A major limitation of HBCGM is that it cannot analyze traits with a complex genetic architecture, which is a major strength for linkage analysis. However, it currently costs only ~$6,000 to sequence the genome of an additional inbred strain with a recently discovered phenotype of interest, which enables it to be used in a HBCGM experiment. In contrast, multiples of $10 million are required to create and maintain new collaborative cross panels that incorporate new strains. Moreover, identification of genetic modifiers affecting a strain-specific phenotype produced by transgene expression or by a gene knockout will be of increased importance in 21st century studies. While it would be prohibitively difficult to introduce a knockout or transgene onto a large panel of recombinant inbred strains, it can be bred onto a set of inbred strains to enable haplotype-based computational genetic studies.
