Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/Universidad de, Santander, Cantabria, Spain.
Bioessays. 2023 Oct;45(10):e2300038. doi: 10.1002/bies.202300038. Epub 2023 May 12.
The interactions between genetic and environmental risk factors contribute to the aetiology of complex human diseases. Genome-wide association studies (GWAS) have revealed that most of the genetic variants associated with complex diseases are located in the non-coding part of the genome, preferentially within enhancers. Enhancers are distal cis-regulatory elements composed of clusters of transcription factors binding sites that positively regulate the expression of their target genes. The generation of genome-wide maps for histone marks (e.g., H3K27ac), chromatin accessibility and transcription factor and coactivator (e.g., p300) binding profiles have enabled the identification of enhancers across many human cell types and tissues. Nonetheless, the functional and pathological consequences of the majority of disease-associated genetic variants located within enhancers seem to be rather minor under normal conditions, thus questioning their medical relevance. Here we propose that, due to the prevalence of enhancer redundancy, the pathological effects of many disease-associated non-coding genetic variants might be preferentially (or even only) manifested under environmental stress.
遗传和环境风险因素之间的相互作用导致了复杂人类疾病的发生。全基因组关联研究（GWAS）表明，与复杂疾病相关的大多数遗传变异位于基因组的非编码部分，优先位于增强子中。增强子是由转录因子结合位点簇组成的远端顺式调控元件，可正向调节其靶基因的表达。组蛋白标记（例如 H3K27ac）、染色质可及性以及转录因子和共激活因子（例如 p300）结合谱的全基因组图谱的生成，使得在许多人类细胞类型和组织中鉴定增强子成为可能。尽管如此，在正常条件下，位于增强子内的大多数与疾病相关的遗传变异的功能和病理后果似乎相当轻微，因此质疑它们的医学相关性。在这里，我们提出，由于增强子冗余的普遍性，许多与疾病相关的非编码遗传变异的病理效应可能主要（甚至仅）在环境压力下表现出来。
