Cheung Vivian G, Ewens Warren J
Department of Pediatrics and Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Genome Res. 2006 Aug;16(8):973-9. doi: 10.1101/gr.5320706. Epub 2006 Jun 29.
Autosomal recessive diseases are those that require mutations in both alleles to exhibit the disorder. Although most recessive conditions are rare, heterozygous carriers of recessive mutations are quite common. In this study, we show that carriers of Nijmegen Breakage Syndrome (NBS) have a distinct gene expression phenotype that differs from that of noncarriers and also from that of carriers of a similar syndrome, Ataxia Telangiectasia (AT). We found 520 genes whose expression levels differ significantly (P < or = 0.001) between NBS carriers and controls. By linear discriminant analysis, we found a combination of 16 genes that allows 100% correct classification of individuals as either NBS carriers or noncarriers in a training set with 25 individuals, and in a test set with 52 individuals. When applied to AT carriers, the discriminant function misclassified only one out of 18 AT carriers as an NBS carrier. Our result shows that NBS carriers have a specific gene expression phenotype. It suggests that heterozygous mutations can contribute significantly to natural variation in gene expression. This has implications for the role that heterozygosity for recessive diseases plays in the overall genetic architecture of complex human traits and diseases.
常染色体隐性疾病是指两个等位基因均发生突变才会表现出病症的疾病。虽然大多数隐性疾病较为罕见，但隐性突变的杂合携带者却相当常见。在本研究中，我们发现尼曼匹克氏症候群（NBS）携带者具有独特的基因表达表型，这一表型既不同于非携带者，也不同于类似综合征共济失调毛细血管扩张症（AT）的携带者。我们发现520个基因在NBS携带者和对照组之间的表达水平存在显著差异（P≤0.001）。通过线性判别分析，我们发现16个基因的组合能够在一个包含25名个体的训练集以及一个包含52名个体的测试集中，将个体100%正确分类为NBS携带者或非携带者。当应用于AT携带者时，判别函数仅将18名AT携带者中的1名误分类为NBS携带者。我们的结果表明NBS携带者具有特定的基因表达表型。这表明杂合突变可能对基因表达的自然变异有显著贡献。这对于隐性疾病的杂合性在复杂人类性状和疾病的整体遗传结构中所起的作用具有重要意义。
