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Nature:自体免疫疾病之间的基因差异

摘要 : 自体免疫的数百个风险位点以前在全基因组关联研究(GWASs)中已被识别出,但所涉及位点包括 “连锁不平衡”中的多种变异体,并且很少改变蛋白编码序列,这使得对它们的解读变得复杂化。

 自体免疫的数百个风险位点以前在全基因组关联研究(GWASs)中已被识别出,但所涉及位点包括 “连锁不平衡”中的多种变异体,并且很少改变蛋白编码序列,这使得对它们的解读变得复杂化。

这项研究采用一个新方法来详细分析21种自体免疫疾病的致病基因变异体,将一个新算法应用于基于GWAS的位点,并针对专门化的免疫细胞将基因型数据与表观基因组图进行整合。

结果表明,增强子的一个非常有针对性的子类参与了T-细胞刺激,充当自体免疫疾病的致病性决定因子。

nature13835-f1

原文链接:

Genetic and epigenetic fine mapping of causal autoimmune disease variants

Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4+ T-cell subsets, regulatory T cells, CD8+ T cells, B cells, and monocytes. We find that ~90% of causal variants are non-coding, with ~60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10–20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

doi:10.1038/nature13835

Epigenomics: Roadmap for regulation

doi:10.1038/518314a

对应Nature杂志: 2015年02月19日Nature杂志精选

来源: Nature 浏览次数:74

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