Effective Genotype-Phenotype Mapping Using Radiation Hybrids

Source: Park et al. (2008). Fine mapping of regulatory loci for mammalian gene expression using radiation hybrids. Nature Genetics 40(4):421-429.

This is a very interesting paper with exciting methods and significant results. I wanted to write about it but instead I decided to ask Joshua Bloom, a good friend of mine and a graduate student in our department, who is the third author of this paper to write a post instead. What follows is a summary of this paper in Josh's words which I truly appreciate.

Until now, the identification of expression QTLs (eQTLs) has relied on segregating polymorphisms in a population. In this paper the authors develop a new approach for understanding the genetics of mammalian gene expression using a panel of mouse-hamster radiation hybrid cells. The introduction thoroughly describes the history and properties of these cells. In brief, each cell has a different random ~30% of mouse DNA split up into 10Mb fragments in the background of a hamster cell line. The advantages of using this panel is that it has an order of magnitude more breakpoints than mouse recombinant inbred strains and is not susceptible to long stretches of linkage disequilibrium, thus allowing finer localization of regulatory loci.

The idea behind the QTL mapping in the context of radiation hybrids is determining what effect the presence or absence of a copy of a mouse gene has on either its own expression (cis) or on the expression of any other gene (trans) in the genome. As expected, considering known effects of gene dosage on expression, the authors find that most genes show significant cis ceQTLs. However, the effect sizes are not proportional to the increase in gene dosage. Also, the effect sizes for cis ceQTLs on the X chromosome are significantly decreased compared to the effect sizes of cis ceQTLs on autosomes. This suggests that expression of X chromosome genes may be less sensitive to gene dosage. Interestingly, the authors identify ~ 30,000 trans ceQTLs, the majority of which induce the regulated gene. They also identify hotspots of regulation and verify one hotspot with a transfection experiment. Although many of the GO categories enriched in trans ceQTLs were identified as transcription related, many other categories were not.

The significant linkages will be a useful community resource for biologists and this approach provides a new strategy for understanding genetic regulation in mammals.