Huang Jingnan, Marini Federico, Solari Fiorella A, Swieringa Frauke, de Laat Bas, De Simone Ilaria, Grassi Luigi, Gui Xiang, Li Kunpeng, Middleton Elizabeth A, Morgan Neil V, Provenzale Isabella, Santos Carina, Schols Saskia, Westbury Sarah, Sickmann Albert, Rondina Matthew T, Ruf Wolfram, Frontini Mattia, Heemskerk Johan W M
Department of Biochemistry, Maastricht University, Maastricht, The Netherlands.
Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany.
Blood Vessel Thromb Hemost. 2025 Mar 28;2(3):100068. doi: 10.1016/j.bvth.2025.100068. eCollection 2025 Aug.
The hemostatic process relies on platelet and coagulation activation, with additional roles of red blood cells and the vessel wall. By systematic screening of databases for gene-linked information on hemostasis, we collected phenotypic profiles of 3474 orthologous human and mouse genes regarding bleeding, arterial thrombosis, thrombophilia, platelet traits, coagulation, and erythrocytes. Comparisons showed that defects in 252 mouse genes led to increased bleeding combined with platelet dysfunction or thrombocytopenia, in addition to 150 human orthologs that are registered for familial bleeding disorders, based on panel sequencing. Additionally, 139 mouse genes contributed to arterial thrombosis without bleeding phenotype. To further investigate the role of platelets in hemostasis, we integrated multiple genome-wide RNA-sequencing transcriptomes and proteomes from healthy subjects and C57BL/6 mice. This provided reference levels for 54 790 (54 247) transcripts and 6379 (4563) proteins in human (mouse) platelets. Orthologous transcripts in human and mouse platelets correlated with 0.75, whereas orthologous platelet proteins correlated with 0.87. Comparison with the phenotypic analysis revealed the following: (i) overall high qualitative similarity of human and mouse platelets regarding composition and function; (ii) presence of transcripts in platelets for most of the 3474 phenotyped genes; (iii) preponderance of syndromic platelet-expressed genes; and (iv) 20-40% overlap with genes from genome-wide association studies. For 42 mouse genes, among which receptors, signaling proteins, and transcription regulators (ASXL1, ERG, GATA2, MEIS1, NFE2, and TAL1), we confirmed novel links with human platelet function or count. This interspecies comparison can serve as a valuable resource for researchers and clinicians studying the genetics of blood-borne hemostasis and thrombosis.
止血过程依赖于血小板和凝血激活，红细胞和血管壁也发挥辅助作用。通过系统筛选数据库中与止血相关的基因信息，我们收集了3474个人类和小鼠直系同源基因在出血、动脉血栓形成、易栓症、血小板特征、凝血及红细胞方面的表型概况。比较结果显示，252个小鼠基因的缺陷除了导致出血增加外，还伴有血小板功能障碍或血小板减少，此外，基于全外显子组测序，有150个人类直系同源基因被登记为家族性出血性疾病。另外，139个小鼠基因导致动脉血栓形成但无出血表型。为进一步研究血小板在止血中的作用，我们整合了来自健康受试者和C57BL/6小鼠的多个全基因组RNA测序转录组和蛋白质组。这提供了人类（小鼠）血小板中54790（54247）个转录本和6379（4563）种蛋白质的参考水平。人类和小鼠血小板中的直系同源转录本相关性为0.75，而直系同源血小板蛋白相关性为0.87。与表型分析的比较显示：（i）人类和小鼠血小板在组成和功能方面总体上具有高度的质量相似性；（ii）3474个表型基因中的大多数在血小板中有转录本；（iii）综合征性血小板表达基因占优势；（iv）与全基因组关联研究中的基因有20 - 40%的重叠。对于42个小鼠基因，其中包括受体、信号蛋白和转录调节因子（ASXL1、ERG、GATA2、MEIS1、NFE2和TAL1），我们证实了它们与人类血小板功能或数量的新联系。这种种间比较可为研究血源性止血和血栓形成遗传学的研究人员和临床医生提供宝贵资源。
