Project 1: The Mouse Brain Library Project 2: Internet Microscopy (iScope) Project 3: Neurocartographer and Segmentation of the MBL Project 4: The Neurogenetics Tool Box


















Principal Investigator/Program Director Williams, Robert W.


Data and map export

The NTB is intended to supplement rather than replace existing QTL mapping programs. In particular, it will make some existing programs more accessible to neuroscientists. Some existing programs, such as Mapmaker/QTL (Lincoln, Daly et al. 1992) and QTL Cartographer (Basten, Weir et al. 1994) , provide sophisticated methods, including maximum-likelihood evaluation and automated model-building.  However, they require the user to create specially formatted data files and marker maps. These requirements can be an insurmountable barrier for the nonspecialist. To enable neuroscientists to use these programs, the NTB will allow export of marker data, trait data, and marker maps in the formats required by these programs.

We will make public the genotype data generated by our Genotyping and Mouse Colony Core as soon as possible, in formats suitable for Map Manager QT and QTX, Mapmaker/QTL, and QTL Cartographer. Even before the proposed Web interface is in place, we will provide Map Manager QT data files for downloading from the <> site. Map Manager data files have been available for downloading from this site since early in 1994. Data sets include complete RI genotype files, complete MIT SSLP map files, and several other major mapping panels. A complete list of Map Manager files currently available online is at <>.

Dominance models

Dominance refers to the fact that the trait value of a heterozygote may not be the mean of the values of the two homozygotes. This phenomenon can be analyzed in intercrosses, in which separate contributions from additive and dominance effects can be estimated. These effects are expressed in the trait equation as coefficients in two terms, one in which the three genotypes (maternal, heterozygous, and paternal) are coded as 1, 0, and 1, and one in which the genotypes are coded as 0, 1, and 0. For interval mapping, the expected genotypes are typically nonintegral and are derived from the genotypes and distances of flanking markers.

For the free dominance model, the two coefficients are allowed to assume any value. For a constrained additive model, the dominance coefficient is set to 0; for constrained dominant (or recessive) models, the dominance coefficient is set to the value of (or the negative of) the additive coefficient. The free model uses two degrees of freedom, the others

only one. The NTB will allow a choice of these models for the target QTL in simple or composite interval mapping. For the background loci in composite interval mapping, it will allow any of the constrained models, that is, those that use one degree of freedom.

Interference models

Genetic interference refers to the observation that, at least in some organisms, two recombination events close to each other are much less common than would be expected by chance. This fact affects the estimation of a QTL genotype from the genotypes of flanking markers. No completely satisfactory model of interference has been described, and even if one were available, its implementation would probably be computationally demanding. However, we can easily implement two extreme models, one in which interference is absent and one in which it is complete (multiple recombinants are absent, at least within an interval).

In recombinant inbred lines and advanced intercrosses, recombination events are derived from multiple rounds of mating, and since adjacent recombinations may be derived from different meioses, interference is assumed to be absent. In addition, the probability of recombination is greater than the nominal map distance between markers (Jiang and Zeng 1997) . QTL mapping in recombinant inbred lines and in the G10 advanced intercross, therefore, will be analyzed by a no-interference model that accounts for the map expansion from multiple rounds of mating.

Fast interval mapping

Whittaker and coworkers (1996) have derived a relationship for estimating the position and effect of an additive QTL directly from the regression coefficients derived from regression of the trait on the two flanking marker genotypes. Background markers can be included in this analysis; that is, this method can be analogous to either SIM or CIM. This method avoids regression at multiple analysis points between the flanking markers, and it should be several-fold faster than SIM or CIM as described above. This elegant method, which has been implemented for the first time in Map Manager QTX, will be implemented in the NTB. It will be the standard method for mapping with RI strains, since there is no question of distinguishing dominance effects with these. This method will also be an option for mapping with intercross and advanced intercross populations.



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