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In the accompanying papers we have shown that sequence errors of public databases and confusion of paralogs and epaktologs (proteins that are related only through the independent acquisition of the same domain types) significantly distort the picture that emerges from comparison of the domain architecture (DA) of multidomain Metazoan proteins since they introduce a strong bias in favor of terminal over internal DA change. The issue of whether terminal or internal DA changes occur with greater probability has very important implications for the DA evolution of multidomain proteins since gene fusion can add domains only at terminal positions, whereas domain-shuffling is capable of inserting domains both at internal and terminal positions. As a corollary, overestimation of terminal DA changes may be misinterpreted as evidence for a dominant role of gene fusion in DA evolution. In this manuscript we show that in several recent studies of DA evolution of Metazoa the authors used databases that are significantly contaminated with incomplete, abnormal and mispredicted sequences (e.g., UniProtKB/TrEMBL, EnsEMBL) and/or the authors failed to separate paralogs and epaktologs, explaining why these studies concluded that the major mechanism for gains of new domains in metazoan proteins is gene fusion. In contrast with the latter conclusion, our studies on high quality orthologous and paralogous Swiss-Prot sequences confirm that shuffling of mobile domains had a major role in the evolution of multidomain proteins of Metazoa and especially those formed in early vertebrates. Full article

In the accompanying paper (Nagy, Szláma, Szarka, Trexler, Bányai, Patthy, Reassessing Domain Architecture Evolution of Metazoan Proteins: Major Impact of Gene Prediction Errors) we showed that in the case of UniProtKB/TrEMBL, RefSeq, EnsEMBL and NCBI’s GNOMON predicted protein sequences of Metazoan species the contribution of erroneous (incomplete, abnormal, mispredicted) sequences to domain architecture (DA) differences of orthologous proteins might be greater than those of true gene rearrangements. Based on these findings, we suggest 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. In this manuscript we examine the impact of confusing paralogous and epaktologous multidomain proteins (i.e., those that are related only through the independent acquisition of the same domain types) on conclusions drawn about DA evolution of multidomain proteins in Metazoa. To estimate the contribution of this type of error we have used as reference UniProtKB/Swiss-Prot sequences from protein families with well-characterized evolutionary histories. We have used two types of paralogy-group construction procedures and monitored the impact of various parameters on the separation of true paralogs from epaktologs on correctly annotated Swiss-Prot entries of multidomain proteins. Our studies have shown that, although public protein family databases are contaminated with epaktologs, analysis of the structure of sequence similarity networks of multidomain proteins provides an efficient means for the separation of epaktologs and paralogs. We have also demonstrated that contamination of protein families with epaktologs increases the apparent rate of DA change and introduces a bias in DA differences in as much as it increases the proportion of terminal over internal DA differences.We have shown that confusing paralogous and epaktologous multidomain proteins significantly increases the apparent rate of DA change in Metazoa and introduces a positional bias in favor of terminal over internal DA changes. Our findings caution that earlier studies based on analysis of datasets of protein families that were contaminated with epaktologs may have led to some erroneous conclusions about the evolution of novel domain architectures of multidomain proteins. A reassessment of the DA evolution of multidomain proteins is presented in an accompanying paper [1]. Full article