title: A refined model of the genomic basis for phenotypic variation in vertebrate hemostasis.
abstract: BACKGROUND
  Hemostasis is a defense mechanism that enhances an organism's survival by minimizing blood loss upon vascular injury. In vertebrates, hemostasis has been evolving with the cardio-vascular and hemodynamic systems over the last 450 million years. Birds and mammals have very similar vascular and hemodynamic systems, thus the mechanism that blocks ruptures in the vasculature is expected to be the same. However, the speed of the process varies across vertebrates, and is particularly slow for birds. Understanding the differences in the hemostasis pathway between birds and mammals, and placing them in perspective to other vertebrates may provide clues to the genetic contribution to variation in blood clotting phenotype in vertebrates. We compiled genomic data corresponding to key elements involved in hemostasis across vertebrates to investigate its genetic basis and understand how it affects fitness.
  
  
  RESULTS
  We found that: i) fewer genes are involved in hemostasis in birds compared to mammals; and ii) the largest differences concern platelet membrane receptors and components from the kallikrein-kinin system. We propose that lack of the cytoplasmic domain of the GPIb receptor subunit alpha could be a strong contributor to the prolonged bleeding phenotype in birds. Combined analysis of laboratory assessments of avian hemostasis with the first avian phylogeny based on genomic-scale data revealed that differences in hemostasis within birds are not explained by phylogenetic relationships, but more so by genetic variation underlying components of the hemostatic process, suggestive of natural selection.
  
  
  CONCLUSIONS
  This work adds to our understanding of the evolution of hemostasis in vertebrates. The overlap with the inflammation, complement and renin-angiotensin (blood pressure regulation) pathways is a potential driver of rapid molecular evolution in the hemostasis network. Comparisons between avian species and mammals allowed us to hypothesize that the observed mammalian innovations might have contributed to the diversification of mammals that give birth to live young.
authors.affiliation: Interdisciplinary Centre of Marine and Environmental Research-CIIMAR/CIMAR, University of Porto, Rua dos Bragas 289, 4050-123, Porto, Portugal. ribeiro.angela@gmail.com.
authors.forename: Ângela M
authors.initials: ÂM
authors.lastname: Ribeiro
authors.affiliation: Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Øster Voldgade 5-7, 1350, Copenhagen, Denmark. lisandracady@gmail.com.
authors.forename: M Lisandra
authors.initials: ML
authors.lastname: Zepeda-Mendoza
authors.affiliation: Centre for Zoo and Wild Animal Health, Copenhagen Zoo, Roskildevej 38, 2000, Frederiksberg, Denmark. MFB@zoo.dk.
authors.forename: Mads F
authors.initials: MF
authors.lastname: Bertelsen
authors.affiliation: Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870, Frederiksberg C, Denmark. atk@sund.ku.dk.
authors.forename: Annemarie T
authors.initials: AT
authors.lastname: Kristensen
authors.affiliation: Department of Neurobiology, Duke University Medical Centre, Durham, NC, 27710, USA. jarvis@neuro.duke.edu.|Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA. jarvis@neuro.duke.edu.
authors.forename: Erich D
authors.initials: ED
authors.lastname: Jarvis
authors.affiliation: Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Øster Voldgade 5-7, 1350, Copenhagen, Denmark. mtpgilbert@gmail.com.|Trace and Environmental DNA Laboratory, Department of Environment and Agriculture, Curtin University, Perth, WA, 6102, Australia. mtpgilbert@gmail.com.
authors.forename: M Thomas P
authors.initials: MT
authors.lastname: Gilbert
authors.affiliation: Interdisciplinary Centre of Marine and Environmental Research-CIIMAR/CIMAR, University of Porto, Rua dos Bragas 289, 4050-123, Porto, Portugal. fonseca@binf.ku.dk.|Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Øster Voldgade 5-7, 1350, Copenhagen, Denmark. fonseca@binf.ku.dk.|The Bioinformatics Centre, University of Copenhagen, Copenhagen, Denmark. fonseca@binf.ku.dk.
authors.forename: Rute R
authors.initials: RR
authors.lastname: da Fonseca
mesh_terms: D000818:Animals; D005075:Biological Evolution; D001717:Birds / Q000145:classification / Q000235:genetics / Q000502:physiology; D001779:Blood Coagulation Factors / Q000235:genetics / Q000502:physiology; D019143:Evolution, Molecular; D014644:Genetic Variation; D006487:Hemostasis; D010802:Phylogeny; D012641:Selection, Genetic; D014714:Vertebrates / Q000145:classification* / Q000235:genetics*
chemical_list: D001779:Blood Coagulation Factors