Novel Transcriptional Activity and Extensive Allelic Imbalance in the Human MHC Region
Novel Transcriptional Activity and Extensive Allelic Imbalance in the Human MHC Region
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DOI：
10.4049/jimmunol.1701061
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发表时间：
2018-02-15
影响因子：
4.4
通讯作者：
Sawalha, Amr H.
中科院分区：
文献类型：
--
作者：
Gensterblum-Miller, Elizabeth;Wu, Weisheng;Sawalha, Amr H.
MHC区域编码HLA基因，是人类基因组中最复杂的区域。HLA的广泛多态性阻碍了该区域内疾病风险位点的准确定位和功能评估。使用靶向捕获测序和构建个体化基因组进行转录组比对，我们在人类MHC区域内鉴定了908个新的转录本。这些包括593个已知基因的新亚型，137个反义链RNA，119个新的长基因间非编码RNA，和3个新的推定蛋白编码人内源性逆转录病毒基因的5个转录本。我们揭示了等位基因依赖的表达失衡，涉及整个MHC转录组中88%的杂合转录单核苷酸多态性。在这些变异体中，与白塞病相关的HLA-B/云母区域的遗传变异体，其标记HLA-B* 51，在新的长基因间非编码RNA转录物内，其仅从具有保护性等位基因而非疾病风险等位基因的单倍型表达。此外，MHC区域内的转录组可以由14个不同的共表达簇定义，其中至少9个簇中有独特转录因子的共调节证据。我们的数据表明人类MHC的一个非常复杂的调控图谱，并可以帮助揭示该区域疾病风险位点的功能后果。
The MHC region encodes HLA genes and is the most complex region in the human genome. The extensively polymorphic nature of the HLA hinders accurate localization and functional assessment of disease risk loci within this region. Using targeted capture sequencing and constructing individualized genomes for transcriptome alignment, we identified 908 novel transcripts within the human MHC region. These include 593 novel isoforms of known genes, 137 antisense strand RNAs, 119 novel long intergenic noncoding RNAs, and 5 transcripts of 3 novel putative protein-coding human endogenous retrovirus genes. We revealed allele-dependent expression imbalance involving 88% of all heterozygous transcribed single nucleotide polymorphisms throughout the MHC transcriptome. Among these variants, the genetic variant associated with Behcet's disease in the HLA-B/MICA region, which tags HLA-B* 51, is within novel long intergenic noncoding RNA transcripts that are exclusively expressed from the haplotype with the protective but not the disease risk allele. Further, the transcriptome within the MHC region can be defined by 14 distinct coexpression clusters, with evidence of coregulation by unique transcription factors in at least 9 of these clusters. Our data suggest a very complex regulatory map of the human MHC, and can help uncover functional consequences of disease risk loci in this region.