Selenoprotein evolution: introduction

Selenoprotein SELU: 3 paralogs, variable timing losses

SELU: This family consists of three deeply diverged (distinct exon patterns) paralogs. The encoding gene has 5 average exons with anomalously short introns like many selenoproteins. In the SELU1 group, selenocysteine occurs in a UxxC motif already in the earliest deuterostome but drops out in mammals after monotremes, being replaced by CxxC in marsupials and placentals. Amphibia separately lost selenocysteine.

The second paralog SELU2 has selenocysteine in bilaterans only to the node of sea urchin, suggesting it was lost early in the deuterostome ancestor. It is the closer paralog of SelU1, 36% vs 27% percent identity. No vestigal SECIS element persists in living species that encode cysteine. (The decayed SECIS elements still identifiable in 3' UTR of cysteine-containing GPX6 genes in rodents and human GPX5 represent much more recent loss of selenocysteine.)

The third paralog SELU3 has cysteine in all species for which a sequence is available. It might be called virtual selenoprotein supposing orthologs in early diverging eukaryotes could be located that contained selenocysteine. This would suggest a scenario in which selenocysteine was present in an ancestral gene prior to gene duplications followed by conversion to cysteine in different phylogenetic patterns within each gene subfamily.

This family exhibits the "selenocysteine rachet": if selenocysteine happens to be replaced by ordinary cysteine (despite catalytic inferiority) in some stem lineage, the unselected 3' UTR SECIS element then deteriorates over a few million years from accrued mutations, for the same reason (lack of purifying selection) the crayfish in the cave loses its imaging opsins. Consequently the whole following clade will contain cysteine -- a reversion to TGA at the cystein codon might occur but it would simultaneously require a multi-step reversion or de novo evolution of a SECIS element, ie all SECIS elements are ancient and selenocysteines cannot wink back on paraphyletically. (However the overall selenoproteome can still increase over time because of gene duplications elsewhere.)

A phylogenetic overview of the occurence of selenocysteine in SELU1 in 38 vertebrates:

                                        .........................*.....
C  Homo sapiens                  genome EPRTFKAKELWEKNGAVIMAVRRPGcFLCRE
C  Pan troglodytes         AACZ02115591 EPRTFKAKELWEKNGAVIMAVRRPGCFLCRE
C  Pongo abelii            ABGA01228099 EPRTLKAKELWEKNGAVIMAVRRPGCFLCRE
C  Macaca mulatta          AANU01282766 EPRTLKAKELWEKNGAVIMAVRRPGCFLCRE
C  Microcebus murinus      ABDC01489848 EPRTFKAKELWEKNGAVIMAVRRPGCFLCRE
C  Otolemur garnettii      AAQR01538573 EPRTFKAKELWEKNGAVIMAVRRPGCFLCRE
C  Tupaia belangeri        AAPY01309022 EPRTFKAKELWGERGAVIMAVRRPGCFLCRE
C  Mus musculus            AAHY01113156 EPRTFKAKELWEKNGAVIMAVRRPGCFLCR.
C  Rattus norvegicus       AAHX01086750 EPRTFKAKELWEKNGAVIMAVRRPGCFLCR.
C  Spermophilus tridec     AAQQ01288000 EPRTFKAKELWEKSGAVIMAVRRPGCFLCRE
C  Cavia porcellus         AAKN02044618 EPRTFKAKELWEKNGAVIMAVRRPGCFLCRE
C  Oryctolagus cuniculus   AAGW01591660 EPRTFKAKELWEKNGAVIMAVRRPGCFLCRE
C  Canis familiaris        AAEX02011808 EPRTFKAKELWEKNGAVIMAVRRPGCFLCRE
C  Bos taurus              AAFC03065652 ...TFKAKALWEKNGAVIMAVRRPGCFLCRE
C  Equus caballus          AAWR02000382 EPRTFKAKELWEKNGAVIMAVRRPGCFLCRE
C  Myotis lucifugus        AAPE01631988 EPRTFKAKELWEEKGAVIMAVRRPGCFLCRE
C  Sorex araneus           AALT01607337 zPKTFKAKELWSKSGAVIMAVRRPGCFLCRE
C  Boreoeuthere ancestralis   ancestral EPRTFKAKELWEKNGAVIMAVRRPGcFLCRE
C  Echinops telfairi       AAIY01623759 ...TFQSKGALGKNGAVIMAVRRPGCFLCRE
C  Dasypus novemcinctus    AAGV01392885 EPRTFKAKELWEKNGAVIMAVRRPGCFLCRE
C  Monodelphis domestica   AAFR03024314 SPKTFKARELWEHRGAVIMAVRRPGCFLCRE
C  Trichosurus vulpecula     transcript SPKTFKARELWEHRGAVIMAVRRPGCFLCRE
C  Macropus eugenii              genome ..KTFKARELWEHRGAVIMAVRRPGCFLCRE
U  Ornithorhynchus anatin  AAPN01249400 EPRTFKARELWQRNGAVIMAVRRPGUFLCRE
U  Tachyglossus aculeatus        genome EPRTFKARELWQRNGAVIMAVRRPGUFLCRE
U  Anolis carolinensis     AAW.01013574 ..RTFKAEELWKKNGAVIMAVRRPGUFLCRE
U  Gallus gallus           AADN02035315 EPRTFKASELWKKNGAVIMAVRRPGUFLCRE
U  Taeniopygia guttata           genome EKRTFKAGELWKQNGAVIMAVRRPGUFLCRE
C  Xenopus tropicalis            genome EPKSFKAKDLWEKNGAVVMAVRRPGCFLCRE
C  Xenopus laevis            transcript EPRLFKAKDLWERDGAVIMAVRRPGCFLCRE
U  Danio rerio             CAAK04015812 DDRVFKARELWESSGAVIMAVRRPGUFMCRE
U  Tetraodon nigroviridis  CAAE01014976 ETKTFKAKTLWEKCGAVVMAVRRPGUFLCRE
U  Fugu rubripes           CAAB01000016 ETKTFKAKSLWENSGAVVMAVRRPGUFLCRE
U  Gasterosteus aculeatus  AANH01005113 ...VIKGRSLWDKNGAVVMAVRRPGUFLCRE
U  Oryzias latipes         BAAE01190338 DTKIIKAKSLWDKNGAVVMAVRRPGUFLCRE
U  Fundulus heteroclitus     transcript .....KAKSLWEKNGAVVMAVRRPGUFLCRE
U  Oncorhynchus mykiss         CR369769 .....KAKALWEKTGAVVMAVRRPGUFLCRE
U  Callorhinchus milii     AAVX01258517 ENRTFRASELWAGRGAVIMAVRRPGUFLCRE

C  Gasterosteus  aculeatus AANH01005113 ......AKTLWDKTGAVVMVVRRPGCLLCRE (anomalous gene duplication with cysteine)

Reference sets of vertebrate selenoproteins

SELU1: 13 vertebrate proteins

>SELU1_homSap Homo sapiens (human) processed pseudogenes chr8 and chr12
0 MSFLQDPSFFTMGMWSIGAGALGAAALALLLANTDVFLSKPQKAALEYLEDIDLKTLEK 1
2 EPRTFKAKELWEKNGAVIMAVRRPGcFLCREE 0
0 AADLSSLKSMLDQLGVPLYAVVKEHIRTEVKDFQPYFKGEIFLDEK 0
0 KKFYGPQRRKMMFMGFIRLGVWYNFFRAWNGGFSGNLEGEGFILGGVFVVGSGKQ 0
0 GILLEHRENEFGDKVNLLSVLEAAKMIKPQTLASEKK* 0

>SELU2_homSap Homo sapiens (human) 7 exons chr1p36.32 36% id NM_152371 
0 MSTVDLARVGACILKHAVTGE 0
0 AVELRSLWREHACVVAGLRRFGCVVCRWIAQDLSSLAGLLDQHGVRLVGVGPEALGLQEFLDGDYFAG 1
2 ELYLDESKQLYKELGFKR 2 
1 YNSLSILPAALGKPVRDVAAK 0
0 AKAVGIQGNLSGDLLQSGGLLVVSK 1
2 GGDKVLLHFVQKSPGDYVPKEHILQVLGISAEVCASDPPQ 0
0 CDREV* 0

>SELU3_homSap Homo sapiens (human) 6 exons chr9q22.32 25% id processed pseudogene chrX
0 MAAPAPVTRQVSGAAALVPAPSGPDSGQPLAAAVAELPVLDARGQRVPFGALFRERRAVVVFVR 0
0 HFLCYICKEYVEDLAKIPRSFLQ 0
0 EANVTLIVIGQSSYHHIE 0
0 PFCKLTGYSHEIYVDPEREIYKRLGMKRGEEIASS 1
2 GQSPHIKSNLLSGSLQSLWRAVTGPLFDFQGDPAQQGGTLILGP 1
2 GNNIHFIHRDRNRLDHKPINSVLQLVGVQHVNFTNRPSVIHV* 0

>SELU1_borAnc Boreoeuthere ancestralis (northern beast) 5 exons no selenocyseine
0 MSFLQDPSFFTMGMWSIGAGALGAAALALLLANTDVFLSKPQKAALEYLEDIDLKTLEK 1
2 EPRTFKAKELWEKNGAVIMAVRRPGcFLCREV 0
0 AADLSSLKPKLDELGVPLYAVVKEHIRTEVKDFQPYFKGEIFLDEK 0
0 KKFYGPQRRKMMFMGFVRLGVWYNFFRAWNGGFSGNLEGEGFILGGVFVVGPGKQ 0
0 GILLEHREKEFGDKVNPVSVLEAARKIKPQTSASEKK* 0

>SELU1_triVul Trichosurus vulpecula (brushtail opossum) EC360881
0 MSFLDLSFFSMGMWSLGAGALGAAVLSLILANTNLFLTKSVTATLEFLEEIELKTLDN 1
2 ESPKTFKARELWEHRGAVIMAVRRPGCFLCREE 0
0 AAELSALKPQLDQLGIPLYAVVKEKIGSEVENFQPYFKGKIFLDER 0
0 KKFYGPQKRKMMFMGFVRLGVWQNFFRARSKGFSGNLEGEGFILGGVYVIGPGKQ 0
0 GILLEHREKEFGDKVDPASVLEAA   * 0

>SELU1_macEug Macropus eugenii (tammar wallaby) EX196548 full
0 MSFLDLSFLSMGMWSLGAGALGAAVLSLILANTDVFLTKSVTATLEFLEDIELKTLDN 1
2 KTFKARELWEHRGAVIMAVRRPGCFLCREE 0
0 AADLSALKPQLDQLGIPLYAVVKEKIGSEVEDFQPYFKGKIFLDER 0
0 KKFYGPQKRKMMFMGFVRLGVWQNFFRARSKGFSGNLEGEGFILGGVYVIGPRKQ 0
0 GILLDHREKELGDKVNPASVLEACKKIKLHA* 0

>SELU1_monDom Monodelphis domestica (opossum) tgt-cys
0 MSFLDLNFFSMSMWSLGAGALGAAALSLILANTDLFLTKSVDATLEFLEEIQLKTLDN 1
2 ESPKTFKARELWEHRGAVIMAVRRPGCFLCREV 0
0 AADLSALKPQLDLLGVPLYAVVKEKIGSEVENFQPYFKGKIFLDER 0
0 KKFYGPQKRKMMFMGFVRLGVWQNFFRARSKGFSGNLEGEGFVLGGVYVIGPGKQ 0
0 GILLEHREKEFGDKVNPASVLEAAKKIKPHTSTSEGK* 0

>SELU1_oan data Ornithorhynchus anatinus (platypus) taa early stop full
0 MPLPPDLGLFNLGMWSVGVGALGAAAVGLLLANTDLLLTKPEKATLEYLEDTELKTLGK 1
2 EPRTFKARELWQRNGAVIMAVRRPGuFLCREE 0
0 AAELSSLKPQLDRLGVPLYAVVKEKIGTEVEDFQPYFKGEIFLDER 0
0 KKFYGPHKRKMLFLGFIRLGVWQNFLRARNRGFSGNLEGEGLILGGVYVLGAGKQ 0
0 GILLEHREREFGDKVSPASVLEAAQRIKPQPL* 0

>SELU1_tacAcu Tachyglossus aculeatus (echidna) 454:EUEMSW405C31QQ (74%) tSASEKK terminus? frag
0 1
2 EPRTFKARELWQRNGAVIMAVRRPGuFLCREE 0
0 AAELSSLKPQLDQLGVPLYAVVKENIGTEVEDFQPYFKGEIFLDER 0
0 KRFYGPHKRKMLFLGLIRLGVWQNFIRARNKGFPPVTWEGEG     0
0 GVLLEHREREFGDKVSPASVLEAAQKIKPQ* 0

>SELU1_gga Gallus gallus (chicken)
0 MSFLPDFGIFTMGMWSVGLGAVGAAITGIVLANTDLFLSKPEKATLEFLEAIELKTLGS 1
2 EPRTFKASELWKKNGAVIMAVRRPGuFLCREE 0
0 ASELSSLKPQLSKLGVPLYAVVKEKIGTEVEDFQHYFQGEIFLDEK 0
0 RSFYGPRKRKMMLSGFFRXGVWQNFFRAWKNGYSGNLEGEGFTLGGVYVIGAGRQ 0
0 GVLLEHREKEFGDKVSLPSVLEAAEKIKPQAS* 0 

>SELU1_tgu Taeniopygia guttata (finch)
0 msflpdfgiFTMGMWSVGLGAIGAAVTGIVLANTDLFLSKPEKATLEFLEEIELKTLGS 1
2 EKRTFKAGELWKQNGAVIMAVRRPGuFLCREE 0
0 ASELSSLKPQLSKLGVPLYAVVKENIGTEVEDFQHYFKGEIFLDEK 0
0 KGFYGPRRRKMMLSGFFRLGVWQNFVRAWRSGYSGNLEGEGFTLGGVYVIGAGRQ 0
0 GVLLEHREKEFGDKVSLPSVLEAAEKIKPQAS* 0 

>SELU1_anoCar Anolis carolinensis (lizard)
0 MWTIGLGAIGAAVTGIILANTDLFLSKAEQASLDFLEAIDLKTLGE 1
2 NQRTFKAEELWKKNGAVIMAVRRPGuFLCREV 0
0 AAELSSLKPQLDKLGVPLYAVVKENLGTEVMDFQPYFKGEIFLDEK 0.
0 KQFYGPQKRKMLFMGFIRCSVWRNFFRAWKSGYTGNIDGEGFVLGGVFVVGPGKQ 0
0 GVLLEHREKEFGDKVSLDAVLEAVKNIQPQPSEKDK* 0

>SelU1_fugRer Fugu rubripes (fugu)
0 MGLLAKLLAAVGGFVTAVMNSVTDAFLTPPLRATLEHLEETDLKTLSG 1
2 ALVIRLIPTRTETKTFKAKSLWENSGAVVMAVRRPGuFLCRE 0
0 EAAELSSLKPRLDQLGVPLYAVVKEDVGTEIQNFRPYFQGEIFLDEK 0
0 RRFYGPRERKMGLLGFLRVGVWMNGLRAFRSGFMGNVLGEGFVLGGVFVIGREQQ 0
0 GILLEHREREFGDKVNIEDVIQAVDRIAQELMPVTQN* 0

>SELU1_gasAcu Gasterosteus aculeatus (stickleback) chrVI.790.1 length=214
MGMWSLGLGAVGAALAGIFLANTDLCLPKAASASLENLEDADLRS
KGRSLWDKNGAVVMAVRRPGuFLCREV
ASGLSSLKPQLEELGVPLVAVVKEDVGTEIRDFRPHFAGDIFIDEK
SFYGPLQRKMGGLGFIRLGVWQNFMRAWRSGYQGNMNGEGFILGGVFVFGAGNQ
GILLEHREKEFGDKVQIADVLEAVKKIVPAK*

>SELU1_calMil Callorhinchus milii (elephantfish) frag
2 ENRTFRASELWAGRGAVIMAVRRPGuFLCRE 0
0 AAALSSLRPSLAQLGVPL
0 GHLLEHREKEFGDAVNLTAVMEAAGKISPRQSAE* 0	
	
>SELU1_squAca Squalus acanthias (spiny dogfish) also selenocysteine
0 MVVVVEDFHMGLWTLGLGALGAAITGVILANTDLLLPKAETASLAYLSGAELRTLDR 1
2 EERTLKAGDLWSRSGAVIMVVRRPGuFLCREE 0
0 AAEISSLRPQLDELGVPLYGVIKENINNELKNFQPFFKGEIFLDVE 0
0 MRFYGPKPRTMGLMGFMRLGVWKNFVRAWQKGFSGNTDGEGFILgGVFVIGAGQQ 0
0 GVLLEHREKEFGDVVNISSVLEARRKIETQRTEP* 0 

SEPW1: 26 vertebrate proteins

>SEPW1_homSap Selenoprotein W *=taa + chr19:52,973,654-52,979,755 87 aa uc002phn.1 many transcripts retroprocessed pseudogene, SEPW1P chr1p35-34 full
0 MALAVRVVYC 2
1 GAuGYKSK 0
0 YLQLKKKLEDEFPGRLDI 0
0 CGEGTPQATGFFEVMVAGKLIHSKK 0
0 KGDGYVDTESKFLKLVAAIKAALAQG* 0

>SEPW1_panTro full
MALAVRVVYC
GAuGYKSK
YLQLKKKLEDEFPGRLDI
RGEGTPQATGFFEVMVAGKLIHSKK
KGDGYVDTESKFLKLVAAIKAALAQG*

>SEPW1_ponPyg Pongo pygmaeus CR926472 full
MALAVRVVYC
GAuGYKSK
YLQLKKKLEDEFPGRLDI
CGEGTPQATGFFEVMVAGKLIHSKK
KGDGYVDTESKFLKLVAAIKAALAQG*

>SEPW1_macMul full
MALAVRVVYC
GAuGYKSK
YLQLKKKLEDEFPGRLDI
CGEGTPQATGFFEVMVAGKLIHSKK
KGDGYVDTESKFLKLVAAIKAALAQG*

>SEPW1_macFas Macaca fascicularis (cynomolgus monkey) AB169486 full
MALAVRVVYC
GAuGYKSK
YLQLKKKLEDEFPGRLDI
CGEGTPQATGFFEVMVAGKLIHSKK
KGDGYVDTESKFLKLVAAIKAALAQG*

>SEPW1_papAnu Papio anubis EY285690 full
MALAVRVVYC
GA*GYKSK
YLQLKKKLEDEFPGRLDI
CGEGTPQATGFFEVMVAGKLIHSKK
KGDGYVDTESKFLKLVAAIKAALAQG*

>SEPW1_calJac full
MALTVRVVYC
GAuGYKSK
YLQLKKKLEDEFPGRLDI
SGEGTPQATGFFEVTVAGKLIHSKK
KGDGYVDTESKFLKLVAAIKAALAQG*

>SEPW1_micMur Microcebus murinus
GAuGYKSK
YLQLKKKLEDEFPGCLDI
CGEGTPQATGFFEVMVAGKLVHSKK
GDGYVDTESKFLKLV

>SEPW1_musMus full
MALAVRVVYC
GAuGYKPK
YLQLKEKLEHEFPGCLDI
CGEGTPQVTGFFEVTVAGKLVHSKK
RGDGYVDTESKFRKLVTAIKAALAQCQ

>SEPW1_ratNor BC087625 full
MALAVRVVYC
GAuGYKPK
YLQLKEKLEHEFPGCLDI
CGEGTPQVTGFFEVTVAGKLVHSKK
RGDGYVDTESKFRKLVTAIKAALAQCQ*

>SEPW1_cavPor full
MALAVRVVYC
GAuGYKPK
YLQLKEKLEDEFPGCLDI
CGEGTPQTTGFFEVTVAGKLVHSKK
GGDGFVDTEGKFRKLVAAIKAALAQG*

>SEPW1_oryCun Oryctolagus cuniculus full
MALAVRVVYC
GAuGYKPK
YLQLKKKLEDEFPGCLDI
CGEGTPQVTGFFEVTVAGKLVHSKK
RGDGYVDTESKFLKLVAAIKAALAQG*

>SEPW1_ochPri Ochotona princeps full
MALSVRVVYW
GAuGYKPK
YLQLKKRLEDEFPGCLDI
GEGTPQVTGFFEVMVAGKLVHSKK
SGDGYVDTESKFLKLVAAIKAALAQG*

>SEPW1_canFam full
MALAVRVVYC
GAuGYKSK
YLQLKKKLEDEFPGCLDI
RGEGTPQATGFFEVTVAGKLVHSKK
RGDGYVDTESKFLRLVAAIKTALAQG*

>SEPW1_felCat
0 2
GAuGYKSK
YLQLKKKLEDEFPGCLDI
RGEGTPQATGFFEVMVGGKLVHSKK
RGDGYVDTESKFLKLVAAIKAALAQG* 

>SEPW1_bosTau full
MAVVVRVVYC
GAuGYKSK
YLQLKKKLEDEFPSRLDI
RGEGTPQVTGFFEVFVAGKLVHSKK
GGDGYVDTESKFLKLVAAIKAALAQA*

>SEPW1_oviAri Ovis aries full
MAVVVRVVYC
GAuGYKPK
YLQLKKKLEDEFPSRLDI
CGEGTPQVTGFFEVFVAGKLVHSKK
GGDGYVDTESKFLKLVAAIKAALAQA* 

>SEPW1_susScr Sus scrofa AF380118 full
MGVAVRVVYC
GAuGYKSK
YLQLKKKLEDEFPGRLDI
CGEGTPQVTGFFEVLVAGKLVHSKK
GGDGYVDTESKFLKLVAAIKAALAQG*

>SEPW1_eriEur full
MALAVRVVYC
GAuGYKSK
YLQLKKKLEDEFPGCLDI
RGEGTPQGTGFFEVLVAGKLVHSKK
KGDGYVDTETKFLKLVTAIKAALAQG*

>SEPW1_sorAra Sorex araneus (shrew)
0 2
GAuGYKSK
YLQLKKKLEDEFPGCVDV
CGEGTPQVTGFFEVMVAGKLVHSKK
RGDGYVDSESKYVRLVTAIKTALAQA*

>SEPW1_choHof full
MALAVRVVYW
GAuGYKPK
YVQLKKKLEDEFPGCLDI
SGEGTPQTTGFFEVMVAGKLVHSKK
QKGDGFVDTESKFLRLVAAIKAALAQG*

>SEPW1_monDom diverged
MAIQVRVVYW
GAuGYKPK
YLLLKKKLEDEYPGLLRH
NGEGTPEVTGFFEVTVAGKLVHSKK
AGHGFVDTADKYLQIVAEIKAALA*

>SEPW1_ornAna 
MASLEAFPRGVVPVHVVYC
GAuGYKPK
FLQLKKKLENEFPGQVEI
SGEGTPQVTGWFEVTVAGKLVHSKK
EGDGFVDSESKFAKIRMAIKAALVPGY*

>SELW_galgal chicken tga confirmed
MPLRVTVLYC
GAuGYKPK
YERLRAELEKRFPGALEM
RGQGTQEVTGWFEVTVGSRLVHSKK
NGDGFVDTNAKLQRIVAAIQAALP*

>SELW_anoCar 
GAuGYSPK
YQQLKRGLEKEFPGKLEI
TGEGTPQVTGWFEVTVAGKLVHSKK
NGDGFVDNDTKLHKILMAIKAALA*

>SELW_str Xenopus tropicalis tga confirmed 
MPDTMVKVNVVYC
GAuGYLSK
FRRLKKELEQRFPGKLSI
DGEGTERMTGWFEVSINGKLVHSKK
NGDGYVDNDAKLQKIILAIEAALKQ*

>SELW_dre1 Danio rerio Zebrafish tga confirmed
MTVKVHVVYC
GGuGYRPK
FIKLKTLLEDEFPNELEI
TGEGTPSTTGWLEVEVNGKLVHSKK
NGDGFVDSDSKMQKIVTAIEQAMGK*