lastname: Bagnara
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States of America.|Departments of Medicine and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, NY, United States of America.
authors.forename: Thomas
authors.identifier: 0000-0003-0025-9285
authors.initials: T
authors.lastname: MacCarthy
mesh_terms: D000328:Adult; D001327:Autoimmune Diseases / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D019295:Computational Biology; D003564:Cytidine Deaminase / Q000235:genetics* / Q000276:immunology; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D018095:Germ-Line Mutation; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D059645:Mutation Rate; D011379:Prognosis; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007143:Immunoglobulin Heavy Chains; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase