Construction of Human Genetic Linkage Maps: II. Methodological Issues

The genetic anatomy of a species consists of the de-scription of the linear arrangement of its genes along chromosomes. Depending on the methods used in this construction, several types of maps can be distin-guished. When genes are assigned to chromosomes or to chromosome subregions through somatic cell hy-brids or in situ hybridization (McKusick, this volume), the map generated is strictly physical. So it is for mo-lecular maps generated on particular genomic regions by restriction mapping of overlapping DNA sequences, and so will it be when extensive restriction maps are constructed with pulsed-field gel electrophoresis (Schwartz and Cantor 1984; Smith and Cantor, this volume). By contrast, genetic maps constructed by analysis of the segregations at two or more loci incorporate infor-mation on both the physical distribution of loci on chromosomes and the distribution of crossing-over in all intervals considered. Because all evidence (for re-view, see White and Lalouel 1986) indicates that the occurrence of crossing-over is not uniform with respect to distance on the physical map, we should not expect more than a monotonic relationship between physical and genetic maps. Our attention in this discussion bears on methodo-logical aspects of the construction of genetic maps in humans. Together with the detection of genetic linkage and the estimation of recombination between a set of loci in appropriate familial data, the construction of genetic maps requires that the order of the genes be inferred from the observed recombination values. This enterprise presents various challenges that will call for carefully designed strategies and analytical methods. We try here to convey our interest in meeting these challenges without undue mathematical rguments, at the risk of oversimplification for the statistically minded reader.