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Reassessing Domain Architecture Evolution of Metazoan Proteins: Major Impact of Gene Prediction Errors

Nagy, Alinda, Szláma, György, Szarka, Eszter, Trexler, Mária, Bányai, László, Patthy, László·2011·Genes
DOI 10.3390/genes2030449PMC PMC3927609
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Abstract

In view of the fact that appearance of novel protein domain architectures (DA) is closely associated with biological innovations, there is a growing interest in the genome-scale reconstruction of the evolutionary history of the domain architectures of multidomain proteins. In such analyses, however, it is usually ignored that a significant proportion of Metazoan sequences analyzed is mispredicted and that this may seriously affect the validity of the conclusions. To estimate the contribution of errors in gene prediction to differences in DA of predicted proteins, we have used the high quality manually curated UniProtKB/Swiss-Prot database as a reference. For genome-scale analysis of domain architectures of predicted proteins we focused on RefSeq, EnsEMBL and NCBI’s GNOMON predicted sequences of Metazoan species with completely sequenced genomes. Comparison of the DA of UniProtKB/Swiss-Prot sequences of worm, fly, zebrafish, frog, chick, mouse, rat and orangutan with those of human Swiss-Prot entries have identified relatively few cases where orthologs had different DA, although the percentage with different DA increased with evolutionary distance. In contrast with this, comparison of the DA of human, orangutan, rat, mouse, chicken, frog, zebrafish, worm and fly RefSeq, EnsEMBL and NCBI’s GNOMON predicted protein sequences with those of the corresponding/orthologous human Swiss-Prot entries identified a significantly higher proportion of domain architecture differences than in the case of the comparison of Swiss-Prot entries. Analysis of RefSeq, EnsEMBL and NCBI’s GNOMON predicted protein sequences with DAs different from those of their Swiss-Prot orthologs confirmed that the higher rate of domain architecture differences is due to errors in gene prediction, the majority of which could be corrected with our FixPred protocol. We have also demonstrated that contamination of databases with incomplete, abnormal or mispredicted sequences introduces a bias in DA differences in as much as it increases the proportion of terminal over internal DA differences. Here we have shown that in the case of RefSeq, EnsEMBL and NCBI’s GNOMON predicted protein sequences of Metazoan species, the contribution of gene prediction errors to domain architecture differences of orthologs is comparable to or greater than those due to true gene rearrangements. We have also demonstrated that domain architecture comparison may serve as a useful tool for the quality control of gene predictions and may thus guide the correction of sequence errors. Our findings caution that earlier genome-scale studies based on comparison of predicted (frequently mispredicted) protein sequences may have led to some erroneous conclusions about the evolution of novel domain architectures of multidomain proteins. A reassessment of the DA evolution of orthologous and paralogous proteins is presented in an accompanying paper [1].

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Figure 1 Correction of the sequence of complement component C7 of Gallus gallus with the FixPred protocol. The DA of GNOMON-predicted sequence of complement component C7 from Gallus gallus (XP_424774) was found to differ from those of its mammalian and fish orthologs (CO7_HUMAN, CO7_PIG, B5X0R1_SALSA): whereas the latter contain TSP_1, Ldl_recept_a, MACPF, TSP_1, Sushi and Sushi domains the ortholog of Gallus gallus lacks the domains downstream of the MACPF domain. The sequence “XP_424774_CORRECTED” was predicted by the use of alternative gene models and is supported by ESTs. The sequence predicted by FixPred was experimentally verified by cloning the full-length cDNA; the cDNA sequence was deposited in GenBank (accession cDNA: HQ878377; accession protein: ADY17228). (a) Comparison of the DAs of XP_424774 and XP_424774_CORRECTED with that of CO7_HUMAN; (b) Alignment of the sequences of XP_424774 and XP_424774_CORRECTED with those P_416936, XP_416936_CORRECTED with those of CO7_HUMAN, CO7_PIG and B5X0R1_SALSA.
Figure 1 Correction of the sequence of complement component C7 of Gallus gallus with the FixPred protocol. The DA of GNOMON-predicted sequence of complement component C7 from Gallus gallus (XP_424774) was found to differ from those of its mammalian and fish orthologs (CO7_HUMAN, CO7_PIG, B5X0R1_SALSA): whereas the latter contain TSP_1, Ldl_recept_a, MACPF, TSP_1, Sushi and Sushi domains the ortholog of Gallus gallus lacks the domains downstream of the MACPF domain. The sequence “XP_424774_CORRECTED” was predicted by the use of alternative gene models and is supported by ESTs. The sequence predicted by FixPred was experimentally verified by cloning the full-length cDNA; the cDNA sequence was deposited in GenBank (accession cDNA: HQ878377; accession protein: ADY17228). (a) Comparison of the DAs of XP_424774 and XP_424774_CORRECTED with that of CO7_HUMAN; (b) Alignment of the sequences of XP_424774 and XP_424774_CORRECTED with those P_416936, XP_416936_CORRECTED with those of CO7_HUMAN, CO7_PIG and B5X0R1_SALSA.CC BY · PubMed Central
Figure 2 Correction of the sequence of cathepsin H of Gallus gallus with the FixPred protocol. The DA of GNOMON-predicted sequence of cathepsin H from Gallus gallus (xp_001232765) was found to differ from those of its mammalian orthologs (CATH_HUMAN, CATH_MOUSE, CATH_PIG, CATH_RAT: whereas the DA of the latter contains an Inhibitor_I29 and a Peptidase_C1 domain, the chicken protein lacks the Inhibitor_I29 domain. The sequence “xp_001232765_corrected” was predicted by the use of ESTs bm427347, bi066433, am064052, bu425005 and bi064908. The sequence predicted by FixPred was experimentally verified by cloning the full-length cDNA; the cDNA sequence was deposited in GenBank (accession cDNA: JF514547; accession protein: AEC13302). (a) Comparison of the DAs of XP_001232765 and XP_001232765_CORRECTED with that of CATH_HUMAN; (b) Alignment of the sequences of XP_001232765 and XP_001232765 _CORRECTED with those of CATH_HUMAN, CATH_MOUSE, CATH_PIG, CATH_RAT.
Figure 2 Correction of the sequence of cathepsin H of Gallus gallus with the FixPred protocol. The DA of GNOMON-predicted sequence of cathepsin H from Gallus gallus (xp_001232765) was found to differ from those of its mammalian orthologs (CATH_HUMAN, CATH_MOUSE, CATH_PIG, CATH_RAT: whereas the DA of the latter contains an Inhibitor_I29 and a Peptidase_C1 domain, the chicken protein lacks the Inhibitor_I29 domain. The sequence “xp_001232765_corrected” was predicted by the use of ESTs bm427347, bi066433, am064052, bu425005 and bi064908. The sequence predicted by FixPred was experimentally verified by cloning the full-length cDNA; the cDNA sequence was deposited in GenBank (accession cDNA: JF514547; accession protein: AEC13302). (a) Comparison of the DAs of XP_001232765 and XP_001232765_CORRECTED with that of CATH_HUMAN; (b) Alignment of the sequences of XP_001232765 and XP_001232765 _CORRECTED with those of CATH_HUMAN, CATH_MOUSE, CATH_PIG, CATH_RAT.CC BY · PubMed Central

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Metadata

Authors
Nagy, A., Szláma, G., Szarka, E., Trexler, M., Bányai, L., & Patthy, L.
Affiliations
Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, H-1113 Budapest, Hungary
Venue
Genes
Publisher
MDPI AG
Published
2011-07-13
Volume
2
Issue
3
Pages
449-501
ISSN
2073-4425
DOI
10.3390/genes2030449
PMC
PMC3927609
Cited by
22
References
3
Language
en
Update notices
correction (2011-07-13)
Licence
creativecommons.org/licenses/by/3.0/ (vor)

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Nagy, A., Szláma, G., Szarka, E., Trexler, M., Bányai, L., & Patthy, L. (2011). Reassessing Domain Architecture Evolution of Metazoan Proteins: Major Impact of Gene Prediction Errors. Genes. https://doi.org/10.3390/genes2030449