The Endocrine Genetics Laboratory, Departments of Pediatrics and Human Genetics, the Research Institute of the McGill University Health Centre, The Montreal Children's Hospital, Montréal, Québec, Canada.
J Med Genet. 2012 Sep;49(9):554-7. doi: 10.1136/jmedgenet-2012-101199.
Much progress has been made in determining loci where gene expression at the steady-state mRNA level is controlled by genetic variants in cis. However, mRNA is only a proxy for what matters in phenotypic variation, which is protein level. We set out to review the evidence for exonic polymorphisms that affect translation of mRNA.
Informal literature review.
There is ample literature on monogenic diseases caused by rare mutations in translationally active mRNA elements. Such mutations may eliminate or create AUG initiation codons or alter the Kozak sequences surrounding them, alter RNA secondary structure, destroy or enhance internal ribosomal entry sequences or Fe-response elements. By contrast, examples of complex phenotypes determined by common polymorphisms in these elements are scarce, although reports (to be confirmed) of functionally polymorphic miRNA binding sites are beginning to appear.
Given the methodological limitations of detecting these translational effects, we posit that existing knowledge of such effects in common complex phenotypes represent the 'tip of the iceberg'. High-throughput quantitative proteomics is beginning to offer a promise to explore this possibility.
在确定基因表达的稳态 mRNA 水平受顺式遗传变异控制的基因座方面已经取得了很大进展。然而，mRNA 只是表型变异的一个替代物，而蛋白质水平才是关键。我们旨在综述影响 mRNA 翻译的外显子多态性的证据。
非正式文献综述。
有大量关于由翻译活性 mRNA 元件中的罕见突变引起的单基因疾病的文献。此类突变可能消除或创建 AUG 起始密码子，或改变其周围的 Kozak 序列，改变 RNA 二级结构，破坏或增强内部核糖体进入序列或 Fe 反应元件。相比之下，由这些元件中的常见多态性决定的复杂表型的例子很少，尽管开始出现功能多态性 miRNA 结合位点的报道（有待证实）。
鉴于检测这些翻译效应的方法学限制，我们假设在常见复杂表型中已经存在这些效应的知识仅代表“冰山一角”。高通量定量蛋白质组学开始提供探索这种可能性的希望。
