Commentary This special issue of Mammalian Genome highlights clude thousands of traits and the requisite multiple the merger of gene expression profiling with quan- testing corrections are the most obvious. The real titative trait locus analysis. Inbred line crosses of analytic challenges however must address the in- model organisms provide a powerful tool for inves- verse problem of reconstructing the genetic archi- tigating complex trait genetics. Yet even the largest tecture of transcriptional regulation based on the crosses provide only a coarse level of resolution, observed response of the transcriptome to perturba- limiting our ability to identify genes. Transcrip- tions. Knock-out models provide singular perturba- tional profiling provides a whole genome view of a tions that are relatively easy to interpret but are primary step intermediate between the genetic var- limited in scope. Genetic crosses, on the other hand, iation encoded in DNA and the expression of this generate a complex set of perturbations in which variation as a physiological trait. The realization natural allelic variants at a multitude of loci are that transcript levels can be analyzed as quantitative varied simultaneously. It remains an open problem traits in a genetically segregating population has gi- to establish methods by which we can interpret ven rise to a synergistic experimental approach that these data as an integrated whole. promises to provide a mechanistic link between ge- At this time, I do not believe that we fully netic and phenotypic variation. understand either the scope or the limitations of this A defining feature of transcript abundance as a powerful new approach to genetic analysis. Gene quantitative trait is its correspondence with a pre- expression in mammals is mediated by multiple cise genomic location the structural gene and its transcription factors that interact through both surrounding regulatory elements. Expression QTL cooperative and competitive binding to promoters. that map near the structural gene are abundant and The potential for polymorphisms in both structural are often observed to have large effects. These cis- genes and their regulatory elements, suggests that QTL most likely represent polymorphisms in regu- pleiotropy and epistasis should be common features latory elements or in the gene itself. Equally inter- of the genetic architecture of gene expression. esting and abundant are the trans-QTL that map to Moreover, many critical components of the biologi- locations distinct from the structural gene. The cal system, such as metabolites, proteins and protein dramatic clustering of trans-QTL suggests that these modification states, remain unobserved but the genomic regions harbor polymorphisms that have technologies required to measure these quantities widespread impact on the fundamental biology of are rapidly maturing. The articles in this issue can the organism. They may represent a homeostatic only hint at the potential for ‘‘systems genetics’’ to response that provides robustness to changes in the provide new and fundamenal insights into mam- internal environment. Whatever the explanation malian biology. may be, the extensive networks of genes associated with trans-QTL attest to the dynamic and global nature of transcriptional regulation. Gary A. Churchill The genetic analysis of gene expression data po- ses some challenging computational problems. Of The Jackson Laboratory these, the scale up of genome scan analysis to in- Bar Harbor, Maine DOI: 10.1007/s00335-006-1100-9 Volume 17, 465 (2006) Springer Science+Business Media, Inc. 2006 465
Mammalian Genome – Springer Journals
Published: Jun 12, 2006
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