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1.  Domain mobility in proteins: functional and evolutionary implications 
Briefings in Bioinformatics  2009;10(3):205-216.
A substantial fraction of eukaryotic proteins contains multiple domains, some of which show a tendency to occur in diverse domain architectures and can be considered mobile (or ‘promiscuous’). These promiscuous domains are typically involved in protein–protein interactions and play crucial roles in interaction networks, particularly those contributing to signal transduction. They also play a major role in creating diversity of protein domain architecture in the proteome. It is now apparent that promiscuity is a volatile and relatively fast-changing feature in evolution, and that only a few domains retain their promiscuity status throughout evolution. Many such domains attained their promiscuity status independently in different lineages. Only recently, we have begun to understand the diversity of protein domain architectures and the role the promiscuous domains play in evolution of this diversity. However, many of the biological mechanisms of protein domain mobility remain shrouded in mystery. In this review, we discuss our present understanding of protein domain promiscuity, its evolution and its role in cellular function.
PMCID: PMC2722818  PMID: 19151098
mobile domain; promiscuous domain; domain network; domain architecture; domain evolution
2.  The Ecoresponsive Genome of Daphnia pulex 
Science (New York, N.Y.)  2011;331(6017):555-561.
We describe the draft genome of the microcrustacean Daphnia pulex, which is only 200 Mb and contains at least 30,907 genes. The high gene count is a consequence of an elevated rate of gene duplication resulting in tandem gene clusters. More than 1/3 of Daphnia’s genes have no detectable homologs in any other available proteome, and the most amplified gene families are specific to the Daphnia lineage. The co-expansion of gene families interacting within metabolic pathways suggests that the maintenance of duplicated genes is not random, and the analysis of gene expression under different environmental conditions reveals that numerous paralogs acquire divergent expression patterns soon after duplication. Daphnia-specific genes – including many additional loci within sequenced regions that are otherwise devoid of annotations – are the most responsive genes to ecological challenges.
PMCID: PMC3529199  PMID: 21292972
3.  Primordial spliceosomal introns were probably U2-type 
Trends in Genetics  2008;24(11):525-528.
The two types of eukaryotic spliceosomal introns, U2 and U12, possess different splice signals and are excised by distinct spliceosomes. The nature of the primordial introns remains uncertain. A comparison of the amino acid distributions at insertion sites of introns that retained their positions throughout eukaryotic evolution with the distributions for human and Arabidopsis thaliana U2 and U12 introns reveals close similarity with U2 but not U12. Thus, the primordial spliceosomal introns were, most likely, U2-type.
PMCID: PMC3381341  PMID: 18824272
4.  Biological Systems Discovery In Silico: Radical S-Adenosylmethionine Protein Families and Their Target Peptides for Posttranslational Modification▿† 
Journal of Bacteriology  2011;193(11):2745-2755.
Data mining methods in bioinformatics and comparative genomics commonly rely on working definitions of protein families from prior computation. Partial phylogenetic profiling (PPP), by contrast, optimizes family sizes during its searches for the cooccurring protein families that serve different roles in the same biological system. In a large-scale investigation of the incredibly diverse radical S-adenosylmethionine (SAM) enzyme superfamily, PPP aided in building a collection of 68 TIGRFAMs hidden Markov models (HMMs) that define nonoverlapping and functionally distinct subfamilies. Many identify radical SAM enzymes as molecular markers for multicomponent biological systems; HMMs defining their partner proteins also were constructed. Newly found systems include five groupings of protein families in which at least one marker is a radical SAM enzyme while another, encoded by an adjacent gene, is a short peptide predicted to be its substrate for posttranslational modification. The most prevalent, in over 125 genomes, featuring a peptide that we designate SCIFF (six cysteines in forty-five residues), is conserved throughout the class Clostridia, a distribution inconsistent with putative bacteriocin activity. A second novel system features a tandem pair of putative peptide-modifying radical SAM enzymes associated with a highly divergent family of peptides in which the only clearly conserved feature is a run of His-Xaa-Ser repeats. A third system pairs a radical SAM domain peptide maturase with selenocysteine-containing targets, suggesting a new biological role for selenium. These and several additional novel maturases that cooccur with predicted target peptides share a C-terminal additional 4Fe4S-binding domain with PqqE, the subtilosin A maturase AlbA, and the predicted mycofactocin and Nif11-class peptide maturases as well as with activators of anaerobic sulfatases and quinohemoprotein amine dehydrogenases. Radical SAM enzymes with this additional domain, as detected by TIGR04085, significantly outnumber lantibiotic synthases and cyclodehydratases combined in reference genomes while being highly enriched for members whose apparent targets are small peptides. Interpretation of comparative genomics evidence suggests unexpected (nonbacteriocin) roles for natural products from several of these systems.
PMCID: PMC3133131  PMID: 21478363
5.  Expansion of ribosomally produced natural products: a nitrile hydratase- and Nif11-related precursor family 
BMC Biology  2010;8:70.
A new family of natural products has been described in which cysteine, serine and threonine from ribosomally-produced peptides are converted to thiazoles, oxazoles and methyloxazoles, respectively. These metabolites and their biosynthetic gene clusters are now referred to as thiazole/oxazole-modified microcins (TOMM). As exemplified by microcin B17 and streptolysin S, TOMM precursors contain an N-terminal leader sequence and C-terminal core peptide. The leader sequence contains binding sites for the posttranslational modifying enzymes which subsequently act upon the core peptide. TOMM peptides are small and highly variable, frequently missed by gene-finders and occasionally situated far from the thiazole/oxazole forming genes. Thus, locating a substrate for a particular TOMM pathway can be a challenging endeavor.
Examination of candidate TOMM precursors has revealed a subclass with an uncharacteristically long leader sequence closely related to the enzyme nitrile hydratase. Members of this nitrile hydratase leader peptide (NHLP) family lack the metal-binding residues required for catalysis. Instead, NHLP sequences display the classic Gly-Gly cleavage motif and have C-terminal regions rich in heterocyclizable residues. The NHLP family exhibits a correlated species distribution and local clustering with an ABC transport system. This study also provides evidence that a separate family, annotated as Nif11 nitrogen-fixing proteins, can serve as natural product precursors (N11P), but not always of the TOMM variety. Indeed, a number of cyanobacterial genomes show extensive N11P paralogous expansion, such as Nostoc, Prochlorococcus and Cyanothece, which replace the TOMM cluster with lanthionine biosynthetic machinery.
This study has united numerous TOMM gene clusters with their cognate substrates. These results suggest that two large protein families, the nitrile hydratases and Nif11, have been retailored for secondary metabolism. Precursors for TOMMs and lanthionine-containing peptides derived from larger proteins to which other functions are attributed, may be widespread. The functions of these natural products have yet to be elucidated, but it is probable that some will display valuable industrial or medical activities.
PMCID: PMC2887384  PMID: 20500830
6.  Analysis of Rare Genomic Changes Does Not Support the Unikont–Bikont Phylogeny and Suggests Cyanobacterial Symbiosis as the Point of Primary Radiation of Eukaryotes 
The deep phylogeny of eukaryotes is an important but extremely difficult problem of evolutionary biology. Five eukaryotic supergroups are relatively well established but the relationship between these supergroups remains elusive, and their divergence seems to best fit a “Big Bang” model. Attempts were made to root the tree of eukaryotes by using potential derived shared characters such as unique fusions of conserved genes. One popular model of eukaryotic evolution that emerged from this type of analysis is the unikont–bikont phylogeny: The unikont branch consists of Metazoa, Choanozoa, Fungi, and Amoebozoa, whereas bikonts include the rest of eukaryotes, namely, Plantae (green plants, Chlorophyta, and Rhodophyta), Chromalveolata, excavates, and Rhizaria. We reexamine the relationships between the eukaryotic supergroups using a genome-wide analysis of rare genomic changes (RGCs) associated with multiple, conserved amino acids (RGC_CAMs and RGC_CAs), to resolve trifurcations of major eukaryotic lineages. The results do not support the basal position of Chromalveolata with respect to Plantae and unikonts or the monophyly of the bikont group and appear to be best compatible with the monophyly of unikonts and Chromalveolata. Chromalveolata show a distinct, additional signal of affinity with Plantae, conceivably, owing to genes transferred from the secondary, red algal symbiont. Excavates are derived forms, with extremely long branches that complicate phylogenetic inference; nevertheless, the RGC analysis suggests that they are significantly more likely to cluster with the unikont–Chromalveolata assemblage than with the Plantae. Thus, the first split in eukaryotic evolution might lie between photosynthetic and nonphotosynthetic forms and so could have been triggered by the endosymbiosis between an ancestral unicellular eukaryote and a cyanobacterium that gave rise to the chloroplast.
PMCID: PMC2817406  PMID: 20333181
eukaryotic phylogeny; rare genomic changes; parsimony; substitutions; insertions; deletions
7.  U12 intron positions are more strongly conserved between animals and plants than U2 intron positions 
Biology Direct  2008;3:19.
We report that the positions of minor, U12 introns are conserved in orthologous genes from human and Arabidopsis to an even greater extent than the positions of the major, U2 introns. The U12 introns, especially, conserved ones are concentrated in 5'-portions of plant and animal genes, where the U12 to U2 conversions occurs preferentially in the 3'-portions of genes. These results are compatible with the hypothesis that the high level of conservation of U12 intron positions and their persistence in genomes despite the unidirectional U12 to U2 conversion are explained by the role of the slowly excised U12 introns in down-regulation of gene expression.
This article was reviewed by John Logsdon and Manyuan Long. For the full reviews, please go to the Reviewers' Reports section.
PMCID: PMC2426677  PMID: 18479526

Results 1-7 (7)