Evolution of the structural repertoire of human VH and VK germline genes

Vargas-Madrazo, Enrique; Lara‐Ochoa, Francisco; Ramirez-Benites, Maria C.; Almagro, Juan C.

doi:10.1016/s0165-2478(97)86587-x

Cited by 1 publication

(1 citation statement)

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“…IGHV3 genes represent the largest IGHV family, are the primary contributors to VH structural diversity, and are evolutionarily distinct from all other IGHVs, being the only members of phylogenetic clan III 59 . Thus, this data suggests that in the case of IGHV3s, both mutability and extensive structural diversification may have contributed to codon deoptimization.…”

Section: Discussionmentioning

confidence: 99%

Mutability and hypermutation antagonize immunoglobulin codon optimality

McGrath,

Park,

Troxell

et al. 2024

Preprint

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The efficacy of polyclonal antibody responses is inherently linked to paratope diversity, as generated through V(D)J recombination and somatic hypermutation (SHM). These processes arose in early jawed vertebrates; however, little is known about how immunoglobulin diversity, mutability, and hypermutation have evolved in tandem with another more ubiquitous feature of protein-coding DNA - codon optimality. Here, we explore these relationships through analysis of germline IG genes, natural V(D)J repertoires, serum VH usage, and monoclonal antibody (mAb) expression, each through the lens of multiple optimality metrics. Strikingly, proteomic serum IgG sequencing showed that germline IGHV codon optimality positively correlated with VH representation after influenza vaccination, and in vitro, codon deoptimization of mAbs with synonymous amino acid sequences caused consistent expression loss. Germline V genes exhibit a range of codon optimality that is maintained by functionality, and inversely related to mutability. SHM caused a load-dependent deoptimization of IGH VDJ repertoires within human tonsils, bone marrow, and lymph nodes (including SARS-CoV-2-specific clones from mRNA vaccinees), influenza-infected mice, and zebrafish. Comparison of natural mutation profiles to true random suggests the presence of selective pressures that constrain deoptimization. These findings shed light on immunoglobulin evolution, providing unanticipated insights into the antagonistic relationship between variable region diversification, codon optimality, and antibody secretion; ultimately, the need for diversity takes precedence over that for the most efficient expression of the antibody repertoire.

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Section: Discussionmentioning

confidence: 99%