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Introduction: Brief Overview on the Major Histocompatibility Complex
Published in Gérard Chaouat, The Immunology of the Fetus, 2020
Jean-Pierre Abastado, P. Kourilsky
The immune system of the host is, therefore, capable of discriminating between self and nonself. Genetic and biochemical studies have shown that the structure recognized on the graft by the immune system is a set of glycoproteins expressed at the surface of its cells and called the transplantation antigens. Some of these antigens cause a more rapid graft rejection (within 12 d in the mouse) and are, therefore, called major transplantation antigens (H-2 in the mouse and HLA in the man). They are expressed on almost all tissues except for the cells of the germinal line and those of the early embryo. They are encoded in several loci. For each locus, a large number of different alleles exists in the populations.1 Since a difference at a single locus is sufficient to trigger the graft rejection, two randomly chosen individuals are generally histo-incompatible. Mutants have been isolated by the virtue of the offspring to reject skin grafts from their parents. The rate of mutation was found very high in some loci (2 × 10−4 per gamete for H-2Kb). Special mechanisms (gene conversion and equal and unequal crossing-over) have been put forward to explain this high rate of mutation and the high level of polymorphism.2
Immune Reconstitution after Hematopoietic Stem Cell Transplantation
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Andreas Thiel, Tobias Alexander, Christian A. Schmidt, Falk Hiepe, Renate Arnold, Andreas Radbruch, Larissa Verda, Richard K. Burt
B cells undergo further affinity maturation within lymph node germinal centers by a process of somatic hypermutation (SHM), gene conversion, and class switching recombination (CSR) (Fig. 4). SHM is the term for insertion of point mutations in the vicinity of the variable region exon (Fig. 4) and results in generation of antigen specific high affinity antibodies. Gene conversion is the transfer of a pseudovariable (ipV)gene sequence into the variable region exon (Fig. 4). Both SHM and gene conversion alters the antigen binding site of the immunoglobulin.71-72 CSR involves switching the constant region heavy change (e.g., IgM to IgG) that alters the effector function of the antibody (Fig. 4). The mechanisms involved in DNA SHM, gene conversion, and CSR although incompletely understood probably involve common mechanisms of DNA recognition, targeting, cleavage, and repair.73 The enzyme activation-induced cytidine deaminase (AID) is involved in all three reactions by helping to create the DNA cut or cleavage.65,74-75
Mobile DNA Sequences and Their Possible Role in Evolution
Published in S. K. Dutta, DNA Systematics, 2019
Georgii P. Georgiev, Yurii V. Ilyin, Alexei P. Ryskov, Tatiana I. Gerasimova
An important feature of mdg is that within each family the elements seem to be very similar, at least in the case of D. melanogaster.16,17,20,36 Such homogeneity may be explained in terms of gene conversion or other correction mechanisms. The mechanism of gene conversion remains obscure, especially in the case of distant genes. It is possible that recombination with gene copies synthesized by reverse transcriptase is involved. If such a mechanism does exist, the selection of a copy (copies) to be used as template would depend on its relative rate of transcription and reverse transcription. The poorly transcribed (and reverse transcribed) genes would diverge much faster than those with a high level of transcription, as the rate of their correction would be decreased.
Pedigree Analysis of Nonhomologous Sequence Recombination of HBA1 and HBA2 Genes
Published in Hemoglobin, 2020
Shi-Qiang Luo, Xing-Yuan Chen, Ning Tang, Jun Huang, Qing-Yan Zhong, Ren Cai, Ti-Zhen Yan
In this study, the proband was a carrier of the Hb QS mutation, but the result of the reverse dot-blot hybridization showed that the wild site and the mutation site were not colored. We then carried out DNA sequencing and found the patchwork gene of the HBA2 and HBA1 genes’ reorganization. The recombination sequence is formed by a complex combination of α1 (HBA1) and α2 (HBA2) sequences, called the α12 allele (HBA12). Given the high sequence identity between the HBA1 and HBA2 genes and the surrounding sequences, the patchwork α-globin gene is caused by two exchanges or gene conversions between the HBA1 and HBA2 genes that are misaligned by normal alleles. Gene conversion involves the non-reciprocal transfer of information from a donor sequence to an acceptor sequence [6]. By comparing the α1 and α2 reference sequences (NG_000006.1) with the α12 homozygous sequence, it was found that a 3′ promoter, exon 1, IVS-I, exon 2 and 5′ IVS-II of the HBA1 on the α12 allele. It was evident from the sequence homology that the 3′ enhancer (774 bp onwards) sequences were from HBA2. However, there is no evidence for the 3′ IVS-II, exon 3′ and 5′ enhancer regions from the donor (HBA1) or acceptor (HBA2) genes. Bidirectional sequencing is mandatory to identify the sequence defects of exon 3 and its HBA12 splice site in patients [7].
A β-Thalassemia Trait with Two Mutations in Cis in a Chinese Family
Published in Hemoglobin, 2019
Jian Li, Fan Jiang, Li Zhen, Xue-Wei Tang, Dong-Zhi Li
As with our case, heterozygosity was expressed as a thalassemia trait in the two subjects. The mechanisms for having two pathogenic mutations in cis are unknown. One might be a de novo mutation occurring on a chromosome already containing a pathogenic mutation. Alternatively, it may be a gene conversion event involving two alleles with single mutations. Mutations in cis can confound genotype-phenotype correlations. Indeed, the likelihood of multiple mutations in cis cannot be excluded in any DNA analysis unless a full gene sequencing analysis is performed. In postnatal cases, double mutations in cis can be easily suspected when the individuals do not show mutation-related diseases or only behave as a carrier. However, it is difficult to distinguish between these two conditions in a prenatal setting if there are no genotypes available from the parents. Therefore, it is mandatory that before performing a molecular PND, the genotypes in the prospective parents should always be accurately characterized and confirmed.
Common light chain chickens produce human antibodies of high affinity and broad epitope coverage for the engineering of bispecifics
Published in mAbs, 2021
Kathryn H. Ching, Kimberley Berg, Kevin Reynolds, Darlene Pedersen, Alba Macias, Yasmina N. Abdiche, William D. Harriman, Philip A. Leighton
In chickens, development of the antibody repertoire is initiated when V(D)J recombination leads to expression of the functional B cell receptor on the surface of early B cells.25 However, unlike in mammals, very little diversity is produced at the recombination step. Chickens contain only a single functional V gene and a single J gene at the heavy and light chain loci,26,27 and the heavy chain contains a cluster of D segments that are highly related to each other.28 No terminal deoxynucleotidyl transferase activity is present in chicken B cells, so no N addition can occur.29 Recombination thus produces essentially the same clonotype in every B cell, with the same V framework and nearly the same complementarity-determining regions (CDRs). As soon as recombination has produced a functional receptor, variable region sequences begin to mutate by the process of gene conversion, which leads to a highly diverse repertoire. Gene conversion incorporates sequences from an array of upstream pseudogenes in a homologous recombination-based process, leading to changes in the functional V. Multiple rounds of overlapping gene conversion occur from different pseudogenes, and indels can also be incorporated. In wild-type chickens, the light chain contains 25 pseudogenes and the heavy chain about 80 pseudogenes (the international ImMunoGeneTics information system, IMGT30). Pseudogene sequences contain diversity mainly in the CDRs, while the sequence of the VL/VH frameworks is largely maintained. However, in addition to gene conversion, random somatic hypermutation can also occur and adds to the sequence diversity in the repertoire.31