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Abstract ᅟ Animals are known to have higher rates of exon skipping than other eukaryotes. In a recent study, Grau-Bové et al. (Genome Biology 19:135, 2018) have used RNA-seq data across 65 eukaryotic species to investigate when and how this high prevalence of exon skipping evolved. They have found that bilaterian Metazoa have significantly increased exon skipping frequencies compared to all other eukaryotic groups and that exon skipping in nearly all animals, including non-bilaterians, is strongly enriched for frame-preserving events. The authors have hypothesized that “the increase of exon skipping rates in animals followed a two-step process. First, exon skipping in early animals became enriched for frame-preserving events. Second, bilaterian ancestors dramatically increased their exon skipping frequencies, likely driven by the interplay between a shift in their genome architectures towards more exon definition and recruitment of frame-preserving exon skipping events to functionally diversify their cell-specific proteomes.” Here we offer a different explanation for the higher frequency of frame-preserving exon skipping in Metzoa than in all other eukaryotes. In our view these observations reflect the fact that the majority of multidomain proteins unique to metazoa and indispensable for metazoan type multicellularity were assembled by exon-shuffling from ‘symmetrical’ modules (i.e. modules flanked by introns of the same phase), whereas this type of protein evolution played a minor role in other groups of eukaryotes, including plants. The higher frequency of ‘symmetrical’ exons in Metazoan genomes provides an explanation for the enrichment for frame-preserving events since skipping or inclusion of ‘symmetrical’ modules during alternative splicing does not result in a reading-frame shift. Reviewers This article was reviewed by Manuel Irimia, Ashish Lal and Erez Levanon. The reviewers were nominated by the Editorial Board.

ᅟ: Animals are known to have higher rates of exon skipping than other eukaryotes. In a recent study, Grau-Bové et al. (Genome Biology 19:135, 2018) have used RNA-seq data across 65 eukaryotic species to investigate when and how this high prevalence of exon skipping evolved. They have found that bilaterian Metazoa have significantly increased exon skipping frequencies compared to all other eukaryotic groups and that exon skipping in nearly all animals, including non-bilaterians, is strongly enriched for frame-preserving events. The authors have hypothesized that "the increase of exon skipping rates in animals followed a two-step process. First, exon skipping in early animals became enriched for frame-preserving events. Second, bilaterian ancestors dramatically increased their exon skipping frequencies, likely driven by the interplay between a shift in their genome architectures towards more exon definition and recruitment of frame-preserving exon skipping events to functionally diversify their cell-specific proteomes." Here we offer a different explanation for the higher frequency of frame-preserving exon skipping in Metzoa than in all other eukaryotes. In our view these observations reflect the fact that the majority of multidomain proteins unique to metazoa and indispensable for metazoan type multicellularity were assembled by exon-shuffling from 'symmetrical' modules (i.e. modules flanked by introns of the same phase), whereas this type of protein evolution played a minor role in other groups of eukaryotes, including plants. The higher frequency of 'symmetrical' exons in Metazoan genomes provides an explanation for the enrichment for frame-preserving events since skipping or inclusion of 'symmetrical' modules during alternative splicing does not result in a reading-frame shift. Reviewers: This article was reviewed by Manuel Irimia, Ashish Lal and Erez Levanon. The reviewers were nominated by the Editorial Board. [ABSTRACT FROM AUTHOR]

Abstract: β-Defensins are a group of vertebrate-specific antimicrobial peptides (AMPs) with microbicidal and immune regulatory functions. In spite of their conservation across the vertebrate lineage ranging from bony fish to human, the evolutionary origin of these molecules remains unsolved. We addressed this issue by comparing three-dimensional (3D) structure and genomic organization of β-defensins with those of big defensins, a family of invertebrate-derived β-defensin-related peptides with two distinct structural and functional domains. β-Defensins and the carboxyl-terminal domain of big defensins adopt a conserved β-sheet topology stabilized by three identical disulfide bridges. Genomic organization analysis revealed that the defensin domain of these two classes of molecules is encoded by a single exon with a positionally conserved phase-1 intron in its upstream. The genomic and 3D structural conservation provides convincing evidence for their evolutionary relationship, in which β-defensins emerged from an ancestral big defensin through exon shuffling or intronization of exonic sequences. The phylogenetic distribution of big defensins in Arthropoda, Mollusca and Cephalochordata suggests an early origin of the β-defensin domain, which can be traced to the common ancestor of bilateral metazoans. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

The testis-specific gene Jingwei ( jgw) is a newly evolved short-chain dehydrogenase/reductase in Drosophila. Preliminary substrate screening indicated that JGW prefers long-chain primary alcohols as substrates, including several exotic alcohols such as farnesol and geraniol. Using steady-state kinetics analyses and molecular docking, we not only confirmed JGW’s substrate specificity, but also demonstrated that the new enzymatic activities of JGW evolved extensively after exon-shuffling from a preexisting enzyme. Analysis of JGW orthologs in sister species shows that subsequent evolutionary changes following the birth of JGW altered substrate specificities and enzyme stabilities. Our results lend support to a general mechanism for the evolution of a new enzyme, in which catalytic chemistry evolves first followed by diversification of substrate utilization. [ABSTRACT FROM AUTHOR]

The chloroplasts of Euglena gracilis bounded by three membranes arose via secondary endosymbiosis of a green alga in a heterotrophic euglenozoan host. Many genes were transferred from symbiont to the host nucleus. A subset of Euglena nuclear genes of predominately symbiont, but also host, or other origin have obtained complex presequences required for chloroplast targeting. This study has revealed the presence of short introns (41–93 bp) either in the second half of presequence-encoding regions or shortly downstream of them in nine nucleus-encoded E. gracilis genes for chloroplast proteins (Eno29, GapA, PetA, PetF, PetJ, PsaF, PsbM, PsbO, and PsbW). In addition, the E. gracilis Pbgd gene contains two introns in the second half of presequence-encoding region and one at the border of presequence-mature peptide-encoding region. Ten of 12 introns present within presequence-encoding regions or shortly downstream of them identified in this study have typical eukaryotic GT/AG borders, are T-rich, 45–50 bp long, and pairwise sequence identities range from 27 to 61%. Thus single recombination events might have been mediated via these cis-spliced introns. A double crossing over between these cis-spliced introns and trans-spliced introns present in 5′-UTRs of Euglena nuclear genes is also likely to have occurred. Thus introns and exon-shuffling could have had an important role in the acquisition of chloroplast targeting signals in E. gracilis. The results are consistent with a late origin of photosynthetic euglenids. [ABSTRACT FROM PUBLISHER]

Abstract: Gene transfer events from organelle genomes (mitochondria and chloroplasts in plants) to the nuclear genome are important processes in the evolution of the eukaryotic cell. It is highly likely that the gene transfer event is still an ongoing process in higher plant mitochondria and chloroplasts. The number and order of genes encoded in the chloroplast genome of higher plants are highly conserved. Recently, several exceptional cases of gene loss from the chloroplast genome have been discovered as the number of complete chloroplast genome sequences has increased. The Populus chloroplast genome has lost the rpl32 gene, while the corresponding the chloroplast rpl32 (cp rpl32) gene has been identified in the nuclear genome. Nuclear genes transferred from the chloroplast genome need to gain a sequence that encodes a transit peptide. Here, we revealed that the nuclear cp rpl32 gene has acquired the exon sequence, which is highly homologous to a transit peptide derived from the chloroplast Cu–Zn superoxide dismutase (cp sod-1) gene. The cp rpl32 gene has acquired the sequence that encodes not only for the transit peptide, but also for the conserved N-terminal portion of the mature SOD protein from the cp sod-1 gene, suggesting the occurrence of DNA sequence duplication. Unlike cp SOD-1, cp RPL32 did not show biased localization in the chloroplasts. This difference may be caused by mutations accumulated in the sequence of the SOD domain on the cp rpl32 gene. We provide new insight into the fate of the inherent sequence derived from a transit peptide. [Copyright &y& Elsevier]

The axonemes serve as motile machineries in sperm flagella. Although atypical axonemal structures are observed in some cases, 9 + 2 microtubule structure of the axoneme is predominant in many organisms. Several structures are bound to these microtubules and comprise a highly organized protein network. Extensive proteomic analysis of the axonemes has led to find several repeats, domains, and motifs in axonemal proteins. Molecular comparison of subunit composition of axonemal substructures between the ascidian Ciona intestinalis and the green algae Chlamydomonas reinhardtti leads to an intriguing molecular aspect concerning the evolution of intracellular functional complex: The architecture of the axonemes has been well conserved through evolution, but the molecular structure of each axonemal component is not always conserved. In light of domain structure in the axonemal proteins, substructures like outer arm dynein and radial spoke contain a set of domain structures, although some domain-containing subunits are different between these two organisms. Thus, conservation of protein domains within a substructure seems to take precedence over that of each protein (“module-dominant conservation”), which may ultimately result in morphological and functional conservation of the axonemes through evolution. [ABSTRACT FROM AUTHOR]

Comparative genome analyses reveal that most functional domains of human genes have homologs in widely divergent species. These shared functional domains, however, are differentially shuffled among evolutionary lineages to produce an increasing number of domain architectures. Combined with duplication and adaptive evolution, domain shuffling is responsible for the great phenotypic complexity of higher eukaryotes. Although the domain-shuffling hypothesis is generally accepted, determining the molecular mechanisms that lead to domain shuffling and novel gene creation has been challenging, as sequence features accompanying the formation of known genes have been obscured by accumulated mutations. The growing availability of genome sequences and EST databases allows us to study the characteristics of newly emerged genes. Here we review recent genome-wide DNA and EST analyses, and discuss the three major molecular mechanisms of gene formation: (1) atypical spicing, both within and between genes, followed by adaptation, (2) tandem and interspersed segmental duplications, and (3) retrotransposition events. [ABSTRACT FROM AUTHOR]

Abstract: It was recently shown that there is a predominance of phase 1 introns near the cleavage site of signal peptides encoded by human genes [Tordai, H. and Patthy, L. (2004) Insertion of spliceosomal introns in proto-splice sites: the case of secretory signal peptides. FEBS Lett. 575, 109–111]. It was suggested that this biased distribution was due to intron insertion at AG∣G proto-splice sites. However, we found that there is no disproportional excess of AG∣G that would support insertion at proto-splice sites. In fact, all nG∣G sites are enriched in the vicinity of the cleavage site. Additional analyses support an alternative scenario in which exon-shuffling is largely responsible for such excess of phase 1 introns. [Copyright &y& Elsevier]

Originally the term ‘protein module’ was coined to distinguish mobile domains that frequently occur as building blocks of diverse multidomain proteins from ‘static’ domains that usually exist only as stand-alone units of single-domain proteins. Despite the widespread use of the term ‘mobile domain’, the distinction between static and mobile domains is rather vague as it is not easy to quantify the mobility of domains. In the present work we show that the most appropriate measure of the mobility of domains is the number of types of local environments in which a given domain is present. Ranking of domains with respect to this parameter in different evolutionary lineages highlighted marked differences in the propensity of domains to form multidomain proteins. Our analyses have also shown that there is a correlation between domain size and domain mobility: smaller domains are more likely to be used in the construction of multidomain proteins, whereas larger domains are more likely to be static, stand-alone domains. It is also shown that shuffling of a limited set of modules was facilitated by intronic recombination in the metazoan lineage and this has contributed significantly to the emergence of novel complex multidomain proteins, novel functions and increased organismic complexity of metazoa. [ABSTRACT FROM AUTHOR]

Exon-shuffling is an important mechanism accounting for the origin of many new proteins in eukaryotes. However, its role in the creation of proteins in the ancestor of prokaryotes and eukaryotes is still debatable. Excess of symmetric exons is thought to represent evidence for exon-shuffling since the exchange of exons flanked by introns of the same phase does not disrupt the reading frame of the host gene. In this report, we found that there is a significant correlation between symmetric units of shuffling and the age of protein domains. Ancient domains, present in both prokaryotes and eukaryotes, are more frequently bounded by phase 0 introns and their distribution is biased towards the central part of proteins. Modern domains are more frequently bounded by phase 1 introns and are present predominantly at the ends of proteins. We propose a model in which shuffling of ancient domains mainly flanked by phase 0 introns was important in the ancestor of eukaryotes and prokaryotes, during the creation of the central part of proteins. Shuffling of modern domains, predominantly flanked by phase 1 introns, accounted for the origin of the extremities of proteins during eukaryotic evolution. [ABSTRACT FROM AUTHOR]

Comparison of the exon–intron structures of human, fly and worm orthologues of mosaic genes assembled from class 1-1 modules by exon-shuffling has revealed that human genes retained significantly more of the original inter-module introns than their protostome orthologues. It is suggested that the much higher rate of intron loss in the worm- and insect lineages than in the chordate lineage reflects their greater tendency for genome compaction. [Copyright &y& Elsevier]