Haplotype exclusion by gene fusion errors based on the Mouse system

The principle: The program Hapex, for haplotype exclusion,uses a cellular automaton approach to calculate the gene rearrangement events in a large sample of cells. The less likely a gene rearrangement pattern, the more cells have to be looked at. At a rough estimate there is little of likely interest when cell numbers exceed one million.

The parameters:

• The STOP condition is either H-stop-H (and LH-stop at the light chain loci) or LH-stop for all loci.
• The Leakiness of the Stop signal. A value of 0.0 is no leak and a value of 1.0 is stopless.
• The number of loci to be analyzed ranges from 2 (H and Kappa) to 4 (H, Kappa, Lambda 1, and Lambda 2).
• The branching ratio that describes the relative probability of a gene rearrangement event being initiated at a given locus. For example, a Heavy to Kappa branching ratio of 3 would mean that gene fusions are initiated at the H locus three time more often than at kappa. A branching ratio of more than 100:1 is the functional equivalent of a sequential ordering of the rearrangements.
• The choice of gene fusion efficiencies requires some adjustments that include the effect of pseudo V segments (for example if 30% of V segments are defective but fusable, then the fusion efficiency of 1/3 drops to around 2/9). If one wishes to take into account effects of receptor editing that allow some productive fusions to be made to reinitiate, this is done by recalculating the effect on the gene fusion efficiency. If half of the productive rearrangements were randomly considered to be non-functional as rearrangements reinitiated, this would result in the fusion efficiency that is typed in to the program to be 50% lower to reflect the 50% loss of productive joints.
• There are up to 9 sets of gene rearrangement configurations that you can monitor. The exact choice is offered on a new page.
• Checking the box for fine structure analysis of J-Kappa allows various kinds of gene fusion events to be monitored at the level of J-Kappa usage.
• There are two options for the number of gene fusion events at J-Kappa, one - meaning only one rearrangement is allowed at the locus, or many - meaning that the J-Kappas are used until there are none left as would occur when J-Kappa-4 is rearranged. The J-Kappa loci are numbered 1-4 based on 1 being the locus immediately 5' to the V-kappa genes and 4 being the locus immediately 3' to the C-Kappa locus.
• If many rearrangements are allowed, they can be sequention from J-1 to J-4 or they can be random.
• The number of cells to be simulated should be around 10^4 at first, then for rare events around 10^6 should be used, though the time taken to simulate a million sets of gene fusion events can be quite long and thus we advise looking at smaller samples to get the rough picture first.
• After clicking the submit button the option list is set out as a series of check boxes that are self-explanatory.

If your model is not accommodated or you have results that seem to be unsimulatable with the options provided, please let us know so that we can adjust the program to simulate your model or the data. Eventually we hope that only one model will simulate all of the data.

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