Detection of putative quantitative trait loci in line crosses under infinitesimal genetic models.

Quantitative trait locus (QTL) mapping studies often employ segregating generations derived from a cross between genetically divergent inbred lines. In the analysis of such data it is customary to fit a single QTL and use a null hypothesis which assumes that the genomic region under study contributes no genetic variance. To explore the situation in which multiple linked genes contribute to the genetic variance, we simulated an F2-mapping experiment in which the genetic difference between the two original inbred strains was caused by a large number of loci, each having equal effect on the quantitative trait. QTLs were either in coupling, dispersion or repulsion phase in the base population of inbred lines, with the expected F2 genetic variance explained by the QTLs being equivalent in the three models. Where QTLs were in coupling phase, one inbred line was fixed for all plus alleles, and the other line was fixed for minus alleles. Where QTLs were in dispersion phase, they were assumed to be randomly fixed for one or other allele (as if the inbred lines had evolved from a common ancestor by random drift). Where QTLs were in repulsion phase alleles within an inbred line were alternating plus and minus at adjacent loci, and alternative alleles were fixed in the two inbred lines. In all these genetic models a standard interval mapping test statistic used to determine whether there is a QTL of large effect segregating in the population was inflated on average. Furthermore, the use of a threshold for QTL detection derived under the assumption that no QTLs were segregating would often lead to spurious conclusions regards the presence of genes of large effects (i.e. type I errors). The employment of an alternative model for the analysis, including linked markers as cofactors in the analysis of a single interval, reduced the problem of type I error rate, although test statistics were still inflated relative to the case of no QTLs. It is argued that in practice one should take into account the difference between the strains or the genetic variance in the F2 population when setting significance thresholds. In addition, tests designed to probe the adequacy of a single-QTL model or of an alternative infinitesimal coupling model are described. Such tests should be applied in QTL mapping studies to help dissect the true nature of genetic variation.