State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College (PUMC), Beijing 100005, China; Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing 100005, China.
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College (PUMC), Beijing 100005, China; Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing 100005, China.
Dev Cell. 2021 Feb 22;56(4):478-493.e11. doi: 10.1016/j.devcel.2020.12.019. Epub 2021 Jan 20.
The human genome harbors 14,000 duplicated or retroposed pseudogenes. Given their functionality as regulatory RNAs and low conservation, we hypothesized that pseudogenes could shape human-specific phenotypes. To test this, we performed co-expression analyses and found that pseudogene exhibited tissue-specific expression, especially in the bone marrow. By incorporating genetic data, we identified a bone-marrow-specific duplicated pseudogene, HBBP1 (η-globin), which has been implicated in β-thalassemia. Extensive functional assays demonstrated that HBBP1 is essential for erythropoiesis by binding the RNA-binding protein (RBP), HNRNPA1, to upregulate TAL1, a key regulator of erythropoiesis. The HBBP1/TAL1 interaction contributes to a milder symptom in β-thalassemia patients. Comparative studies further indicated that the HBBP1/TAL1 interaction is human-specific. Genome-wide analyses showed that duplicated pseudogenes are often bound by RBPs and less commonly bound by microRNAs compared with retropseudogenes. Taken together, we not only demonstrate that pseudogenes can drive human evolution but also provide insights on their functional landscapes.
人类基因组中含有 14000 个重复或反转录的假基因。鉴于它们作为调节 RNA 的功能和低保守性，我们假设假基因可以塑造人类特有的表型。为了验证这一点，我们进行了共表达分析，发现假基因表现出组织特异性表达，特别是在骨髓中。通过整合遗传数据，我们鉴定了一个骨髓特异性重复假基因 HBBP1（η-珠蛋白），它与β-地中海贫血有关。广泛的功能测定表明，HBBP1 通过与 RNA 结合蛋白（RBP）HNRNPA1 结合来上调关键的红细胞生成调节剂 TAL1，从而对红细胞生成至关重要。HBBP1/TAL1 相互作用导致β-地中海贫血患者的症状较轻。比较研究进一步表明，HBBP1/TAL1 相互作用是人类特有的。全基因组分析表明，与反转录假基因相比，重复假基因通常与 RBPs 结合，而与 microRNAs 结合较少。总之，我们不仅证明了假基因可以驱动人类进化，还提供了它们功能景观的见解。
