Effisim is an efficiency cost-estimation tool, used to help in planning and designing recessive screens for experiments. It can aid in selecting the most efficient design on of an experiment, given the cost of each design. A series of simulations can be run with varying parameters - such as the breeding scheme, the number of matings or a range of other parameters - in order to gauge how well certain designs will fair against other designs.
Even in well-studied organisms, the function of many genes remains unknown. One path to illuminating the role a gene plays is to examine the physical characteristics of individuals carrying unusual variants of the gene. In experimental organisms, novel alleles can be generated by artificially-induced mutations. The offspring of a mutagenised animal can be screened for dominant traits.
Screens for recessive traits require a three-generation breeding strategy. Thus they are more expensive and time-consuming than screens for dominant traits. Since a G1 animal can only carry, and therefore transmit, a finite number of mutations, the law of diminishing returns will apply at some point.
When designing a recessive screen, the aim is to maximise the number of distinct mutations one can expect to screen within a given budget. This strikes a balance between thoroughly examining mutations of each G1, and using more G1. Different designs are determined by the relative numbers of mice to breed at each generation. EffiSim can assist in the planning of recessive screens by estimating the cost efficiency of the proposed design. The best screen can be found by considering a range of designs.
EffiSim is program that calculates two different measures of efficiency of mutation screens for recessive phenotypes. The first measure is the expected number of distinct mutations screened, and the second is the expected number of mutations screened for a given amount of work. The first measure is called the efficiency and the second is called the balanced efficiency. This program can be used to determine the most efficient design (i.e. it will screen, on average, the largest number of mutations for a given amount of work), given the costs of a screen. It can also be used to help determine which of the backcross (BC) and intercross (IC) breeding strategies is most appropriate for a given mutation screen.
A screen for recessively acting mutations requires a three-generation breeding strategy to produce homozygotes for the novel mutations. The design of a screen describes the numbers of mice bred at each generation. Let us define a few variables. Let x be the number of mutations inherited per G1, d be the number of G1 pairs, h be the number of G2 crosses per G1 pair (h = 1 for the backcross, however the intercross can have h > 1), k be the number of G2 females mating with each G2 male, n be the number of G3 pups born to each G2 male and r be the number of pups born to each G2 male (thus r = nk).
An important feature of EffiSim is the cost equation, or the weights attributed to each generation. Any G1 mice carries, and therefore can transmit, only a finite number of mutations. The law of diminishing returns suggests that the greatest returns (in terms of the numbers of mutations screened) will come after screening the first few mice. This line of thought implies that to screen the greatest number of distinct mutations, one should screen only few G3 progeny of any G1 pair. However, the generation of the G1 and G2 mice is time-consuming and expensive in itself. This implies that it is worth screening many G3 pups to make this effort worthwhile. Hence there are two competing interests that must be balanced. This can be done by finding the screen that has the greatest balanced efficiency - it will screen the greatest number of equations for a given amount of work.
To do this requires careful consideration of where the costs go in a screen. One simple way of doing this would be to calculate the average amount of work required (wGi) for each mouse in generation i. Using the design parameters above (d, h, k, and r), we can calculate the number of mice in each generation. Putting these things together, we have a way of calculateing the costs of a screen that uses the same variables that are required to estimate the returns. Thus it is important that the weights accurately represent the cost/labour/time/space/effort involved in conducting the screen. The equation used to calculate the cost of the screen is g(d,h,k,r) = 2dwG1 + 2dhkG2 + dhrG3. This equation has been designed to take into account all mice bred, not only mice that are used in the screen (e.g. in the backcross, any male G2 mice are not used in the screen). It should be altered as necessary.
Effisim can also be run from the command line. If you prefer to run this tool from the command line, then visit http://bioinf.wehi.edu.au/software/EffiSim/main.html, where the tool is available for download.
Comments/Questions? Contact: Jeremy Silver: firstname.lastname@example.org.
Web Interface designed by: Vineeth Varughese