SOMATIC MUTATION OF IG VARIABLE REGIONS

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from Investigator's abstract): Somatic hypermutation
of the variable regions of immunoglobulin genes is responsible for the
increase in affinity and changes in fine specificity of antibodies during
the secondary response. The detailed mechanisms responsible for this
process are largely unknown and until now could only be investigated by
examining the sequences of endogenous Ig genes of transgenes in vivo. The
applicant has recently established a tissue culture system in which mutation
can be studied by reversion analysis, and transfected and manipulated heavy
chain genes can undergo V region point mutations at rates as high as 10E-4
to 10E-3/base pair/generation that are comparable to the rates that occur in
vivo. He will determine whether the size and borders of the target of
mutation in the transfected Ig gene is the same in these cultured cells as
it is in vivo. In these cultured cells, mutations occur more frequently in
a motif that is a favored target for mutation in vivo. He will use this in
vitro system to explore the role of the target sequence, the surrounding
sequence environment, and the distance from the promoter in generating these
hot spots. Constructs that differ by 1000 fold in their rate of mutation in
the NSO cell line will be dissected to identify the cis-acting sequences
that are involved in mutation. He will also examine the role of
transcription and of the promoter and enhancers in mutation and compare the
interactions of the different cis-acting sequences in cell lines that are
permissive and non-permissive for mutation. These studies should lead to a
better understanding of the mechanisms responsible for the high rate of V
region mutation in cultured B cells and, if the characteristics of the
process are the same as the normal process, to new insights into the
regulation of V region hypermutation in vivo.
StatusFinished
Effective start/end date9/15/978/31/98

Funding

  • National Cancer Institute

ASJC

  • Genetics
  • Molecular Medicine
  • Molecular Biology
  • Cell Biology
  • Developmental Biology

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