Soma‐to‐germline feedback is implied by the extreme polymorphism at IGHV relative to MHC

  title={Soma‐to‐germline feedback is implied by the extreme polymorphism at IGHV relative to MHC},
  author={Edward J. Steele and Sally S Lloyd},
Soma‐to‐germline feedback is forbidden under the neo‐Darwinian paradigm. Nevertheless, there is a growing realization it occurs frequently in immunoglobulin (Ig) variable (V) region genes. This is a surprising development. It arises from a most unlikely source in light of the exposure of co‐author EJS to the haplotype data of RL Dawkins and others on the polymorphism of the Major Histocompatibility Complex, which is generally assumed to be the most polymorphic region in the genome (spanning ∼4… 
Germline V repertoires: Origin, maintenance, diversification
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Regulatory T cells and co‐evolution of allele‐specific MHC recognition by the TCR
It is argued that the same direct SHM processes for TCRs occur in post‐antigenic Germinal Centres, but now occurring in peripheral pTregs, which can donate their TCR V sequences via soma‐to‐germline feedback as discussed earlier.
Worldwide genetic variation of the IGHV and TRBV immune receptor gene families in humans
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Darwin’s sub-cellular theory of inheritance: unknown or ignored?
Although Weismann argued against the inheritance of acquired characters and Darwin’s Pangenesis, he recognized that BDarwin was the first to think out a theory of heredity which was worthy of the name of theory, for it was not merely an idea hastily suggested, but an attempt at elaborating a definite hypothesis.
Evidence of gene orthology and trans‐species polymorphism, but not of parallel evolution, despite high levels of concerted evolution in the major histocompatibility complex of flamingo species
High sequence similarity between all species regardless of codon position is found, which is consistent with balancing selection maintaining TSP, as under this mechanism amino acid sites under pathogen‐mediated selection should be characterized by fewer synonymous codons than under parallel evolution.
Dangers of Adhering to an Obsolete Paradigm: Could Zika Virus Lead to a Reversal of Human Evolution?
It is argued that adhering to the obsolete paradigm of closed-box Darwinian evolution is a major obstacle to progress and if the Zika virus escalates unchecked its soma-to-germ line transfer might effectively lead to the emergence of a new human species with a diminished level of cognition.


Hypothesis: A memory lymphocyte‐specific soma‐to‐germline genetic feedback loop
The mechanism described proposes that the interactions that may result in the soma‐to‐germline transfer of somatically selected IgV genes occur in the epididymis of the male reproductive tract and are restricted to memory lymphocytes.
Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease
A model of the evolution of the human MHC is proposed and explanations for co‐occurrence of genomic polymorphism, duplication and HERVs are considered and it is asked how these features encode susceptibility to numerous and very diverse diseases.
The signature of somatic hypermutation appears to be written into the germline IgV segment repertoire
Summary: We present here a unifying hypothesis for the molecular mechanism of somatic hypermutation and somatic gene conversion in IgV genes involving reverse transcription using RNA templates from
Origin and maintenance of germ‐line V genes
The data in this report of work in progress indicate non‐random selection for variability in the second antigen‐contact or complementarity‐determining region (CDR2) for 12 germ‐line V genes isolated using the polymerase chain reaction (PCR) technique from genomic C57BL/6 mouse liver DNA.
Reflections on Ancestral Haplotypes: Medical Genomics, Evolution, and Human Individuality
  • E. Steele
  • Biology
    Perspectives in biology and medicine
  • 2014
The block haplotype structure of the genome, as shown for the MHC (and other genetic regions), is a story that needs to be understood in its own right, particularly given the promotion of the “HapMap” project and single nucleotide polymorphism linkage disequilibrium (LD) analysis, which has been wrongly touted as the only way to pinpoint those genes that are important in genetic disorders or other desired (qualitative) characteristics.
Somatic hypermutation in 5′ flanking regions of heavy chain antibody variable regions
The data are consistent with a mutational mechanism that requires transcription of the rearranged target V(D)J gene which appears to result in the generation of a positively skewed asymmetrical distribution of somatic mutations.
Critical Analysis of Strand-Biased Somatic Mutation Signatures in TP53 versus Ig Genes, in Genome-Wide Data and the Etiology of Cancer
The goal is to understand the genesis of the strand-biased mutation patterns in TP53—and in genome-wide data—that may arise by “endogenous” mechanisms as opposed to adduct-generated DNA-targeted strand- biased mutations caused by well-characterised “external” carcinogenic influences in cigarette smoke, UV-light, and certain dietary components.
The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease
How poorly the authors understand the distribution of haplotype variation in this genomic region is examined, and it is argued that this lack of information may mask candidate loci in the IGHV gene cluster as causative factors for infectious and autoimmune diseases.
Ancestral haplotypes reveal the role of the central MHC in the immunogenetics of IDDM
These findings suggest that both HLA and non-HLA genes are involved in conferring susceptibility to IDDM, and that the region between HLA-B and BAT3 contains some of the relevant genes.