Many immune
responses are initiated through the binding of antibody receptors present on the
surface of B cells. Once activated, these B cells proliferate and undergo a
process of somatic hypermutation whereby point mutations are introduced into the
DNA coding for their antibody receptor. These mutations have important
consequences for the affinity and specificity of the response.
Despite the significance of somatic hypermutation,
precise estimates of the mutation rate do not currently exist. We have used mathematical modeling and computer
simulation to interpret data from microdissection studies and estimate this rate
more accurately than previously possible. Each microdissection experiment
provides a number of clonally related sequences that, through the analysis of
shared mutations, can be genealogically related to each other. The 'shape' of
these clonal trees is influenced by many processes including the hypermutation
rate. Modeling and simulation are used to relate the ‘shapes’ of these trees
to the underlying biology. This talk will describe two different methods to
estimate the mutation rate based on these data. The first relies on a computer
simulation of clonal expansion as a stochastic branching process. The second is
analytical. By combining these models with optimization techniques we have
developed precise methods for estimating the mutation rate in vivo.
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