PAIRWISE ANALYSIS OF RADIATION HYBRID MAPPING DATA

Two point lod scores are widely used in pedigree analysis as they prov ide a fast and efficient method of establishing linkage. Groups of mar kers that lie in close proximity to one another can be formed by admit ting any locus that is linked to at least one existing member of the g roup with lod score greater than some predetermined value. It seems na tural to extend this technique to Radiation Hybrid Mapping both for co nstructing groups of tightly linked loci that may then be analysed usi ng more powerful statistics and as a method of ordering in its own rig ht. A general extension of two point analysis is derived and the probl ems associated with radiation hybrid data are discussed. In particular , the additional parameters representing the probabilities of differen t fragments being retained (which have no parallel in classical linkag e analysis) lead to a range of estimators of the breakage probability, theta, which have equal and maximal likelihood. Ways of circumventing this problem are discussed along with the potential errors they intro duce. Importantly the ambiguity in estimation of theta is not carried through to the lod score as this depends only on the maximum value of the likelihood and not on the particular value of theta at which it oc curs. Thus even though two point analysis fails to provide robust esti mates of either breakage probabilities or the distance between loci, i t represents a simple and effective method of constructing linkage gro ups that may be analysed with more powerful statistical methods. This is particularly important given the number of microsatellites, ESTs an d candidate genes currently being typed on radiation hybrids.