Publications [#281835] of Thomas B. Kepler
Papers Published
- Radmacher, MD; Kepler, TB, Waiting times to appearance and dominance of advantageous mutants: estimation based on the likelihood.,
Mathematical Biosciences, vol. 170 no. 1
(March, 2001),
pp. 59-77, ISSN 0025-5564 [11259803]
(last updated on 2018/07/04)Abstract:
The germinal center reaction (GCR) of vertebrate immunity provides a remarkable example of evolutionary succession, in which an advantageous phenotype arises as a spontaneous mutation from the parental type and eventually displaces the parental type altogether. In the case of the immune response to the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP), as with several other designed immunogens, the process is dominated by a single key mutation, which greatly simplifies the modeling of and analysis of data. We developed a two-stage model of this process in which the primary stage represents the appearance and establishment of the mutant population as a stochastic process while the second stage represents the growth and dominance of the clone as a deterministic process, conditional on its time of establishment from stage one. We applied this model to the analysis of population samples from several germinal center (GC) reactions and used maximum-likelihood methods to estimate the waiting times to arrival and to dominance of the mutant clone. We determined the sampling properties of the maximum-likelihood estimates using Monte Carlo methods and compared them to their asymptotic distributions. The methods we present here are well-suited for use in the analysis of other systems, such as tumor growth and the experimental evolution of bacteria.Keywords:
Animals • Antibody Formation • B-Lymphocytes • Computer Simulation • Genes, Dominant • Germinal Center • Likelihood Functions • Models, Genetic* • Monte Carlo Method • Mutation • Nitrophenols • Phenylacetates • Selection, Genetic* • Stochastic Processes • Vertebrates • genetics • genetics* • immunology • immunology*