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VKORC1 and VKORC1L1: Why do Vertebrates Have Two Vitamin K 2,3-Epoxide Reductases?

Oldenburg J, Watzka M, Bevans CG - Nutrients (2015)

Bottom Line: Despite single gene and whole genome duplications on the largest evolutionary timescales, and the fact that most gene duplications eventually result in loss of one copy, it is surprising that all jawed vertebrates (gnathostomes) have retained two paralogous VKOR genes.In particular, we look to published studies about tissue- and developmental stage-specific expression, enzymatic function, phylogeny, biological roles and associated pathways that together suggest subfunctionalization as a major influence in evolutionary fixation of both paralogs.Additionally, we investigate on what evolutionary timescale the paralogs arose and under what circumstances in order to gain insight into the biological raison d'être for both VKOR paralogs in gnathostomes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn 53105, Germany. johannes.oldenburg@ukb.uni-bonn.de.

ABSTRACT
Among all cellular life on earth, with the exception of yeasts, fungi, and some prokaryotes, VKOR family homologs are ubiquitously encoded in nuclear genomes, suggesting ancient and important biological roles for these enzymes. Despite single gene and whole genome duplications on the largest evolutionary timescales, and the fact that most gene duplications eventually result in loss of one copy, it is surprising that all jawed vertebrates (gnathostomes) have retained two paralogous VKOR genes. Both VKOR paralogs function as entry points for nutritionally acquired and recycled K vitamers in the vitamin K cycle. Here we present phylogenetic evidence that the human paralogs likely arose earlier than gnathostomes, possibly in the ancestor of crown chordates. We ask why gnathostomes have maintained these paralogs throughout evolution and present a current summary of what we know. In particular, we look to published studies about tissue- and developmental stage-specific expression, enzymatic function, phylogeny, biological roles and associated pathways that together suggest subfunctionalization as a major influence in evolutionary fixation of both paralogs. Additionally, we investigate on what evolutionary timescale the paralogs arose and under what circumstances in order to gain insight into the biological raison d'être for both VKOR paralogs in gnathostomes.

No MeSH data available.


Reconstructed phylogeny (unrooted) for full-length sequences of index metazoans using PhyML with a WAG+I+G4 substitution model in the IQ-TREE ver1.2.3 server-based phylogenetics package with graphics generated using the iToL server (see Bevans et al. [20] in this Special Issue for details). Linnaean taxonomic names and primary sequence lengths are shown to the right; groupings shown on the left: Placozoa, basal invertebrate outgroup; Echinodermata and Hemichordata, basal deuterostomes belonging to the Ambulacaria; Cnidaria, basal metazoan invertebrates including jellyfish and sea anemonae; Urochordata, an invertebrate sister group to vertebrates; Porifera, basal non-metazoan animals including sponges; Ctenophora, basal non-bileterian metazoans including comb jellies; Cephalochordata, a basal chordate sister group to Olfactores which includes Urochordata and vertebrates; Chordates includes Cephalochordates, Tunicates (here represented by the Urochordate Ciona intestinalis) and Vertebrates; Gnathostomes are a subgroup of vertebrates with jaw bones that includes Chondrichthyes (sharks and rays—not included among the analyzed sequences; see Note 2 [54]) and Osteichthyes (bony fishes and tetrapods); VKORC1 and VKORC1L1 are paralog clades for Gnathostomes. Scale bar (upper left, labeled 0.1) represents single nucleotide substitution rate per million years; VKORC1 clade is represented by red lines, VKORC1L1 clade by cyan lines; numbers on branches are % support for 1000 bootstrap trees. VKOR paralogs encoded by non-gnathostome genomes are shown in blue (Hemichordata), orange (Cephalochordata) and green (Cnidaria) (see also Note 3 [55]).
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nutrients-07-05280-f002: Reconstructed phylogeny (unrooted) for full-length sequences of index metazoans using PhyML with a WAG+I+G4 substitution model in the IQ-TREE ver1.2.3 server-based phylogenetics package with graphics generated using the iToL server (see Bevans et al. [20] in this Special Issue for details). Linnaean taxonomic names and primary sequence lengths are shown to the right; groupings shown on the left: Placozoa, basal invertebrate outgroup; Echinodermata and Hemichordata, basal deuterostomes belonging to the Ambulacaria; Cnidaria, basal metazoan invertebrates including jellyfish and sea anemonae; Urochordata, an invertebrate sister group to vertebrates; Porifera, basal non-metazoan animals including sponges; Ctenophora, basal non-bileterian metazoans including comb jellies; Cephalochordata, a basal chordate sister group to Olfactores which includes Urochordata and vertebrates; Chordates includes Cephalochordates, Tunicates (here represented by the Urochordate Ciona intestinalis) and Vertebrates; Gnathostomes are a subgroup of vertebrates with jaw bones that includes Chondrichthyes (sharks and rays—not included among the analyzed sequences; see Note 2 [54]) and Osteichthyes (bony fishes and tetrapods); VKORC1 and VKORC1L1 are paralog clades for Gnathostomes. Scale bar (upper left, labeled 0.1) represents single nucleotide substitution rate per million years; VKORC1 clade is represented by red lines, VKORC1L1 clade by cyan lines; numbers on branches are % support for 1000 bootstrap trees. VKOR paralogs encoded by non-gnathostome genomes are shown in blue (Hemichordata), orange (Cephalochordata) and green (Cnidaria) (see also Note 3 [55]).

Mentions: Robertson (2004) previously suggested that an ancestral VKOR gene duplication likely occurred in early vertebrates and resulted in the extant human and other gnathostome VKOR paralogs [3]. This would be in agreement with the divergence of the common ancestor of the jawed vertebrates (gnathostomes) from urochordates and cephalochordates, as has been suggested for many other vertebrate protein paralog pairs [53]. In the article by Bevans et al. [20] in this special issue, a broad phylogenetic study of VKOR family homologs yielded strong support for distinct monophyletic clades comprising vertebrate VKORC1 and VKORC1L1 homologs. Thus, it is likely that the paralogs arose one time and quickly became fixed in the genomes of subsequently diverged early (crown) vertebrate lineages. That all extant gnathostome genomes sequenced to date include both paralog genes suggests that the functions of both paralogs are indispensable to vertebrate life. In order to more accurately confirm the divergence point of the last common ancestor of modern vertebrates with two VKOR family paralogs, we chose a series of index genomes sampling various evolutionary groupings that diverged before, during and after the last universal common ancestor of gnathostomes, many only very recently sequenced in draft form, to reconstruct a likely metazoan VKOR phylogeny (Figure 2).


VKORC1 and VKORC1L1: Why do Vertebrates Have Two Vitamin K 2,3-Epoxide Reductases?

Oldenburg J, Watzka M, Bevans CG - Nutrients (2015)

Reconstructed phylogeny (unrooted) for full-length sequences of index metazoans using PhyML with a WAG+I+G4 substitution model in the IQ-TREE ver1.2.3 server-based phylogenetics package with graphics generated using the iToL server (see Bevans et al. [20] in this Special Issue for details). Linnaean taxonomic names and primary sequence lengths are shown to the right; groupings shown on the left: Placozoa, basal invertebrate outgroup; Echinodermata and Hemichordata, basal deuterostomes belonging to the Ambulacaria; Cnidaria, basal metazoan invertebrates including jellyfish and sea anemonae; Urochordata, an invertebrate sister group to vertebrates; Porifera, basal non-metazoan animals including sponges; Ctenophora, basal non-bileterian metazoans including comb jellies; Cephalochordata, a basal chordate sister group to Olfactores which includes Urochordata and vertebrates; Chordates includes Cephalochordates, Tunicates (here represented by the Urochordate Ciona intestinalis) and Vertebrates; Gnathostomes are a subgroup of vertebrates with jaw bones that includes Chondrichthyes (sharks and rays—not included among the analyzed sequences; see Note 2 [54]) and Osteichthyes (bony fishes and tetrapods); VKORC1 and VKORC1L1 are paralog clades for Gnathostomes. Scale bar (upper left, labeled 0.1) represents single nucleotide substitution rate per million years; VKORC1 clade is represented by red lines, VKORC1L1 clade by cyan lines; numbers on branches are % support for 1000 bootstrap trees. VKOR paralogs encoded by non-gnathostome genomes are shown in blue (Hemichordata), orange (Cephalochordata) and green (Cnidaria) (see also Note 3 [55]).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4555119&req=5

nutrients-07-05280-f002: Reconstructed phylogeny (unrooted) for full-length sequences of index metazoans using PhyML with a WAG+I+G4 substitution model in the IQ-TREE ver1.2.3 server-based phylogenetics package with graphics generated using the iToL server (see Bevans et al. [20] in this Special Issue for details). Linnaean taxonomic names and primary sequence lengths are shown to the right; groupings shown on the left: Placozoa, basal invertebrate outgroup; Echinodermata and Hemichordata, basal deuterostomes belonging to the Ambulacaria; Cnidaria, basal metazoan invertebrates including jellyfish and sea anemonae; Urochordata, an invertebrate sister group to vertebrates; Porifera, basal non-metazoan animals including sponges; Ctenophora, basal non-bileterian metazoans including comb jellies; Cephalochordata, a basal chordate sister group to Olfactores which includes Urochordata and vertebrates; Chordates includes Cephalochordates, Tunicates (here represented by the Urochordate Ciona intestinalis) and Vertebrates; Gnathostomes are a subgroup of vertebrates with jaw bones that includes Chondrichthyes (sharks and rays—not included among the analyzed sequences; see Note 2 [54]) and Osteichthyes (bony fishes and tetrapods); VKORC1 and VKORC1L1 are paralog clades for Gnathostomes. Scale bar (upper left, labeled 0.1) represents single nucleotide substitution rate per million years; VKORC1 clade is represented by red lines, VKORC1L1 clade by cyan lines; numbers on branches are % support for 1000 bootstrap trees. VKOR paralogs encoded by non-gnathostome genomes are shown in blue (Hemichordata), orange (Cephalochordata) and green (Cnidaria) (see also Note 3 [55]).
Mentions: Robertson (2004) previously suggested that an ancestral VKOR gene duplication likely occurred in early vertebrates and resulted in the extant human and other gnathostome VKOR paralogs [3]. This would be in agreement with the divergence of the common ancestor of the jawed vertebrates (gnathostomes) from urochordates and cephalochordates, as has been suggested for many other vertebrate protein paralog pairs [53]. In the article by Bevans et al. [20] in this special issue, a broad phylogenetic study of VKOR family homologs yielded strong support for distinct monophyletic clades comprising vertebrate VKORC1 and VKORC1L1 homologs. Thus, it is likely that the paralogs arose one time and quickly became fixed in the genomes of subsequently diverged early (crown) vertebrate lineages. That all extant gnathostome genomes sequenced to date include both paralog genes suggests that the functions of both paralogs are indispensable to vertebrate life. In order to more accurately confirm the divergence point of the last common ancestor of modern vertebrates with two VKOR family paralogs, we chose a series of index genomes sampling various evolutionary groupings that diverged before, during and after the last universal common ancestor of gnathostomes, many only very recently sequenced in draft form, to reconstruct a likely metazoan VKOR phylogeny (Figure 2).

Bottom Line: Despite single gene and whole genome duplications on the largest evolutionary timescales, and the fact that most gene duplications eventually result in loss of one copy, it is surprising that all jawed vertebrates (gnathostomes) have retained two paralogous VKOR genes.In particular, we look to published studies about tissue- and developmental stage-specific expression, enzymatic function, phylogeny, biological roles and associated pathways that together suggest subfunctionalization as a major influence in evolutionary fixation of both paralogs.Additionally, we investigate on what evolutionary timescale the paralogs arose and under what circumstances in order to gain insight into the biological raison d'être for both VKOR paralogs in gnathostomes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn 53105, Germany. johannes.oldenburg@ukb.uni-bonn.de.

ABSTRACT
Among all cellular life on earth, with the exception of yeasts, fungi, and some prokaryotes, VKOR family homologs are ubiquitously encoded in nuclear genomes, suggesting ancient and important biological roles for these enzymes. Despite single gene and whole genome duplications on the largest evolutionary timescales, and the fact that most gene duplications eventually result in loss of one copy, it is surprising that all jawed vertebrates (gnathostomes) have retained two paralogous VKOR genes. Both VKOR paralogs function as entry points for nutritionally acquired and recycled K vitamers in the vitamin K cycle. Here we present phylogenetic evidence that the human paralogs likely arose earlier than gnathostomes, possibly in the ancestor of crown chordates. We ask why gnathostomes have maintained these paralogs throughout evolution and present a current summary of what we know. In particular, we look to published studies about tissue- and developmental stage-specific expression, enzymatic function, phylogeny, biological roles and associated pathways that together suggest subfunctionalization as a major influence in evolutionary fixation of both paralogs. Additionally, we investigate on what evolutionary timescale the paralogs arose and under what circumstances in order to gain insight into the biological raison d'être for both VKOR paralogs in gnathostomes.

No MeSH data available.