Pastinen Tomi, Sladek Robert, Gurd Scott, Sammak Alya'a, Ge Bing, Lepage Pierre, Lavergne Karine, Villeneuve Amelie, Gaudin Tiffany, Brändström Helena, Beck Allon, Verner Andrei, Kingsley Jade, Harmsen Eef, Labuda Damian, Morgan Kenneth, Vohl Marie-Claude, Naumova Anna K, Sinnett Daniel, Hudson Thomas J
McGill University and Genome Quebec Innovation Centre H3A 1A4, Canada.
Physiol Genomics. 2004 Jan 15;16(2):184-93. doi: 10.1152/physiolgenomics.00163.2003.
The identification of human sequence polymorphisms that regulate gene expression is key to understanding human genetic diseases. We report a survey of human genes that demonstrate allelic differences in gene expression, reflecting the presence of putative allele-specific cis-acting factors of either genetic or epigenetic nature. The expression of allelic transcripts in heterozygous samples is assessed directly by relative quantitation of intragenic marker alleles in messenger or heteronuclear RNA derived from cells or tissues. This survey used 193 single-nucleotide polymorphisms (SNPs) from 129 genes expressed in lymphoblastoid cell lines, to identify 23 genes (18%) with common allele-specific transcripts whose expression deviated from the expected equimolar ratio. A subset of these deviations, or "allelic imbalances," can be observed in multiple samples derived from reference CEPH ("Centre d'Etude du Polymorphisme Humain") pedigrees and demonstrate a spectrum of patterns of transmission, including cosegregation of allelic skewing across generations compatible with Mendelian inheritance as well as random monoallelic expression for three genes (IL1A, HTR2A, and FGB). Additional studies for BTN3A2 provide evidence of SNPs and haplotypes in complete linkage disequilibrium with high- and low-expressing transcripts. The pipeline described herein offers tools for efficient identification and characterization of allelic expression allowing identification of regulatory sequence variants as well as epigenetic variation affecting human gene expression.
识别调控基因表达的人类序列多态性是理解人类遗传疾病的关键。我们报告了一项对人类基因的调查，这些基因在基因表达上表现出等位基因差异，反映了可能存在的遗传或表观遗传性质的等位基因特异性顺式作用因子。通过对来自细胞或组织的信使RNA或异核RNA中的基因内标记等位基因进行相对定量，直接评估杂合样本中等位基因转录本的表达。这项调查使用了来自淋巴母细胞系中表达的129个基因的193个单核苷酸多态性（SNP），以鉴定出23个基因（18%），这些基因具有常见的等位基因特异性转录本，其表达偏离了预期的等摩尔比。在来自参考CEPH（“人类多态性研究中心”）家系的多个样本中可以观察到这些偏差的一个子集，即“等位基因失衡”，并展示了一系列传递模式，包括与孟德尔遗传相容的跨代等位基因偏斜的共分离，以及三个基因（IL1A、HTR2A和FGB）的随机单等位基因表达。对BTN3A2的进一步研究提供了与高表达和低表达转录本完全连锁不平衡的SNP和单倍型的证据。本文所述的流程提供了用于有效鉴定和表征等位基因表达的工具，从而能够鉴定调控序列变异以及影响人类基因表达的表观遗传变异。
