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Genetical Genomics: Spotlight on QTL Hotspots

2008; Public Library of Science; Volume: 4; Issue: 10 Linguagem: Inglês

10.1371/journal.pgen.1000232

1553-7404

Rainer Breitling, Yang Li, Bruno Tesson, Jingyuan Fu, Chunlei Wu, Tim Wiltshire, A.M. Gerrits, Leonid Bystrykh, Gerald de Haan, Andrew I. Su, Ritsert C. Jansen,

Gene expression and cancer classification

Genetical genomics aims at identifying quantitative trait loci (QTLs) for molecular traits such as gene expression or protein levels (eQTL and pQTL, respectively).One of the central concepts in genetical genomics is the existence of hotspots [1], where a single polymorphism leads to widespread downstream changes in the expression of distant genes, which are all mapping to the same genomic locus.Several groups have hypothesized that many genetic polymorphisms-e.g., in major regulators or transcription factors-would lead to large and consistent biological effects that would be visible as eQTL hotspots.Rather surprisingly, however, there have been only very few verified hotspots in published genetical genomics studies to date.In contrast to local eQTLs, which coincide with the position of the gene and are presumably acting in cis-e.g., by polymorphisms in the promoter regiondistant eQTLs have been found to be more elusive.They seem to show smaller effect sizes and are less consistent, perhaps due to the indirect regulation mechanism, resulting in lower statistical power to detect them and, consequently, an inability to reliably delimit hotspots [2].While there are typically hundreds to thousands of strong local eQTLs per study, the number of associated hotspots is much lower.For example, a recent very large association study in about 1,000 humans did not find a single significant hotspot [3].Other studies have reported up to about 30 hotspots, far less than the number of significant local eQTLs (Table 1).The molecular basis is known for less than a handful of cases.An example is the Arabidopsis ERECTA locus, which leads to a drastic phenotypic change in the plant and has broad pleiotropic effects on many molecular (and morphological) traits [4].Recently, Wu et al.[5] reported the large-scale identification of hotspots.They studied gene expression in adipose tissue of 28 inbred mouse strains and performed eQTL analysis by genome-wide association analysis.The paper reports the identification of over 1,600 candidate hotspots, each