- Comparative genomic analysis of eutherian fibroblast growth factor genes. - Background: The eutherian fibroblast growth factors were implicated as key regulators in developmental. - However, there were major disagreements in descriptions of comprehensive eutherian fibroblast growth factors gene data sets including either 18 or 22 homologues. - The present analysis attempted to revise and update comprehensive eutherian fibroblast growth factor gene data sets, and address and resolve major discrepancies in their descriptions using eutherian comparative genomic analysis protocol and 35 public eutherian reference genomic sequence data sets.. - Results: Among 577 potential coding sequences, the tests of reliability of eutherian public genomic sequences annotated most comprehensive curated eutherian third-party data gene data set of fibroblast growth factor genes including 267 complete coding sequences. - The present study first described 8 superclusters including 22 eutherian fibroblast growth factor major gene clusters, proposing their updated classification and nomenclature.. - Conclusions: The integrated gene annotations, phylogenetic analysis and protein molecular evolution analysis argued that comprehensive eutherian fibroblast growth factor gene data set classifications included 22 rather than 18 homologues.. - The eutherian fibroblast growth factors or FGFs were implicated as key developmental regulators [1–3]. - Sec- ond, there were 3 endocrine fibroblast growth factors FGF19, FGF21 and FGF23 binding FGFRs and klotho protein cofactors . - Third, the 4 intracellular fibroblast growth factors named fibroblast homologous factors in- cluded FGF11 or FHF3, FGF12 or FHF1, FGF13 or FHF2 and FGF14 or FGF . - However, there were major disagreements in descriptions of comprehensive eutherian FGF gene data sets. - On the other hand, the eutherian FGF classifications by Goldfarb [1]. - Therefore, the present analysis attempted to revise and update comprehensive eutherian FGF gene data sets, and address and resolve major disagreements in their descriptions using eutherian comparative genomic ana- lysis protocol and 35 public eutherian reference genomic sequence data sets.. - The most comprehensive curated eutherian FGF third-party data gene data set was deposited in European Nucleotide Archive under accessions: LR130242-LR . - The present study first described 8 superclusters FGF1–8 including 22 major gene clusters of eutherian FGF genes, proposing their updated nomenclature (Fig.. - The eutherian FGF genes included ei- ther 5 coding exons (5 major gene clusters FGF1A-D. - Therefore, the present study annotating 22 eutherian FGF major gene clusters agreed with Goldfarb [1] and Ornitz and Itoh [3] but disagreed with Belov and Mohammadi [2] and Beenken and Mohammadi [7].. - 1) and calculations of pairwise nucleotide sequence identity patterns (Additional file 3) first classi- fied 22 eutherian FGF major gene clusters among 8. - 1 Phylogenetic analysis of eutherian fibroblast growth factor genes. - [13], Coulier et al. - [28] but dis- agreed with phylogenetic analyses of Ornitz and Itoh [3, 21], Coulier et al. - Indeed, the calculations of pairwise nucleotide se- quence identity patterns confirmed present phylogenetic classification of eutherian FGF genes (Additional file 3).. - The eutherian FGF gene data set included average pair- wise nucleotide sequence identity ā = 0,3 (a max = 1, a min = 0,115, ā ad . - Among 22 eutherian FGF major gene clusters re- spectively, there were nucleotide sequence identity pat- terns of very close eutherian orthologues (FGF1A-B, FGF4B), close eutherian orthologues (FGF1C-D, FGF2A- B, FGF4A, FGF4C, FGF5B, FGF6A, FGF7B), typical eu- therian orthologues (FGF3A, FGF5A, FGF5C-D, FGF6B- C, FGF7A, FGF8A, FGF8C) and distant eutherian ortho- logues (FGF8B). - Finally, in comparisons between eutherian FGF major gene clusters between superclusters, there. - Therefore, the present phylogenetic analysis proposed updated classification of eutherian FGF genes.. - The protein molecular evolution analysis used protein primary structure features as major alignment landmarks in eutherian FGF protein amino acid sequence align- ments, including common cysteine amino acid residues, common exon-intron splice site amino acid sites and common predicted N-glycosylation sites (Fig. - There were between 1 and 9 common cysteine amino acid residues included among eutherian FGF major protein clusters respectively. - For example, whereas the major protein cluster FGF5D included 1 common cysteine amino acid residue, major protein cluster FGF5A included 9 common cysteine amino acid residues. - There were either 4 common exon-intron splice site amino acid sites (5 major protein clusters FGF1A-D and FGF6A) or 2 common exon-intron splice site amino acid sites (17 other major protein clusters) among eutherian FGF major protein clusters respect- ively. - Finally, there were between 0 and 2 common pre- dicted N-glycosylation sites among eutherian FGF major protein clusters respectively.. - Next, the tests of protein molecular evolution first cal- culated relative synonymous codon usage statistics (R) of eutherian FGF gene data set using 267 FGF complete coding sequences (Additional file 4), and described 20 amino acid codons including R ≤ 0,7 as not preferable amino acid codons (Fig. - The tests used human FGF1A protein primary structure as reference protein amino acid sequence (Fig. - Among 243 human FGF1A protein amino acid residues, the tests of protein molecular evolution described 19 invariant amino acid sites, viz.: M1, C41, C55, P68, Q69, L70, K71, G72, I73, V74, T75, L77, G112, M129, G133, C145, Y159, G181 and C206, as well as 3 forward amino acid sites S101, E149 and Y208. - First, the human FGF1A amino acid sites M1, L77, G133, C145 and Y159 were invariant among 267 eutherian FGF protein primary structures (except that M1 was invariant among 266 FGF protein primary structures). - For example, the human FGF1A in- variant amino acid sites L77, G133 and C145 were de- scribed by Goetz et al. - [12, 24], Smallwood et al. - [17], Venkataraman et al. - [18], Plotnikov et al. - Furthermore, the human FGF1A amino acid sites G112 and M129 respectively were invariant among 21 eutherian FGF major protein clusters. - For example, the human FGF1A amino acid site G112 was homologous to human FGF2B amino amino acid site G67 that was implicated in interactions between FGF2B ligand and FGFR2 receptor [19, 20]. - the human FGF1A amino acid site G181 that was invari- ant among 7 eutherian FGF1–7 protein superclusters was described as first glycine amino acid residue in para- crine FGF glycine box protein amino acid sequence motif G-x(4)-G-x(2)-S/T [2]. - The human FGF1A amino acid sites P68, Q69, L70, K71, G72, I73, V74 and T75 were invariant among 4 eutherian FGF1A-D major pro- tein clusters. - For example, the human FGF1A amino acid sites K71 and I73 were described as residues en- gaged in voltage-gated sodium channel binding [24]. - Fi- nally, the human FGF1A forward amino acid sites S101 and E149 were described among 267 eutherian FGF pro- tein primary structures, and forward amino acid site Y208 was described among 2 eutherian FGF1–2 protein. - For example, the human FGF1A forward amino acid site E149 was homologous to human FGF2A amino amino acid site E105 that was implicated in hydrogen bonding between FGF2A ligand and D3 do- main of FGFR2 receptor [19, 26].. - Therefore, the tests of protein molecular evolution using relative synonymous codon usage statistics de- scribed amino acid sites implicated as critical in FGF protein secondary, tertiary and quaternary structural features.. - The major disagreements in descriptions of comprehen- sive eutherian FGF gene data sets included classifications. - 2 Major landmarks in eutherian fibroblast growth factor protein sequence alignments. - The black squares labelled common cysteine amino acid residues. - The grey squares labelled common exon-intron splice site amino acid sites. - The numbers indicated numbers of amino acid residues. - Second, the present study first described 8 superclusters of eutherian FGF genes that included 22 major gene clusters, proposing their updated nomencla- ture. - Fourth, the present phylogenetic ana- lysis proposed updated classification of eutherian FGF genes. - 3 Tests of protein molecular evolution of eutherian fibroblast growth factors. - a Relative synonymous codon usage statistics of eutherian FGF gene data set. - The not preferable amino acid codons were indicated by white letters on red backgrounds. - Counts, observed amino acid codon counts. - b Reference human FGF1A protein amino acid sequence. - The 19 invariant amino acid sites were shown using white letters on violet backgrounds. - Whereas the 5 amino acid sites that were invariant among 22 FGF major protein clusters were indicated by black arrows (except that M1 was invariant among 266 FGF protein primary structures), grey arrows indicated 2 amino acid sites that were invariant among 21 FGF major protein clusters respectively. - The 3 forward amino acid sites were shown using white letters on red backgrounds. - The stars labelled 2 forward amino acid sites described among 22 FGF major protein clusters. - using relative synonymous codon usage statistics de- scribed 19 invariant amino acid sites and 3 forward amino acid sites in reference human FGF1A protein pri- mary structure, including amino acid residues described as critical in FGF protein secondary, tertiary and quater- nary structural features. - The protocol used guidelines of human gene nomenclature [61] and guidelines of mouse gene nomenclature [62] in updated eutherian FGF gene classification and nomenclature.. - Third, the protocol used new genomics tests of contiguity of eutherian public genomic sequences in eutherian FGF gene annotations. - The protocol used protein and nucleotide sequence alignments, calculations of phylogenetic trees, calcula- tions of pairwise nucleotide sequence identities and ana- lysis of differential gene expansions in phylogenetic analysis of eutherian FGF gene data set. - First, using BioEdit 7.0.5.3, the protocol translated FGF complete coding sequences, and aligned them at amino acid level using ClustalW implemented in BioEdit 7.0.5.3. - The Microsoft Office Excel common statistical functions were used in calculations of pairwise nucleo- tide sequence identity patterns of eutherian FGF gene data set. - The protocol used analysis of FGF protein amino acid sequence features and tests of protein molecular evolu- tion integrating patterns of FGF nucleotide sequence similarities with FGF protein primary structures in pro- tein molecular evolution analysis. - Among eutherian FGF complete coding sequences, the average number of codons was 219. - Using MEGA 6.06, the rela- tive synonymous codon usage statistics were calculated as ratios between observed and expected amino acid codon counts (R = Counts / Expected counts). - The protocol then described 20 amino acid codons including R ≤ 0,7 as not preferable amino acid codons, viz.: TTA, TTG, CTT, CTA, ATA, GTT, GTA, TCA, TCG, CCG, ACG, GCG, TAT, CAT, CAA, GAT, TGT, CGT, CGA, GGT (Fig. - Finally, the protocol described reference human FGF1A protein sequence amino acid sites as in- variant amino acid sites (invariant alignment positions), forward amino acid sites (variant alignment positions that did not include amino acid codons with R ≤ 0,7) or compensatory amino acid sites (variant alignment posi- tions that included amino acid codons with R ≤ 0,7).. - Third-party data gene data set of eutherian fibroblast growth factor genes.. - Additional file 2 Multiple pairwise genomic sequence alignments of eutherian fibroblast growth factor genes. - Pairwise nucleotide sequence identity patterns of eutherian fibroblast growth factor genes.. - Protein amino acid sequence alignments of eutherian fibroblast growth factors. - The amino acid positions were labelled using white letters on black background (100% sequence identity level), white letters on dark grey background. - The 19 invariant amino acid sites were shown using white letters on violet backgrounds and 3 forward amino acid sites were shown using white letters on red backgrounds in reference human FGF1A protein primary structure (top). - FGF: Fibroblast growth factor. - FGF1–8 : Eutherian fibroblast growth factor gene superclusters. - The original curated third-party data gene data set including 267 eutherian FGF complete coding sequences was deposited in European Nucleotide Archive under accessions: LR130242-LR130508 [47]. - The public eutherian reference genomic sequence data sets (Additional file 1) were available in NCBI GenBank [51, 52] and Ensembl [54].. - Fibroblast growth factor homologous factors: evolution, structure, and function. - Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology. - The fibroblast growth factor signaling pathway. - Fibroblast growth factor signaling in skeletal development and disease. - Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. - Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development. - Signaling by fibroblast growth factors: the inside story. - Fibroblast growth factor homologous factors are intracellular signaling proteins. - Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels. - Of worms and men: an evolutionary perspective on the fibroblast growth factor (FGF) and FGF receptor families. - Molecular characteristics of fibroblast growth factor-fibroblast growth factor receptor- heparin-like glycosaminoglycan complex. - Structural interactions of fibroblast growth factor receptor with its ligands. - Fibroblast growth factors. - Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs. - Crystal structure of a fibroblast growth factor homologous factor (FHF) defines a conserved surface on FHFs for binding and modulation of voltage-gated sodium channels. - Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease
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