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Spin-orbit coupling emerging out of a material's global inversion symmetry breaking has been long known to act as a pair breaking mechanism to the superconducting order parameter. However, when spin-orbit coupling emerges from local inversion symmetry breaking, an unexpected coexistence with superconductivity might occur. Although lattice driven local symmetry breaking is intrinsic to a variety of unconventional superconductors, little is known about its close connection to spin-orbit coupling, and how the combination of the two can impact electronic properties and the microscopic classification of the order parameter. By using high-resolution spin- and angle-resolved photoemission spectroscopy we reveal the presence of a universal momentum-dependent spin texture throughout the hole-doped side of the cuprate phase diagram for the Bi-based family, which becomes negligible on the electron-doped side. We attribute this spin asymmetry to local inversion symmetry breaking induced by local distortions of the CuO octahedra, revealing an interplay between spin-orbit coupling and lattice symmetry. The implication of this connection in steering the ground state properties of cuprate superconductors is discussed, together with the intriguing possibility that it might provide the long missing link to explain the complexity and asymmetry of the cuprate phase diagram.

We performed an exhaustive pairwise comparison of whole-genome sequences of 3120 individuals, representing 232 populations from all continents and seven prehistoric people including archaic and modern humans. In order to reveal an intricate picture of worldwide human genetic relatedness, 65 million very rare single nucleotide polymorphic (SNP) alleles have been bioinformatically processed. The number and size of shared identical-by-descent (IBD) genomic fragments for every pair of 3127 individuals have been revealed. Over 17 million shared IBD fragments have been described. Our approach allowed detection of very short IBD fragments (&lt, 20 kb) that trace common ancestors who lived up to 200,000 years ago. We detected nine distinct geographical regions within which individuals had strong genetic relatedness, but with negligible relatedness between the populations of these regions. The regions, comprising nine unique genetic components for mankind, are the following: East and West Africa, Northern Europe, Arctica, East Asia, Oceania, South Asia, Middle East, and South America. The level of admixture in every studied population has been apportioned among these nine genetic components. Genetically, long-term neighboring populations are strikingly similar to each other in spite of any political, religious, and cultural differences. The topmost admixture has been observed at the center of Eurasia. These admixed populations (including Uyghurs, Azerbaijanis, Uzbeks, and Iranians) have roughly equal genetic contributions from the Middle East, Europe, China, and India, with additional significant traces from Africa and Arctic. The entire picture of relatedness of all the studied populations unfolds and presents itself in the form of shared number/size of IBDs.

A novel computational method for detecting identical-by-descent (IBD) chromosomal segments between sequenced genomes is presented. It utilizes the distribution patterns of very rare genetic variants (vrGVs), which have minor allele frequencies

In 1974, Takeo Maruyama deduced that neutral mutations should, on average, be older than deleterious or beneficial ones. This theory is based on the diffusion approximation for a branching process, which considers mutations independently of one another and not as multiple groups of interconnected mutations with strong linkage disequilibrium (haplotypes). However, mammalian genomes contain thousands of haplotypes, in which beneficial, neutral, and deleterious mutations are tightly linked to each other. This complex haplotype organization should not be ignored for estimation of allelic ages. We employed our GEMA computer simulation program for genome evolution to re-evaluate Maruyama's phenomenon in modeled populations that include haplotypes approximating real genomes. We determined that only under specific conditions (high recombination rates and abundance of neutral mutations), the deleterious and beneficial mutations are younger than neutral ones as predicted by Maruyama. Under other conditions, the ages of negative, neutral, and beneficial mutations were almost the same.

Nucleotide sequence differences on the whole-genome scale have been computed for 1,092 people from 14 populations publicly available by the 1000 Genomes Project. Total number of differences in genetic variants between 96,464 human pairs has been calculated. The distributions of these differences for individuals within European, Asian, or African origin were characterized by narrow unimodal peaks with mean values of 3.8, 3.5, and 5.1 million, respectively, and standard deviations of 0.1–0.03 million. The total numbers of genomic differences between pairs of all known relatives were found to be significantly lower than their respective population means and in reverse proportion to the distance of their consanguinity. By counting the total number of genomic differences it is possible to infer familial relations for people that share down to 6% of common loci identical-by-descent. Detection of familial relations can be radically improved when only very rare genetic variants are taken into account. Counting of total number of shared very rare single nucleotide polymorphisms (SNPs) from whole-genome sequences allows establishing distant familial relations for persons with eighth and ninth degrees of relationship. Using this analysis we predicted 271 distant familial pairwise relations among 1,092 individuals that have not been declared by 1000 Genomes Project. Particularly, among 89 British and 97 Chinese individuals we found three British–Chinese pairs with distant genetic relationships. Individuals from these pairs share identical-by-descent DNA fragments that represent 0.001%, 0.004%, and 0.01% of their genomes. With affordable whole-genome sequencing techniques, very rare SNPs should become important genetic markers for familial relationships and population stratification.

Background GC-Biased Gene Conversion (gBGC) is one of the important theories put forward to explain profound long-range non-randomness in nucleotide compositions along mammalian chromosomes. Nucleotide changes due to gBGC are hard to distinguish from regular mutations. Here, we present an algorithm for analysis of millions of known SNPs that detects a subset of so-called “SNP flip-over” events representing recent gBGC nucleotide changes, which occurred in previous generations via non-crossover meiotic recombination. Results This algorithm has been applied in a large-scale analysis of 1092 sequenced human genomes. Altogether, 56,328 regions on all autosomes have been examined, which revealed 223,955 putative gBGC cases leading to SNP flip-overs. We detected a strong bias (11.7% ± 0.2% excess) in AT- > GC over GC- > AT base pair changes within the entire set of putative gBGC cases. Conclusions On average, a human gamete acquires 7 SNP flip-over events, in which one allele is replaced by its complementary allele during the process of meiotic non-crossover recombination. In each meiosis event, on average, gBGC results in replacement of 7 AT base pairs by GC base pairs, while only 6 GC pairs are replaced by AT pairs. Therefore, every human gamete is enriched by one GC pair. Happening over millions of years of evolution, this bias may be a noticeable force in changing the nucleotide composition landscape along chromosomes. Electronic supplementary material The online version of this article (10.1186/s12864-018-4593-1) contains supplementary material, which is available to authorized users.

Background Inferring history from genomic sequences is challenging and problematic because chromosomes are mosaics of thousands of small Identicalby-descent (IBD) fragments, each of them having their own unique story. However, the main events in recent evolution might be deciphered from comparative analysis of numerous loci. A paradox of why humans, whose effective population size is only 104, have nearly three million frequent SNPs is formulated and examined. Results We studied 5398 loci evenly covering all human autosomes. Common haplotypes built from frequent SNPs that are present in people from various populations have been examined. We demonstrated highly non-random arrangement of alleles in common haplotypes. Abundance of mutually exclusive pairs of common haplotypes that have different alleles at every polymorphic position (so-called Yin/Yang haplotypes) was found in 56% of loci. A novel widely spread category of common haplotypes named Mosaic has been described. Mosaic consists of numerous pieces of Yin/Yang haplotypes and represents an ancestral stage of one of them. Scenarios of possible appearance of large number of frequent human SNPs and their habitual arrangement in Yin/Yang common haplotypes have been evaluated with an advanced genomic simulation algorithm. Conclusions Computer modeling demonstrated that the observed arrangement of 2.9 million frequent SNPs could not originate from a sole stand-alone population. A “Great Admixture” event has been proposed that can explain peculiarities with frequent SNP distributions. This Great Admixture presumably occurred 100–300 thousand years ago between two ancestral populations that had been separated from each other about a million years ago. Our programs and algorithms can be applied to other species to perform evolutionary and comparative genomics. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3776-5) contains supplementary material, which is available to authorized users.

Mammalian genomes are replete with millions of polymorphic sites, among which those genetic variants that are colocated on the same chromosome and exist close to one another form blocks of closely linked mutations known as haplotypes. The linkage within haplotypes is constantly disrupted due to meiotic recombination events. Whole ensembles of such numerous haplotypes are subjected to evolutionary pressure, where mutations influence each other and should be considered as a whole entity—a gigantic matrix, unique for each individual genome. This idea was implemented into a computational approach, named Genome Evolution by Matrix Algorithms (GEMA) to model genomic changes taking into account all mutations in a population. GEMA has been tested for modeling of entire human chromosomes. The program can precisely mimic real biological processes that have influence on genome evolution such as: 1) Authentic arrangements of genes and functional genomic elements, 2) frequencies of various types of mutations in different nucleotide contexts, and 3) nonrandom distribution of meiotic recombination events along chromosomes. Computer modeling with GEMA has demonstrated that the number of meiotic recombination events per gamete is among the most crucial factors influencing population fitness. In humans, these recombinations create a gamete genome consisting on an average of 48 pieces of corresponding parental chromosomes. Such highly mosaic gamete structure allows preserving fitness of population under the intense influx of novel mutations (40 per individual) even when the number of mutations with deleterious effects is up to ten times more abundant than those with beneficial effects.

Little is known about pre-mRNA splicing in Dictyostelium discoideum although its genome has been completely sequenced. Our analysis suggests that pre-mRNA splicing plays an important role in D. discoideum gene expression as two thirds of its genes contain at least one intron. Ongoing curation of the genome to date has revealed 40 genes in D. discoideum with clear evidence of alternative splicing, supporting the existence of alternative splicing in this unicellular organism. We identified 160 candidate U2-type spliceosomal proteins and related factors in D. discoideum based on 264 known human genes involved in splicing. Spliceosomal small ribonucleoproteins (snRNPs), PRP19 complex proteins and late-acting proteins are highly conserved in D. discoideum and throughout the metazoa. In non-snRNP and hnRNP families, D. discoideum orthologs are closer to those in A. thaliana, D. melanogaster and H. sapiens than to their counterparts in S. cerevisiae. Several splicing regulators, including SR proteins and CUG-binding proteins, were found in D. discoideum, but not in yeast. Our comprehensive catalog of spliceosomal proteins provides useful information for future studies of splicing in D. discoideum where the efficient genetic and biochemical manipulation will also further our general understanding of pre-mRNA splicing.

For the nearly 400 attendees, the 2010 ALS Users' Meeting was a smashing success. In his opening remarks, Users' Executive Committee (UEC) Chair David Osborn thanked meeting co-chairs Hendrik Bluhm and Brandy Toner for what was to be an enjoyable and stimulating conference and a year of innovation with the first Student Poster Slam and ALS Photography Competition.

Among thousands of non-protein-coding RNAs which have been found in humans, a significant group represents snoRNA molecules that guide other types of RNAs to specific chemical modifications, cleavages, or proper folding. Yet, hundreds of mammalian snoRNAs have unknown function and are referred to as "orphan" molecules. In 2006, for the first time, it was shown that a particular orphan snoRNA (HBII-52) plays an important role in the regulation of alternative splicing of the serotonin receptor gene in humans and other mammals. In order to facilitate the investigation of possible involvement of snoRNAs in the regulation of pre-mRNA processing, we developed a new computational web resource, snoTARGET, which searches for possible guiding sites for snoRNAs among the entire set of human and rodent exonic and intronic sequences. Application of snoTARGET for finding possible guiding sites for a number of human and rodent orphan C/D-box snoRNAs showed that another subgroup of these molecules (HBII-85) have statistically elevated guiding preferences toward exons compared to introns. Moreover, these energetically favorable putative targets of HBII-85 snoRNAs are non-randomly associated with genes producing alternatively spliced mRNA isoforms. The snoTARGET resource is freely available at: (http://hsc.utoledo.edu/depts/bioinfo/snotarget.html).

Investigation of exon ^ intron gene structures is a non-trivial task due to enormous expansions of the eukaryotic genomes, great variety of gene forms, and the imperfectness in sequence data. A number of available informational systems on various gene characteristics complement each other and are indispensable for many genomic studies. Among them, the Exon-Intron Database (EID) is a good choice for large-scale computational examination of exon/intron structure and splicing. It has many internal filters that control for sequence quality, consistency of gene descriptions, accordance to standards, and possible errors. New innovations in EID are described. The collection of exons and introns has been extended beyond coding regions and current versions of EID contain data on untranslated regions of gene sequences as well. Intron-less genes are included as a special part of EID. For species with entirely sequenced genomes, species-specific databases have been generated. A novel Mammalian Orthologous Intron Database (MOID) has been introduced which includes the full set of introns that come from orthologous genes that have the same positions relative to the reading frames. Examples of statistical analyses of gene sequences using EID are provided. We present the latest data on our comparison of intron positions in 11025 orthologous genes of human, mouse and rat, and find no convincing cases of intron gain. We discuss relevant data-quality issues of genomic databases. In particular, 5% of genes in genomic databases contain internal stop codons. This fact is due to a combination of biological reasons and also to errors in sequence annotations. The EID is freely available at www.meduohio.edu/bioinfo/eid/.

Motivation: Using bioinformatic approaches we aimed to characterize poorly understood abnormalities in splicing known as exon scrambling, exon repetition and trans-splicing. Results: We developed a software package that allows large-scale comparison of all human expressed sequence tags (EST) sequences to the entire set of human gene sequences. Among 5 992 495 EST sequences, 401 cases of exon repetition and 416 cases of exon scrambling were found. The vast majority of identified ESTs contain fragments rather than full-length repeated or scrambled exons. Their structures suggest that the scrambled or repeated exon fragments may have arisen in the process of cDNA cloning and not from splicing abnormalities. Nevertheless, we found 11 cases of full-length exon repetition showing that this phenomenon is real yet very rare. In searching for examples of trans-splicing, we looked only at reproducible events where at least two independent ESTs represent the same putative trans-splicing event. We found 15 ESTs representing five types of putative trans-splicing. However, all 15 cases were derived from human malignant tissues and could have resulted from genomic rearrangements. Our results provide support for a very rare but physiological occurrence of exon repetition, but suggest that apparent exon scrambling and trans-splicing result, respectively, from in vitro artifact and gene-level abnormalities. Availability: Exon–Intron Database (EID) is available at . Programs are available at . The Laboratory website is available at Contact: afedorov@meduohio.edu Supplementary information: Supplementary file is available at

Based on comparative genomics, we created a bioinformatic package for computer prediction of small nucleolar RNA (snoRNA) genes in mammalian introns. The core of our approach was the use of the Mammalian Orthologous Intron Database (MOID), which contains all known introns within the human, mouse and rat genomes. Introns from orthologous genes from these three species, that have the same position relative to the reading frame, are grouped in a special orthologous intron table. Our program SNO.pl searches for conserved snoRNA motifs within MOID and reports all cases when characteristic snoRNA-like structures are present in all three orthologous introns of human, mouse and rat sequences. Here we report an example of the SNO.pl usage for searching a particular pattern of conserved C/D-box snoRNA motifs (canonical C- and D-boxes and the 6 nt long terminal stem). In this computer analysis, we detected 57 triplets of snoRNA-like structures in three mammals. Among them were 15 triplets that represented known C/D-box snoRNA genes. Six triplets represented snoRNA genes that had only been partially characterized in the mouse genome. One case represented a novel snoRNA gene, and another three cases, putative snoRNAs. Our programs are publicly available and can be easily adapted and/or modified for searching any conserved motifs within mammalian introns.

The relationship among the three cellular domains Archaea, Bacteria, and Eukarya has become a central problem in unraveling the tree of life. This relationship can now be studied as the completely sequenced genomes of representatives of these cellular domains become available. We performed a bioinformatic investigation of the Encephalitozoon cuniculi proteome. E. cuniculi has the smallest sequenced eukaryotic genome, 2.9 megabases coding for 1997 proteins. The proteins of E. cuniculi were compared with a previously characterized set of eukaryotic signature proteins (ESPs). ESPs are found in a eukaryotic cell, whether from an animal, a plant, a fungus, or a protozoan, but are not found in the Archaea and the Bacteria. We demonstrated that 85% of the ESPs have significant sequence similarity to proteins in E. cuniculi. Hence, E. cuniculi, a minimal eukaryotic cell that has removed all inessential proteins, still preserves most of the ESPs that make it a member of the Eukarya. The locations and functions of these ESPs point to the earliest history of eukaryotes.

We compared intron–exon structures in 1,560 human–mouse orthologs and 360 mouse–rat orthologs. The origin of differences in intron positions between species was inferred by comparison with an outgroup, Fugu for human–mouse and human for mouse–rat. Among 10,020 intron positions in the human–mouse comparison, we found unequivocal evidence for five independent intron losses in the mouse lineage but no evidence for intron loss in humans or for intron gain in either lineage. Among 1,459 positions in rat–mouse comparisons, we found evidence for one loss in rat but neither loss in mouse nor gain in either lineage. In each case, the intron losses were exact, without change in the surrounding coding sequence, and involved introns that are extremely short, with an average of 200 bp, an order of magnitude shorter than the mammalian average. These results favor a model whereby introns are lost through gene conversion with intronless copies of the gene. In addition, the finding of widespread conservation of intron–exon structure, even over large evolutionary distances, suggests that comparative methods employing information about gene structures should be very successful in correctly predicting exon boundaries in genomic sequences.

For nearly 15 years, it has been widely believed that many introns were recently acquired by the genes of multicellular organisms. However, the mechanism of acquisition has yet to be described for a single animal intron. Here, we report a large-scale computational analysis of the human, Drosophila melanogaster, Caenorhabditis elegans, and Arabidopsis thaliana genomes. We divided 147,796 human intron sequences into batches of similar lengths and aligned them with each other. Different types of homologies between introns were found, but none showed evidence of simple intron transposition. Also, 106,902 plant, 39,624 Drosophila, and 6021 C. elegans introns were examined. No single case of homologous introns in nonhomologous genes was detected. Thus, we found no example of transposition of introns in the last 50 million years in humans, in 3 million years in Drosophila and C. elegans, or in 5 million years in Arabidopsis. Either new introns do not arise via transposition of other introns or intron transposition must have occurred so early in evolution that all traces of homology have been lost.

We purge large databases of animal, plant, and fungal intron-containing genes to a 20% similarity level and then identify the most similar animal-plant, animal-fungal, and plant-fungal protein pairs. We identify the introns in each BLAST 2.0 alignment and score matched intron positions and slid (near-matched, within six nucleotides) intron positions automatically. Overall we find that 10% of the animal introns match plant positions, and a further 7% are "slides." Fifteen percent of fungal introns match animal positions, and 13% match plant positions. Furthermore, the number of alignments with high numbers of matches deviates greatly from the Poisson expectation. The 30 animal-plant alignments with the highest matches (for which 44% of animal introns match plant positions) when aligned with fungal genes are also highly enriched for triple matches: 39% of the fungal introns match both animal and plant positions. This is strong evidence for ancestral introns predating the animal-plant-fungal divergence, and in complete opposition to any expectations based on random insertion. In examining the slid introns, we show that at least half are caused by imperfections in the alignments, and are most likely to be actual matches at common positions. Thus, our final estimates are that approximately equal 14% of animal introns match plant positions, and that approximately equal 17-18% of fungal introns match animal or plant positions, all of these being likely to be ancestral in the eukaryotes.

In ancient genes whose products have known 3-dimensional structures, an excess of phase zero introns (those that lie between the codons) appear in the boundaries of modules, compact regions of the polypeptide chain. These excesses are highly significant and could support the hypothesis that ancient genes were assembled by exon shuffling involving compact modules. (Phase one and two introns, and many phase zero introns, appear to arise later.) However, as more genes, with larger numbers of homologs and intron positions, were examined, the effects became smaller, dropping from a 40% excess to an 8% excess as the number of intron positions increased from 570 to 3,328, even though the statistical significance remained strong. An interpretation of this behavior is that novel inserted positions appearing in homologs washed out the signal from a finite number of ancient positions. Here we show that this is likely to be the case. Analyses of intron positions restricted to those in genes for which relatively few intron positions from homologs are known, or to those in genes with a small number of known homologous gene structures, show a significant correlation of phase zero intron positions with the module structure, which weakens as the density of attributed intron positions or the number of homologs increases. These effects do not appear for phase one and phase two introns. This finding matches the expectation of the mixed model of intron origin, in which a fraction of phase zero introns are left from the assembly of the first genes, while other introns have been added in the course of evolution.

Do introns delineate elements of protein tertiary structure? This issue is crucial to the debate about the role and origin of introns. We present an analysis of the full set of proteins with known three-dimensional structures that have homologs with intron positions recorded in GenBank. A computer program was generated that maps on a reference sequence the positions of all introns in homologous genes. We have applied this program to a set of 665 nonredundant protein sequences with defined three-dimensional structures in the Protein Data Bank (PDB), which yielded 8,217 introns in 407 proteins. For the subset of proteins corresponding to ancient conserved regions (ACR), we find that there is a correlation of phase-zero introns with the boundary regions of modules and no correlation for the phase-one and phase-two positions. However, for a subset of proteins without prokaryotic counterparts (131 non-ACR proteins), a set of presumably modern proteins (or proteins that have diverged extremely far from any ancestral form), we do not find any correlation of phase-zero intron positions with three-dimensional structure. Furthermore, we find an anticorrelation of phase-one intron positions with module boundaries: they actually have a preference for the interior of modules. This finding is explicable as a preference for phase-one introns to lie in glycines, between G|G sequences, the preference for glycines being anticorrelated with the three-dimensional modules. We interpret this anticorrelation as a sign that a number of phase-one introns, and hence many modern introns, have been inserted into G|G “protosplice” sequences.

Another expected legacy of ancient phase-zero introns is that putatively ancient introns (those widely phylogenetically distributed) should have a stronger phase-zero bias. We tested this notion by examining widely distributed C. elegans intron positions: those present in two or more kingdoms. We used a database of ancient genes with known corresponding protein structures (culled from the Protein Data Bank) and the introns from their homologues, compiled by Fedorov and collaborators (unpublished). Of 6568 total intron positions, C. elegans introns are found at 1539 positions within 280 gene families. At 233 of these C. elegans positions there are also introns in the copies of the gene from non-animal organisms. Such coincident positions are candidates for the positions of ancient introns, based on this very wide phylogenetic distribution. (These coincident intron positions do, in fact, show a stronger correlation with module boundaries 6xCentripetal modules and ancient introns. Roy, S.W. et al. Gene. 1999; 238: 85–91Crossref | PubMed | Scopus (40)See all References6.) If these positions are indeed ancient, and if the phase-zero bias of introns is due to the presence of ancient introns, this ancient subset of C. elegans introns should have a higher phase-zero bias than should the set of animal-unique C. elegans introns.Table 2Table 2 shows that this ancient subset does have a significantly stronger phase-zero bias (62.2% versus 50.8%), with a χ2 of 10.4 (P = 0.0013). This is a striking verification of the expectation that part of the phase-zero bias is due to the presence of truly ancient introns. Table 3Table 3 shows further that this is a general phenomenon. There is a highly-significant difference between the phase bias of animal intron positions at which introns are found in two or more kingdoms and those positions that are exclusively animal. The same is true for invertebrates and vertebrates separately, for plants, and for fungi, and there is a significant difference for protists. This trend is seen even further in positions where introns are found in three or more kingdoms. This result suggests that there were in fact ancient intron positions and that the observed excess of phase-zero positions is, at least in part, due to their presence in modern eukaryotes.Table 2Phase patterns of introns in Caenorhabditis elegans genesPhase zeroχ2Phase onePhase twoTotal intronsExclusively animal C. elegans positions663 50.8%306 23.4%337 25.8%1306Widely distributed C. elegans positions145 62.2%10.446 19.7%42 18.0%233Widely distributed signifies that an intron is also found at that position in a non-animal copy of the gene. The introns are from the database of 6568 intron positions in the set of ancient genes that have three-dimensional structures for the corresponding proteins compiled by Fedorov and collaborators (unpublished). The χ2 is calculated comparing phase zero with (phase one + phase two).Table 3Phase patterns of introns in different kingdomsaPhase zeroχ2Phase onePhase twoTotal intronsAnimalExclusively animal1607 50.2%860 26.9%735 23.0%3202Animal and other kingdom(s)329 59.8%17.4127 23.1%94 17.1%550Exclusively vertebrate504 48.2%324 31.0%217 20.8%1045Vertebrate and other kingdom(s)194 61.8%17.869 22.0%51 16.2%314Exclusively invertebrate906 51.6%423 24.1%428 24.4%1757Invertebrate and other kingdom(s)246 58.9%7.296 23.0%76 18.2%418 PlantExclusively plant1166 59.9%398 20.5%381 19.6%1945Plant and other kingdom(s)323 66.1%6.199 20.2%67 13.7%489 FungiExclusively fungi303 42.7%236 33.3%170 24.0%709Fungi and other kingdom(s)118 54.1%8.756 25.7%44 20.2%218 ProtistExclusively protist34 38.6%28 31.8%26 29.5%88Protists and other kingdom(s)41 56.9%5.316 22.2%15 20.8%72 AllOnly one kingdom3110 52.3%1522 25.6%1312 22.1%5944Two or more kingdoms371 60.4%14.7142 23.1%101 16.4%614Three or more kingdoms51 64.6%13 16.5%15 19.0%79The introns are from the database of 6568 intron positions in the set of ancient genes that have three-dimensional structures for the corresponding proteins compiled by Fedorov and collaborators (unpublished). The χ2 is calculated comparing phase zero with (phase one + phase two).These twin findings – first, that the intron phases in ancient genes, defined by BLAST scores, differ from those of recently transferred genes by having a stronger phase-zero bias, and second, that phylogenetically ancient intron positions also show a stronger phase-zero bias – support the theory that introns, mostly in phase zero, were present in the LUCA.Furthermore, as phase-zero, widely phylogenetically-distributed intron positions are highly correlated with the boundaries of modules 6xCentripetal modules and ancient introns. Roy, S.W. et al. Gene. 1999; 238: 85–91Crossref | PubMed | Scopus (40)See all References6, the subset of introns possessing one characteristic expected of ancient intron positions – wide phylogenetic distribution – also possesses two other traits expected of ancient positions. This is a result easily explained on a mixed intron-origin model, but not easily explained on strictly insertional ones.

Orthologous introns have identical positions relative to the coding sequence in orthologous genes of different species. By analyzing the complete genomes of five plants we generated a database of 40,512 orthologous intron groups of dicotyledonous plants, 28,519 orthologous intron groups of angiosperms, and 15,726 of land plants (moss and angiosperms). Multiple sequence alignments of each orthologous intron group were obtained using the Mafft algorithm. The number of conserved regions in plant introns appeared to be hundreds of times fewer than that in mammals or vertebrates. Approximately three quarters of conserved intronic regions among angiosperms and dicots, in particular, correspond to alternatively-spliced exonic sequences. We registered only a handful of conserved intronic ncRNAs of flowering plants. However, the most evolutionarily conserved intronic region, which is ubiquitous for all plants examined in this study, including moss, possessed multiple structural features of tRNAs, which caused us to classify it as a putative tRNA-like ncRNA. Intronic sequences encoding tRNA-like structures are not unique to plants. Bioinformatics examination of the presence of tRNA inside introns revealed an unusually long-term association of four glycine tRNAs inside the Vac14 gene of fish, amniotes, and mammals.

To aid studies of molecular evolution and to assist in gene prediction research, we have constructed an Exon-Intron Database (EID) in FASTA format. Currently, the database is derived from GenBank release 112, and it contains 51 289 protein-coding genes (287 209 exons) that harbor introns, along with extensive descriptions of each gene and its DNA and protein sequences, as well as splice motif information. There is 17% redundancy inherited from GenBank-a purge at the 99% identity level reduced the database to 42 460 genes (243 589 exons). We have created subdatabases of genes whose intron positions have been experimentally determined. One such database, constructed by comparing genomic and mRNA sequences, contains 11 242 genes (62 474 exons). A larger database of 22 196 genes (105 595 exons) was constructed by selecting on keywords to eliminate computer-predicted genes. By examining the two nucleotides adjacent to the intron boundary, we infer that there is a 2% rate of errors or other deviations from the standard GTellipsisAG motif in nuclear genes. This criterion can be used to eliminate 4921 genes from the overall database. Various tools are provided to enable generation of user-specific subsets of the EID. The EID distribution can be obtained from http://mcb.harvard.edu/gilbert/EID

We have isolated two alpha-tubulin cDNAs from the leech, Hirudo medicinalis. Both encode putative proteins of 451 amino-acids which differ from each other at only two positions. Southern blotting suggests that there are only two alpha-tubulin genes in the leech. The genes contain two introns and, because of the extremely high homology of the nucleotide sequence from the second intron to the end of the genes, we have inferred that a gene conversion event about 9.5 million years ago has homogenised the Hirudo alpha-tubulin sequences. Using in situ hybridisation to tissue sections, we have shown that the two genes are probably expressed in all neurons of the leech ganglia and that their spatial distribution remains unchanged during neuronal regeneration. The deduced amino-acid sequences of the leech alpha-tubulins show that they have greatest similarity to those from a platyhelminth, echiuran and mollusc with rather less to arthropod alpha-tubulins. The protein sequences of the leech alpha-tubulins have been compared with representatives of those from across all phyla to determine if any specific feature labels certain isotypes of tubulin for neuronal expression.

We have constructed a subtractive cDNA library from regenerating Retzius cells of the leech, Hirudo medicinalis. It is highly enriched in sequences up-regulated during nerve regeneration. Sequence analysis of selected recombinants has identified both novel sequences and sequences homologous to molecules characterised in other species. Homologies include alpha-tubulin, a calmodulin-like protein, CAAT/enhancer-binding protein (C/EBP), protein 4.1 and synapsin. These types of proteins are exactly those predicted to be associated with axonal growth and their identification confirms the quality of the library. Most interesting, however, is the isolation of 5 previously uncharacterised cDNAs which appear to be up-regulated during regeneration. Their analysis is likely to provide new information on the molecular mechanisms of neuronal regeneration.

Two factors are thought to have contributed to the origin of codon usage bias in eukaryotes: 1) genome-wide mutational forces that shape overall GC-content and create context-dependent nucleotide bias, and 2) positive selection for codons that maximize efficient and accurate translation. Particularly in vertebrates, these two explanations contradict each other and cloud the origin of codon bias in the taxon. On the one hand, mutational forces fail to explain GC-richness (~60%) of third codon positions, given the GC-poor overall genomic composition among vertebrates (~40%). On the other hand, positive selection cannot easily explain strict regularities in codon preferences. Large-scale bioinformatic assessment, of nucleotide composition of coding and non-coding sequences in vertebrates and other taxa, suggests a simple possible resolution for this contradiction. Specifically, we propose that the last common vertebrate ancestor had a GC-rich genome (~65% GC). The data suggest that whole-genome mutational bias is the major driving force for generating codon bias. As the bias becomes prominent, it begins to affect translation and can result in positive selection for optimal codons. The positive selection can, in turn, significantly modulate codon preferences.

Messenger RNA sequences possess specific nucleotide patterns distinguishing them from non-coding genomic sequences. In this study, we explore the utilization of modified Markov models to analyze sequences up to 44 bp, far beyond the 8-bp limit of conventional Markov models, for exon/intron discrimination. In order to analyze nucleotide sequences of this length, their information content is first reduced by conversion into shorter binary patterns via the application of numerous abstraction schemes. After the conversion of genomic sequences to binary strings, homogenous Markov models trained on the binary sequences are used to discriminate between exons and introns. We term this approach the Binary Abstraction Markov Model (BAMM). High-quality abstraction schemes for exon/intron discrimination are selected using optimization algorithms on supercomputers. The best MM classifiers are then combined using support vector machines into a single classifier. With this approach, over 95% classification accuracy is achieved without taking reading frame into account. With further development, the BAMM approach can be applied to sequences lacking the genetic code such as ncRNAs and 5 0 -untranslated regions.

A direct and element-specific measurement of the local Fe spin moment has been provided by analyzing the Fe 3s core level photoemission spectra in the parent and optimally doped CeFeAsO1-xFx (x = 0, 0.11) and Sr(Fe1-xCox )2As2 (x = 0, 0.10) pnictides. The rapid time scales of the photoemission process allowed the detection of large local spin moments fluctuating on a 10-15 s time scale in the paramagnetic, antiferromagnetic, and superconducting phases, indicative of the occurrence of ubiquitous strong Hund's magnetic correlations. The magnitude of the spin moment is found to vary significantly among different families, 1.3?B in CeFeAsO and 2.1?B in SrFe2As2. Surprisingly, the spin moment is found to decrease considerably in the optimally doped samples, 0.9?B in CeFeAsO0.89F0.11 and 1.3?B in Sr(Fe0.9Co0.1)2As2. The strong variation of the spin moment against doping and material type indicates that the spin moments and the motion of itinerant electrons are influenced reciprocally in a self-consistent fashion, reflecting the strong competition between the antiferromagnetic superexchange interaction among the spin moments and the kinetic energy gain of the itinerant electrons in the presence of a strong Hund's coupling. By describing the evolution of the magnetic correlations concomitant with the appearance of superconductivity, these results constitute a fundamental step toward attaining a correct description of the microscopic mechanisms shaping the electronic properties in the pnictides, including magnetism and high-temperature superconductivity.

Non-coding genomic regions in complex eukaryotes, including intergenic areas, introns, and untranslated segments of exons, are profoundly non-random in their nucleotide composition and consist of a complex mosaic of sequence patterns. These patterns include so-called Mid-Range Inhomogeneity (MRI) regions -- sequences 30-10000 nucleotides in length that are enriched by a particular base or combination of bases (e.g. (G+T)-rich, purine-rich, etc.). MRI regions are associated with unusual (non-B-form) DNA structures that are often involved in regulation of gene expression, recombination, and other genetic processes (Fedorova & Fedorov 2010). The existence of a strong fixation bias within MRI regions against mutations that tend to reduce their sequence inhomogeneity additionally supports the functionality and importance of these genomic sequences (Prakash et al. 2009). Here we demonstrate a freely available Internet resource -- the Genomic MRI program package -- designed for computational analysis of genomic sequences in order to find and characterize various MRI patterns within them (Bechtel et al. 2008). This package also allows generation of randomized sequences with various properties and level of correspondence to the natural input DNA sequences. The main goal of this resource is to facilitate examination of vast regions of non-coding DNA that are still scarcely investigated and await thorough exploration and recognition.

—This Small nucleolar RNA (snoRNA) are a group of non-protein-coding RNA molecules among hundreds of others in the human genome. These molecules bind specifically to other cellular RNA targets via base pairing to form short, double-stranded structures. This binding causes the snoRNA targets to undergo specific chemical modifications. There are a number of (orphan) snoRNAs whose targets are still unknown; yet they clearly seem to play an important cellular function as their removal seems to cause genetic diseases like Prader-Willi Syndrome. In this project we aim to computationally predict targets for a specific group of orphan snoRNA of human and mouse (known as HBII-85 and MBII-85 respectively) that are known to be associated directly in the development of Prader-Willi Syndrome [1]. We started off by modifying our previously published snoTARGET program [2], to search for targets in the entire set of human and mouse genomic sequences. Then we generated a computational pipeline to characterize targets common to these two species. This resulted in the discovery of dozens of putative HBII-85/MBII-85 targets within the evolutionarily conserved segments of mRNAs, introns, and intergenic regions. Several of these targets have been found to be very well conserved evolutionarily among other mammals, and seem to have distinctive secondary structures detected by Evofold program [3]. Hence these targets can form the primary objects for further experimental validation. This could enhance the understanding of the function and clinical relevance of this group of snoRNA and could pave novel modes of intervention for arresting or alleviating the Prader-Willi Syndrome. The human genome contains hundreds of small non-protein-coding RNA molecules of which one group are the snoRNA (small nucleolar RNA). These molecules bind specifically to other cellular RNA targets via base pairing to form short, double-stranded structures. This binding causes the snoRNA targets to undergo specific chemical modifications. There are a number of (orphan) snoRNAs whose targets are still unknown; yet, because their removal causes genetic diseases such as Prader-Willi Syndrome, they clearly seem to play an important cellular function. In this project we aimed to computationally predict targets for a specific group of orphan snoRNA of human and mouse (known as HBII-85 and MBII-85 respectively) that are known to be directly involved in the development of Prader-Willi Syndrome. To fulfill this task we modified our previously published snoTARGET program, to search for targets in the entire set of human and mouse genomic sequences. Then we generated a computational pipeline to characterize targets common for these two species. This approach resulted in the discovery of dozens of putative HBII-85/MBII-85 targets within the evolutionary conserved segments of mRNAs, introns, and intergenic regions. Several of these targets are located within mammalian-wide evolutionary conserved sequences that have distinctive secondary structures detected by Evofold program. These targets are the primary objects for further experimental validation of our findings.