Wilkins James M, Southam Lorraine, Price Andrew J, Mustafa Zehra, Carr Andrew, Loughlin John
University of Oxford, Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford OX3 7LD, UK.
Hum Mol Genet. 2007 Mar 1;16(5):537-46. doi: 10.1093/hmg/ddl488. Epub 2007 Jan 12.
Variability in cis-regulation of gene expression has been implicated in the phenotypic manifestation of complex traits including common, multifactorial diseases. The differential expression of alleles due to polymorphism in cis-regulatory elements is common in the human genome, but there is a paucity of information about the context specificity of these control elements. In this study, we examined the differential allelic expression (DAE) of BMP5 in human mesenchymal tissues obtained from 16 donors undergoing joint replacement for treatment of osteoarthritis. We observed significant differences in BMP5 allelic output, with allelic ratios greater than 4:1 (P < 10(-20)) in the tissues of some donors. We also discovered a significant variability in allelic expression within the different tissues of donors. For 12 of our donors, we examined the allelic expression of BMP5 in two different regions of cartilage: cartilage adjacent to the site of the osteoarthritic lesion and cartilage distal from the lesion. Five of these 12 donors demonstrated highly significant differences (P < or = 10(-8)) in allelic expression between the different regions of their cartilage. Using DAE as a phenotype, we attempted to map tissue-specific cis-regulatory polymorphisms, and we identified a single nucleotide polymorphism located downstream of BMP5, which was significantly associated with DAE in some but not all of the examined tissues. These findings suggest that allelic expression can be highly context specific and that when interrogating the cis-regulatory control of a particular gene, one cannot necessarily assume that allelic expression is conserved across different tissues or even across different regions of the same tissue.
基因表达顺式调控的变异性与包括常见多因素疾病在内的复杂性状的表型表现有关。由于顺式调控元件中的多态性导致的等位基因差异表达在人类基因组中很常见，但关于这些调控元件的上下文特异性的信息却很少。在本研究中，我们检测了从16名因骨关节炎接受关节置换手术的供体获取的人间充质组织中BMP5的差异等位基因表达（DAE）。我们观察到BMP5等位基因输出存在显著差异，在一些供体的组织中等位基因比率大于4:1（P < 10(-20)）。我们还发现供体不同组织内等位基因表达存在显著变异性。对于我们的12名供体，我们检测了BMP5在软骨两个不同区域的等位基因表达：骨关节炎病变部位附近的软骨和远离病变的软骨。这12名供体中有五名在其软骨的不同区域之间的等位基因表达显示出高度显著差异（P ≤ 10(-8)）。以DAE作为表型，我们试图定位组织特异性的顺式调控多态性，并且我们鉴定出一个位于BMP5下游的单核苷酸多态性，其在一些但并非所有检测组织中与DAE显著相关。这些发现表明等位基因表达可能具有高度的上下文特异性，并且在研究特定基因的顺式调控时，不能必然假设等位基因表达在不同组织甚至同一组织的不同区域之间是保守的。
