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Title: The human immunoglobulin diversity segment repertoire
Author: Corbett, S. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1997
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Combination recombination of Variable (V), Diversity (D) and Joining (J) immunoglobulin gene segments with imprecise loss and gain of nucleotides at segment joins creates a diverse primary antibody repertoire. In humans it has also been proposed that utilisation of DIR segments, multiple D segments and inverted D segments increases diversity further. However to date, incomplete knowledge of the germline D segment repertoire has made it difficult to dissect out the precise mechanisms involved. This thesis describes the complete nucleotide sequence of the functional human D segment locus on chromosome 14q32.3, identifying a germline repertoire of 27 D segments, including 13 novel sequences. Criteria which confidently assign somatically rearranged sequences to germline D segments have been established and show that the human antibody repertoire is only created by the recombination of 25 functional D segments with extensive junctional diversity according to the "12/23 rule". No convincing evidence for inverted D joins, double D joins or the use of DIR segments in human antibodies could be found. Furthermore, the D segment repertoire in expressed human antibodies has been found to be markedly biased, with over-representation of particular segments and reading frames. In contrast to mouse, chicken and rabbit whose D segments are restricted to expression in only one reading frame comprising mainly hydrophilic residues, a significant proportion of human antibodies express D segments in reading frames comprising predominantly hydrophobic residues. D segments thereby impart a range of sequence characteristics to the third hypervariable loop of the human heavy chain variable domain at the heart of the antigen binding site.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available