title: Albuminoid genes: evolving at the interface of dispensability and selection.
abstract: The albuminoid gene family comprises vitamin D-binding protein (GC), alpha-fetoprotein (AFP), afamin (AFM), and albumin (ALB). Albumin is the most abundant human serum protein, and, as the other family members, acts as a transporter of endogenous and exogenous substances including thyroxine, fatty acids, and drugs. Instead, the major cargo of GC is 25-hydroxyvitamin D. We performed an evolutionary study of albuminoid genes and we show that ALB evolved adaptively in mammals. Most positively selected sites are located within albumin-binding sites for fatty acids and thyroxine, as well as at the contact surface with neonatal Fc receptor. Positive selection was also detected for residues forming the prostaglandin-binding pocket. Adaptation to hibernation/torpor might explain the signatures of episodic positive selection we detected for few mammalian lineages. Application of a population genetics-phylogenetics approach showed that purifying selection represented a major force acting on albuminoid genes in both humans and chimpanzees, with the strongest constraint observed for human GC. Population genetic analysis revealed that GC was also the target of locally exerted selective pressure, which drove the frequency increase of different haplotypes in distinct human populations. A search for known variants that modulate GC and 25-hydroxyvitamin D concentrations revealed linkage disequilibrium with positively selected variants, although European and Asian major GC haplotypes carry alleles with reported opposite effect on GC concentration. Data herein indicate that albumin, an extremely abundant housekeeping protein, was the target of pervasive and episodic selection in mammals, whereas GC represented a selection target during the recent evolution of human populations.
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E.MEDEA, Bosisio Parini, Italy manuela.sironi@bp.lnf.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mozzi
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E.MEDEA, Bosisio Parini, Italy manuela.sironi@bp.lnf.it.
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E.MEDEA, Bosisio Parini, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E.MEDEA, Bosisio Parini, Italy.
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E.MEDEA, Bosisio Parini, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Vertemara
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E.MEDEA, Bosisio Parini, Italy Dino Ferrari Centre, Department of Physiopathology and Transplantation, University of Milan, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E.MEDEA, Bosisio Parini, Italy manuela.sironi@bp.lnf.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001665:Binding Sites; D019143:Evolution, Molecular; D005227:Fatty Acids / Q000378:metabolism; D006239:Haplotypes; D006605:Hibernation; D006801:Humans; D015810:Linkage Disequilibrium; D002679:Pan troglodytes; D011453:Prostaglandins / Q000378:metabolism; D011485:Protein Binding; D012641:Selection, Genetic; D012709:Serum Albumin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000075462:Serum Albumin, Human; D013974:Thyroxine / Q000378:metabolism; D014809:Vitamin D-Binding Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C097353:AFP protein, human; C422455:ALB protein, human; D005227:Fatty Acids; D011453:Prostaglandins; D012709:Serum Albumin; D014809:Vitamin D-Binding Protein; D000509:alpha-Fetoproteins; D013974:Thyroxine; D000075462:Serum Albumin, Human
keywords: albumin; albuminoids; hibernation; positive selection; vitamin D; vitamin D-binding protein