Delineation of selective influences shaping the mutated expressed human Ig heavy chain repertoire

Thomas Dörner, Hans Peter Brezinschek, Sandra J. Foster, Ruth I. Brezinschek, Nancy L. Farner, Peter E. Lipsky

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

After Ag exposure, somatic hypermutation and subsequent selection play significant roles in shaping the peripheral B cell repertoire. However, the disparate impact of each process has not been completely delineated. To address this, the mutational patterns of a large panel of productive V(H)DJ(H) rearrangements of individual human B cells were analyzed and compared with those of a previously reported panel of nonproductive V(H)DJ(H) rearrangements. The productive V(H) rearrangements exhibited a significantly lower mutational frequency and a significantly smaller number of replacement mutations than nonproductively ranged genes, suggesting that structural constraints of the Ig molecule and selective influences both impacted the repertoire, militating against replacement mutations. Positive selection favored a mean of four to six replacements in complementarity-determining region 1 (CDR1) and CDR2, and less than two replacements in the framework regions (FRs). In contrast, the negative impact of replacement mutations generated an increased number of silent mutations within both the CDRs and FRs of the productive repertoire accompanied by a net increase in the ratio of replacement to silent mutations in the CDRs compared with that in the FRs. Moreover, there was a negative influence on the distribution of amino acid changes resulting from mutations of highly mutable codons, such as AGY, TAY, GTA, and GCT, preferentially leading to conservative changes in the expressed Ig repertoire. The results are consistent with the conclusion that the expressed repertoire is limited, compared with the potential generated by the mutational machinery, by the dual requirements of avoiding autoreactivity and satisfying structural constraints of an intact Ig molecule.

Original languageEnglish (US)
Pages (from-to)2831-2841
Number of pages11
JournalJournal of Immunology
Volume160
Issue number6
StatePublished - Mar 15 1998

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Immunoglobulin Heavy Chains
Mutation
B-Lymphocytes
Complementarity Determining Regions
Codon
Amino Acids
Genes
Silent Mutation

ASJC Scopus subject areas

  • Immunology

Cite this

Dörner, T., Brezinschek, H. P., Foster, S. J., Brezinschek, R. I., Farner, N. L., & Lipsky, P. E. (1998). Delineation of selective influences shaping the mutated expressed human Ig heavy chain repertoire. Journal of Immunology, 160(6), 2831-2841.

Delineation of selective influences shaping the mutated expressed human Ig heavy chain repertoire. / Dörner, Thomas; Brezinschek, Hans Peter; Foster, Sandra J.; Brezinschek, Ruth I.; Farner, Nancy L.; Lipsky, Peter E.

In: Journal of Immunology, Vol. 160, No. 6, 15.03.1998, p. 2831-2841.

Research output: Contribution to journalArticle

Dörner, T, Brezinschek, HP, Foster, SJ, Brezinschek, RI, Farner, NL & Lipsky, PE 1998, 'Delineation of selective influences shaping the mutated expressed human Ig heavy chain repertoire', Journal of Immunology, vol. 160, no. 6, pp. 2831-2841.
Dörner T, Brezinschek HP, Foster SJ, Brezinschek RI, Farner NL, Lipsky PE. Delineation of selective influences shaping the mutated expressed human Ig heavy chain repertoire. Journal of Immunology. 1998 Mar 15;160(6):2831-2841.
Dörner, Thomas ; Brezinschek, Hans Peter ; Foster, Sandra J. ; Brezinschek, Ruth I. ; Farner, Nancy L. ; Lipsky, Peter E. / Delineation of selective influences shaping the mutated expressed human Ig heavy chain repertoire. In: Journal of Immunology. 1998 ; Vol. 160, No. 6. pp. 2831-2841.
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