https://orcid.org/0000-0001-6471-8693
Key points
Multiple mouse genes regulating bleeding and platelet traits contribute to human hemostasis
Combined assessment of orthologous human and mouse platelet transcriptomes and proteomes reveals roles in hemostasis
Abstract
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 3,474 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, on top of the 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-seq transcriptomes and proteomes from healthy subjects and C57BL/6 mice. This provided reference levels for 54,790 (54,247) transcripts and 6,379 (4,563) proteins in human (mouse) platelets. Orthologous transcripts in human and mouse platelets correlated with R=0.75, while orthologous platelet proteins correlated with R=0.87. Comparison with the phenotypic analysis revealed: (i) overall high qualitative similarity of human and mouse platelets regarding composition and function; (ii) presence of transcripts in platelets of most 3,474 phenotyped genes; (iii) preponderance of syndromic platelet-expressed genes; (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, TAL1), we confirmed novel links with human platelet function or count. This inter-species comparison can serve as a valuable resource for researchers and clinicians studying the genetics of blood-borne hemostasis and thrombosis.
Author notes
Equal contribution
Data Sharing Statement: All raw data are deposited on sites as indicated in the supplementary materials. All derived primary are incorporated as datafiles (currently shortened versions, complete versions to add on request of the editor)
