Current Genomics (v.13, #1)

Foreword by Christian Neri (1-1).
The past year has seen several important developments for Current Genomics. We have achieved a citation index impact factor of 2.48, indicating that the Journal reaches an increasingly wide audience. To achieve a citation index, papers must be formatted by the publisher and submitted for indexing. I want to thank the staff of Bentham Science for their effort in handling these procedures and ensuring the journal reaches a large audience. I also want to thank the members of the Editorial Board, the Section Editors, Associate Editors and Co-Editor for their effort in promoting editorial diversity and excellence in the wide field of genome sciences. Current Genomics aims at providing a unique forum for discussing the impact of genome sciences and systems biology in specific fields of research such as Evolution, Developmental biology, Aging and Disease research. To this end, the journal offers different formats such as regular reviews as well as Mini-Hot-Topic and Hot-Topic issues. This past year, we published five Hot-Topics issues including ‘Genes Coding Industrially Relevant Enzymes in Fungi: Isolation and Protein Engineering of Laccases’ edited by Dr. Vincenza Faraco, ‘Genomics of Childhood Obesity’ edited by Dr. Merlin G. Butler, ‘Retinitis pigmentosa: criticisms and management’ edited by Dr. Francesco Parmeggiani, ‘Evolutionary system biology’ edited by Dr. Jianying Gu, and ‘Thyroid: from genes to the disease’ edited by Dr. Katja Zaletel. All five issues greatly illustrate the increasingly important role of genome sciences in the various fields of biology and medicine. We plan to publish five more Hot-Topics issues this year including ‘Replicating strand asymmetry in bacterial and eukaryotic genomes’ organized by Dr. Feng-Biao Guo, ‘Comparative genomics and genome evolution’ organized by Drs. Sabyasachi Das and Masayuki Hirano, ‘Genetics dissection of complex traits in the genomic era’ organized by Dr. Bernardo Ordas, ‘Genomics-based medicine, single cell analysis and the prospects for risk assessment

It is my pleasure as a Guest Editor of Current Genomics to present you with a ‘hot topic issue’ on DNA replication. DNA replication adopts a set of asymmetric mechanisms. One of them is the division of leading and lagging strands. In 1991, the nucleotide composition bias between the two replicating strands was originally found in genomes of echinoderm and vertebrate mitochondria. In the following twenty years, more and more bacterial genomes are found to have much different nucleotide composition between the two replicating strands. More importantly, eukaryotes and even mammalians are found to have such strand bias (asymmetry) in recent years. Besides composition bias, there are also other types of biases between two replicating strands, such as gene orientation bias, gene function bias and substitution rate bias. This topic of replicating strand bias has attracted numerous researchers to perform abundant and in-depth researches. In my view, it will continue to be one of the hot topics of genomics. A better understanding of replicating strand asymmetry will greatly advance our knowledge about the mechanism of DNA replication. This theme issue aims mainly to summarize various types of biases between the two replicating strands in bacterial and eukaryotic genomes. Another aim is to try to elucidate the underlying mechanisms of various strand biases. Therefore, this theme issue includes papers reviewing types, extents, application and underlying mechanism of strand asymmetry both in bacterial and eukaryotic genomes. K. Arakawa and M. Tomita reviewed the measures of strand bias that have been proposed to date, including the ΔGC skew, the predictability score of linear discriminant analysis for gene orientation and so on. These methods measure the general composition bias, gene distribution bias and the composition bias of certain oligonucleotides, respectively. Although these measures were predominantly designed for and applied in analyzing replication-related mutational processes of prokaryotes, the authors also give research examples in eukaryotes. X. Xia summarized the diverse patterns of strand asymmetry among different taxonomic groups and made four suggestions. The survey was involved with bacterial, archaeal and mitochondrial genomes. The four suggestions concern the numbers of replication origins and replicating mechanism in certain taxa. Lin et al. reviewed composition bias between light and heavy strands of animal mitochondrial genomes. They discussed the influence of replication-associated mutation pressure on nucleotide and amino acid compositions as well as gene organization in these genomes.....

The compositional asymmetry of complementary bases in nucleotide sequences implies the existence of a mutational or selectional bias in the two strands of the DNA duplex, which is commonly shaped by strand-specific mechanisms in transcription or replication. Such strand bias in genomes, frequently visualized by GC skew graphs, is used for the computational prediction of transcription start sites and replication origins, as well as for comparative evolutionary genomics studies. The use of measures of compositional strand bias in order to quantify the degree of strand asymmetry is crucial, as it is the basis for determining the applicability of compositional analysis and comparing the strength of the mutational bias in different biological machineries in various species. Here, we review the measures of strand bias that have been proposed to date, including the ΔGC skew, the B1 index, the predictability score of linear discriminant analysis for gene orientation, the signal-to-noise ratio of the oligonucleotide bias, and the GC skew index. These measures have been predominantly designed for and applied to the analysis of replication-related mutational processes in prokaryotes, but we also give research examples in eukaryotes.

Different patterns of strand asymmetry have been documented in a variety of prokaryotic genomes as well as mitochondrial genomes. Because different replication mechanisms often lead to different patterns of strand asymmetry, much can be learned of replication mechanisms by examining strand asymmetry. Here I summarize the diverse patterns of strand asymmetry among different taxonomic groups to suggest that (1) the single-origin replication may not be universal among bacterial species as the endosymbionts Wigglesworthia glossinidia, Wolbachia species, cyanobacterium Synechocystis 6803 and Mycoplasma pulmonis genomes all exhibit strand asymmetry patterns consistent with the multiple origins of replication, (2) different replication origins in some archaeal genomes leave quite different patterns of strand asymmetry, suggesting that different replication origins in the same genome may be differentially used, (3) mitochondrial genomes from representative vertebrate species share one strand asymmetry pattern consistent with the stranddisplacement replication documented in mammalian mtDNA, suggesting that the mtDNA replication mechanism in mammals may be shared among all vertebrate species, and (4) mitochondrial genomes from primitive forms of metazoans such as the sponge and hydra (representing Porifera and Cnidaria, respectively), as well as those from plants, have strand asymmetry patterns similar to single-origin or multi-origin replications observed in prokaryotes and are drastically different from mitochondrial genomes from other metazoans. This may explain why sponge and hydra mitochondrial genomes, as well as plant mitochondrial genomes, evolves much slower than those from other metazoans.

The nucleotide composition of the light (L-) and heavy (H-) strands of animal mitochondrial genomes is known to exhibit strand-biased compositional asymmetry (SCA). One of the possibilities is the existence of a replicationassociated mutational pressure (RMP) that may introduce characteristic nucleotide changes among mitochondrial genomes of different animal lineages. Here, we discuss the influence of RMP on nucleotide and amino acid compositions as well as gene organization. Among animal mitochondrial genomes, RMP may represent the major force that compels the evolution of mitochondrial protein-coding genes, coupled with other process-based selective pressures, such as on components of translation machinery- tRNAs and their anticodons. Through comparative analyses of sequenced mitochondrial genomes among diverse animal lineages and literature reviews, we suggest a strong RMP effect, observed among invertebrate mitochondrial genes as compared to those of vertebrates, that is either a result of positive selection on the invertebrate or a relaxed selective pressure on the vertebrate mitochondrial genes.

Distances from heavy and light strand replication origins determine duration mitochondrial DNA remains singlestranded during replication. Hydrolytic deaminations from A- > G and C- > T occur more on single- than doublestranded DNA. Corresponding replicational nucleotide gradients exist across mitochondrial genomes, most at 3rd, least 2nd codon positions. DNA singlestrandedness during RNA transcription causes gradients mainly in long-lived species with relatively slow metabolism (high transcription/replication ratios). Third codon nucleotide contents, evolutionary results of mutation cumulation, follow replicational, not transcriptional gradients in Homo; observed human mutations follow transcriptional gradients. Synonymous third codon position transitions potentially alter adaptive off frame information. No mutational gradients occur at synonymous positions forming off frame stops (these adaptively stop early accidental frameshifted protein synthesis), nor in regions coding for putative overlapping genes according to an overlapping genetic code reassigning stop codons to amino acids. Deviation of 3rd codon nucleotide contents from deamination gradients increases with coding importance of main frame 3rd codon positions in overlapping genes (greatest if these are 2nd position in overlapping genes). Third codon position deamination gradients calculated separately for each codon family are strongest where synonymous transitions are rarely pathogenic; weakest where transitions are frequently pathogenic. Synonymous mutations affect translational accuracy, such as error compensation of misloaded tRNAs by codon-anticodon mismatches (prevents amino acid misinsertion despite tRNA misacylation), a potential cause of pathogenic mutations at synonymous codon positions. Indeed, codon-family-specific gradients are inversely proportional to error compensation associated with gradient-promoted transitions. Deamination gradients reflect spontaneous chemical reactions in singlestranded DNA, but functional coding constraints modulate gradients.

In the present review, we summarized current knowledge on replicative strand asymmetries in prokaryotic genomes. A cornerstone for the creation of a theory of their formation has been overviewed. According to our recent works, the probability of nonsense mutation caused by replication-associated mutational pressure is higher for genes from lagging strands than for genes from leading strands of both bacterial and archaeal genomes. Lower density of open reading frames in lagging strands can be explained by faster rates of nonsense mutations in genes situated on them. According to the asymmetries in nucleotide usage in fourfold and twofold degenerate sites, the direction of replicationassociated mutational pressure for genes from lagging strands is usually the same as the direction of transcriptionassociated mutational pressure. It means that lagging strands should accumulate more 8-oxo-G, uracil and 5-formyl-uracil, respectively. In our opinion, consequences of cytosine deamination (C to T transitions) do not lead to the decrease of cytosine usage in genes from lagging strands because of the consequences of thymine oxidation (T to C transitions), while guanine oxidation (causing G to T transversions) makes the main contribution into the decrease of guanine usage in fourfold degenerate sites of genes from lagging strands. Nucleotide usage asymmetries and bias in density of coding regions can be found in archaeal genomes, although, the percent of “inversed” asymmetries is much higher for them than for bacterial genomes. “Homogenized” and “inversed” replicative strand asymmetries in archaeal genomes can be used as retrospective indexes for detection of OriC translocations and large inversions.

Replication and transcription are key aspects of DNA metabolism that take place on the same template and potentially interfere with each other. Conflicts between these two activities include head-on or co-directional collisions between DNA and RNA polymerases, which can lead to the formation of DNA breaks and chromosome rearrangements. To avoid these deleterious consequences and prevent genomic instability, cells have evolved multiple mechanisms preventing replication forks from colliding with the transcription machinery. Yet, recent reports indicate that interference between replication and transcription is not limited to physical interactions between polymerases and that other cotranscriptional processes can interfere with DNA replication. These include DNA-RNA hybrids that assemble behind elongating RNA polymerases, impede fork progression and promote homologous recombination. Here, we discuss recent evidence indicating that R-loops represent a major source of genomic instability in all organisms, from bacteria to human, and are potentially implicated in cancer development.

Homology can have different meanings for different kinds of biologists. A phylogenetic view holds that homology, defined by common ancestry, is rigorously identified through phylogenetic analysis. Such homologies are taxic homologies (=synapomorphies). A second interpretation, “biological homology” emphasizes common ancestry through the continuity of genetic information underlying phenotypic traits, and is favored by some developmental geneticists. A third kind of homology, deep homology, was recently defined as “the sharing of the genetic regulatory apparatus used to build morphologically and phylogenetically disparate features.” Here we explain the commonality among these three versions of homology. We argue that biological homology, as evidenced by a conserved gene regulatory network giving a trait its “essential identity” (a Character Identity Network or “ChIN”) must also be a taxic homology. In cases where a phenotypic trait has been modified over the course of evolution such that homology (taxic) is obscured (e.g. jaws are modified gill arches), a shared underlying ChIN provides evidence of this transformation. Deep homologies, where molecular and cellular components of a phenotypic trait precede the trait itself (are phylogenetically deep relative to the trait), are also taxic homologies, undisguised. Deep homologies inspire particular interest for understanding the evolutionary assembly of phenotypic traits. Mapping these deeply homologous building blocks on a phylogeny reveals the sequential steps leading to the origin of phenotypic novelties. Finally, we discuss how new genomic technologies will revolutionize the comparative genomic study of non-model organisms in a phylogenetic context, necessary to understand the evolution of phenotypic traits.