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PubMed2002

Associations between human disease genes and overlapping gene groups and multiple amino acid runs.

Overlapping gene groups (OGGs) arise when exons of one gene are contained within the introns of another. Typically, the two overlapping genes are encoded on opposite DNA strands. OGGs are often associated with specific disease phenotypes. In this report, we identify genes with OGG architecture and genes encoding multiple long amino acid runs and examine their relations to diseases. OGGs appear to be susceptible to genomic rearrangements as happens commonly with the loci of the DiGeorge syndrome on human chromosome 22. We also examine the degree of conservation of OGGs between human and mouse. Our analyses suggest that (i) a high proportion of genes in OGG regions are disease-associated, (ii) genomic rearrangements are likely to occur within OGGs, possibly as a consequence of anomalous sequence features prevalent in these regions, and (iii) multiple amino acid runs are also frequently associated with pathologies.

Amino Acids↗

PubMed1977

Bacteriophage phiX174: gene A overlaps gene B.

The map position of several phiX174 mutations in the genes A and B was determined by marker rescue with DNA fragments produced by the restriction enzymes Hha I, HindII, Hae III, and Alu I. All the gene B mutants were found to be located within gene A. Genetic complementation and analysis of phage-specific protein synthesis show that, under restrictive conditions, nonsense mutants in gene A do not block the synthesis and activity of the B protein and nonsense mutants in gene B do not affect the gene A function. The map position of the COOH-terminal end of gene A was determined using an amber mutant that synthesizes slightly shortened A and A proteins. It is concluded from these experiments that gene A overlaps gene B completely (or almost completely) and that the overlap region can be translated in two ways with different reading frames: one frame for the synthesis of the A and A proteins and another for the synthesis of the B protein.

Coliphages↗

PubMed2006

Origin and evolution of overlapping genes in the family Microviridae.

The possibility of creating novel genes from pre-existing sequences, known as overprinting, is a widespread phenomenon in small viruses. Here, the origin and evolution of gene overlap in the bacteriophages belonging to the family Microviridae have been investigated. The distinction between ancestral and derived frames was carried out by comparing the patterns of codon usage in overlapping and non-overlapping genes. By this approach, a gradual increase in complexity of the phage genome--from an ancestral state lacking gene overlap to a derived state with a high density of genetic information--was inferred. Genes encoding less-essential proteins, yet playing a role in phage growth and diffusion, were predicted to be novel genes that originated by overprinting. Evaluation of the rates of synonymous and non-synonymous substitution yielded evidence for overlapping genes under positive selection in one frame and purifying selection in the alternative frame.

Coliphages↗

PubMed2004

Mammalian overlapping genes: the comparative perspective.

It is believed that 3.2 billion bp of the human genome harbor approximately 35000 protein-coding genes. On average, one could expect one gene per 300000 nucleotides (nt). Although the distribution of the genes in the human genome is not random,it is rather surprising that a large number of genes overlap in the mammalian genomes. Thousands of overlapping genes were recently identified in the human and mouse genomes. However,the origin and evolution of overlapping genes are still unknown. We identified 1316 pairs of overlapping genes in humans and mice and studied their evolutionary patterns. It appears that these genes do not demonstrate greater than usual conservation. Studies of the gene structure and overlap pattern showed that only a small fraction of analyzed genes preserved exactly the same pattern in both organisms.

Animals↗

PubMed1988

Overlapping two genes in human DNA: a salivary amylase gene overlaps with a gamma-actin pseudogene that carries an integrated human endogenous retroviral DNA.

The human salivary amylase gene (amy1), consisting of eleven exons, is expressed in the salivary gland and in some amylase-producing tumors. Its uppermost exon and the following intron, along with the 5'-flanking region of this gene, are shown to be superimposed with a gamma-actin pseudogene sequence, a portion of which is transcribed into salivary amylase mRNA and another portion of which serves as a promoter for the amy1 gene. In the further upstream region, the gamma-actin pseudogene sequence is interrupted by a human endogenous retroviral nucleotide sequence.

Actins↗

PubMed1996

The miniaturized nuclear genome of eukaryotic endosymbiont contains genes that overlap, genes that are cotranscribed, and the smallest known spliceosomal introns.

Chlorarachniophyte algae contain a complex, multi-membraned chloroplast derived from the endosymbiosis of a eukaryotic alga. The vestigial nucleus of the endosymbiont, called the nucleomorph, contains only three small linear chromosomes with a haploid genome size of 380 kb and is the smallest known eukaryotic genome. Nucleotide sequence data from a subtelomeric fragment of chromosome III were analyzed as a preliminary investigation of the coding capacity of this vestigial genome. Several housekeeping genes including U6 small nuclear RNA (snRNA), ribosomal proteins S4 and S13, a core protein of the spliceosome [small nuclear ribonucleoprotein (snRNP) E], and a cip-like protease (clpP) were identified. Expression of these genes was confirmed by combinations of Northern blot analysis, in situ hybridization, immunocytochemistry, and cDNA analysis. The protein-encoding genes are typically eukaryotic in overall structure and their messenger RNAs are polyadenylylated. A novel feature is the abundance of 18-, 19-, or 20-nucleotide introns; the smallest spliceosomal introns known. Two of the genes, U6 and S13, overlap while another two genes, snRNP E and clpP, are cotranscribed in a single mRNA. The overall gene organization is extraordinarily compact, making the nucleomorph a unique model for eukaryotic genomics.

Amoeba↗

PubMed2000

Detection of signature sequences in overlapping genes and prediction of a novel overlapping gene in hepatitis G virus.

In viruses an increased coding ability is provided by overlapping genes, in which two alternative open reading frames (ORFs) may be translated to yield two distinct proteins. The identification of signature sequences in overlapping genes is a topic of particular interest, since additional out-of-frame coding regions can be nested within known genes. In this work, a novel feature peculiar to overlapping coding regions is presented. It was detected by analysis of a sample set of 21 virus genomic sequences and consisted in the repeated occurrence of a cluster of basic amino acid residues, encoded by a frame, combined to a stretch of acidic residues, encoded by the corresponding overlapping frame. A computer scan of an additional set of virus sequences demonstrated that this feature is common to several other known overlapping ORFs and led to prediction of a novel overlapping gene in hepatitis G virus (HGV). The occurrence of a bifunctional coding region in HGV was also supported by its extremely lower rate of synonymous nucleotide substitutions compared to that observed in the other gene regions of the HGV genome. Analysis of the amino acid sequence that was deduced from the putative overlapping gene revealed a high content of basic residues and the presence of a nuclear targeting signal; these characteristics suggest that a core-like protein may be expressed by this novel ORF.

Algorithms↗

PubMed2001

Introns resolve the conflict between base order-dependent stem-loop potential and the encoding of RNA or protein: further evidence from overlapping genes.

Many eukaryotic genes are split into exons and introns, the latter being removed post-transcriptionally so that only exon sequences appear in cytoplasmic RNAs. Since introns appear in both protein-encoding RNAs and non-protein-coding RNAs, they interrupt genetic information per se, not just protein-encoding information. A DNA sequence has the potential to carry more than one type of genetic information, but different types may conflict. Thus, it has been proposed that introns arose because sequences were unable to contain concomitantly complete information for the encoding both of stem-loops and of cytoplasmic products (protein and/or RNA). Stem-loop potential is held to be selectively advantageous since it promotes the recombination-dependent correction of genetic errors. Stem-loop potential, the best local measure of which is base order-dependent stem-loop potential, tends to be less in exons than in introns. This is particularly evident in genes evolving rapidly under positive Darwinian selection, where the protein-encoding function is dominant. Evidence is now presented that the rare regions where genes overlap also impose excessive encoding demands so that the concomitant coding of base order-dependent stem-loop potential is decreased. Our results are consistent with the hypothesis that sequences with high stem-loop potential arose in the early 'RNA world'. Ancestors of modern genes would have entered this world when sequences (exons) encoding cytoplasmic products, were interspersed with sequences (introns) encoding selectively advantageous stem-loops. Purine-loading pressure would also have favoured intron formation.

Animals↗

PubMed1999

Finding prokaryotic genes by the 'frame-by-frame' algorithm: targeting gene starts and overlapping genes.

MOTIVATION: Tightly packed prokaryotic genes frequently overlap with each other. This feature, rarely seen in eukaryotic DNA, makes detection of translation initiation sites and, therefore, exact predictions of prokaryotic genes notoriously difficult. Improving the accuracy of precise gene prediction in prokaryotic genomic DNA remains an important open problem. RESULTS: A software program implementing a new algorithm utilizing a uniform Hidden Markov Model for prokaryotic gene prediction was developed. The algorithm analyzes a given DNA sequence in each of six possible global reading frames independently. Twelve complete prokaryotic genomes were analyzed using the new tool. The accuracy of gene finding, predicting locations of protein-coding ORFs, as well as the accuracy of precise gene prediction, and detecting the whole gene including translation initiation codon were assessed by comparison with existing annotation. It was shown that in terms of gene finding, the program performs at least as well as the previously developed tools, such as GeneMark and GLIMMER. In terms of precise gene prediction the new program was shown to be more accurate, by several percentage points, than earlier developed tools, such as GeneMark.hmm, ECOPARSE and ORPHEUS. The results of testing the program indicated the possibility of systematic bias in start codon annotation in several early sequenced prokaryotic genomes. AVAILABILITY: The new gene-finding program can be accessed through the Web site: http:@dixie.biology.gatech.edu/GeneMark/fbf.cgi CONTACT: mark@amber.gatech.edu.

Algorithms↗

PubMed1992

Sequence complementarity between the 5'-terminal regions of mRNAs for rat mitochondrial cytochrome P-450c27/25 and a growth hormone-inducible serine protease inhibitor. A possible gene overlap.

Recently we reported that a P-450c27/25 cDNA probe hybridizes to two RNA species of about 1.9 and 2.3-2.4 kilobase pairs (kb) in some rat tissues. To understand the molecular relationship between the two mRNAs, we have isolated and characterized a cDNA for the larger, previously uncharacterized 2.3-kb mRNA species. The 2.3-kb cDNA is identical to the previously reported 1.9-kb P-450c27/25 cDNA excepting a 400-nucleotide-long 5' extension. The terminal 291 nucleotides of this extension exhibit 100% complementarity with the 5'-translated region of the mRNA belonging to a family of growth hormone-inducible serine protease inhibitors (SPI). Northern blot analysis, using strand-specific probes, and S1 nuclease protection revealed the presence of the 2.3-kb mRNA exhibiting the sequence characteristics of the larger cDNA. These results were further confirmed by polymerase chain reaction amplification of reverse transcribed RNA. Expression of the 2.3-kb cDNA in COS cells resulted in the correct mitochondrial targeting of a 52-kDa protein exhibiting the properties of P-450c27/25. Furthermore, both the 1.9- and 2.3-kb mRNAs appear to direct the synthesis of a similarly sized 55-kDa precursor protein in a reticulocyte lysate system. Restriction mapping, polymerase chain reaction amplification and partial sequencing of a 25-kb genomic DNA clone suggest the proximal location of the SPI and the P-450c27/25 protein coding regions in the rat genome on either side of a common overlap region. The results also show that the P-450c27/25 mRNAs are regulated by growth hormone in parallel to the SPI mRNAs. These results collectively suggest that a growth hormone-inducible SPI family mRNA and the P-450c27/25 mRNA are encoded by two closely linked, possibly overlapping genes.

Amino Acid Sequence↗

PubMed1983

Homologous recombination in mammalian cells mediates formation of a functional gene from two overlapping gene fragments.

Chinese hamster cells with a lesion in the CAD gene (cell line Urd-A) require exogenous uridine to survive. Uridine prototrophs could be isolated after introducing two recombinant plasmids containing overlapping fragments of a cloned Syrian hamster CAD gene. In contrast, no uridine prototrophs were obtained after introducing a plasmid containing only one of the two overlapping fragments. DNA restriction analysis showed that the prototrophic transformants contain a functional CAD gene which was formed by a recombination event in the overlapping region of the two clones. Most of the recombination events involved homologous exchanges, and some of them apparently were reciprocal. In situ hybridization analysis revealed that the donated sequences were integrated at a single chromosomal site which was different in each transformant. These results demonstrate the existence of a recombination system(s) in mammalian cells that can catalyze homologous exchanges. Recombination between donated sequences is a means by which this system can be characterized and also utilized for the production of novel gene fusions.

Animals↗

PubMed2005

Overlapping genes in vertebrate genomes.

Overlapping genes in mammalian genomes are unexpected phenomena even though hundreds of pairs of protein coding overlapping genes have been reported so far. Overlapping genes can be divided into different categories based on direction of transcription as well as on sequence segments being shared between overlapping coding regions. The biologic functions of natural antisense transcripts, their involvement in physiological processes and gene regulation in living organisms are not fully understood. Number of documented examples indicates that they may exert control at various levels of gene expression, such as transcription, mRNA processing, splicing, stability, transport, and translation. Similarly, evolutionary origin of such genes is not known, existing hypotheses can explain only selected cases of mammalian gene overlaps which could originate as result of rearrangements, overprinting and/or adoption of signals in the neighboring gene locus.

Animals↗

PubMed2003

On dynamics of overlapping genes in bacterial genomes.

A genome-wide computational analysis of overlapping genes in various prokaryotic genomes was conducted to study the evolutionary rates of the formation and degradation of overlapping genes. Overlapping genes are adjacent genes that overlap partially or entirely. Overlapping gene pairs extracted from complete bacterial genome sequences were classified into three directional patterns, namely, 'convergent' (--><--), 'unidirectional' (-->-->), and 'divergent' (<---->). Divergent overlapping genes were rare compared to the other two patterns. We also compared the structures of overlapping genes that are not conserved in the homologous genes of different species. We found that overlapping genes are mainly generated from gene pairs with short intergenic regions. Overlapping genes caused by mutations at the 3'-end of genes occur more frequently than overlapping genes generated by mutations at the 5'-end of genes in closely related species. In contrast, gene overlaps due to mutations at the 5'-ends accumulate in distant species. These differences presumably correlate to the genomic divergence among species. The evolution of these overlapping gene structures is probably related to the evolutionary time scale, which suggests that the evolution of overlapping genes occurs at a universal mutation rate across species.

Bacteria↗

PubMed1986

The trfB region of broad host range plasmid RK2: the nucleotide sequence reveals incC and key regulatory gene trfB/korA/korD as overlapping genes.

We report the nucleotide sequence of the trfB region of broad host range plasmid RK2. This region encodes the following loci: trfB, identical to korA and korD, which encodes a key transcriptional repressor of certain RK2 operons; incC, which appears to be involved in plasmid maintenance, possibley through post-transcriptional regulation of trfA product levels; the start of korB, which encodes a second transcriptional repressor of operons involved in stable inheritance of RK2. These loci are expressed as part of the trfB operon. In combination with deletion analysis, transcriptional and translation fusions and 'maxicell' analysis of polypeptides, the DNA sequence allows a number of conclusions to be drawn. First, the korB ORF start codon overlaps the incC ORF stop codon, suggesting the possibility of translational coupling between these two genes. Second, the trfB ORF lies entirely within the first third of the incC ORF using a different phase. Third, the incC ORF appears to contain a second transcriptional start whose function appears to be coupled to translation of the trfB ORF. Analysis of codon usage in the region of overlap between incC and trfB suggests that the incC gene may have evolved before the trfB gene. Determination of the DNA sequence of a mutant in which the product of trfB is rendered defective for transcriptional repression reveals an amino acid alteration within a region of this polypeptide which exhibits homology to the alpha helix-turn-alpha helix motif characteristic of many DNA binding proteins, and which is probably responsible for recognition of the trfB operator by this protein.

Amino Acid Sequence↗

PubMed2004

Properties of overlapping genes are conserved across microbial genomes.

There are numerous examples from the genomes of viruses, mitochondria, and chromosomes that adjacent genes can overlap, sharing at least one nucleotide. Overlaps have been hypothesized to be involved in genome size minimization and as a regulatory mechanism of gene expression. Here we show that overlapping genes are a consistent feature (approximately one-third of all genes) across all microbial genomes sequenced to date, have homologs in more microbes than do non-overlapping genes, and are therefore likely more conserved. In addition, the size, phase (reading frame offset), and distribution, among other characteristics, of overlapping genes are most consistent with the hypothesis that overlaps function in the regulation of gene expression. The upstream sequences and conservation of overlapping orthologs of two model organisms from the genus Prochlorococcus that have significantly different GC-content, and therefore different nucleotide sequences for orthologs, are also consistent with small overlapping sequence regions and programmed shifts in reading frame as a common mechanism in the regulation of microbial gene expression.

Computational Biology↗

PubMed2000

The role of population size, pleiotropy and fitness effects of mutations in the evolution of overlapping gene functions.

Sheltered from deleterious mutations, genes with overlapping or partially redundant functions may be important sources of novel gene functions. While most partially redundant genes originated in gene duplications, it is much less clear why genes with overlapping functions have been retained, in some cases for hundreds of millions of years. A case in point is the many partially redundant genes in vertebrates, the result of ancient gene duplications in primitive chordates. Their persistence and ubiquity become surprising when it is considered that duplicate and original genes often diversify very rapidly, especially if the action of natural selection is involved. Are overlapping gene functions perhaps maintained because of their protective role against otherwise deleterious mutations? There are two principal objections against this hypothesis, which are the main subject of this article. First, because overlapping gene functions are maintained in populations by a slow process of "second order" selection, population sizes need to be very high for this process to be effective. It is shown that even in small populations, pleiotropic mutations that affect more than one of a gene's functions simultaneously can slow the mutational decay of functional overlap after a gene duplication by orders of magnitude. Furthermore, brief and transient increases in population size may be sufficient to maintain functional overlap. The second objection regards the fact that most naturally occurring mutations may have much weaker fitness effects than the rather drastic "knock-out" mutations that lead to detection of partially redundant functions. Given weak fitness effects of most mutations, is selection for the buffering effect of functional overlap strong enough to compensate for the diversifying force exerted by mutations? It is shown that the extent of functional overlap maintained in a population is not only independent of the mutation rate, but also independent of the average fitness effects of mutation. These results are discussed with respect to experimental evidence on redundant genes in organismal development.

Animals↗

PubMed1999

Comparative study of overlapping genes in the genomes of Mycoplasma genitalium and Mycoplasma pneumoniae.

Overlapping genes are defined, in this paper, as a pair of adjacent genes whose coding regions are partly overlapping. We systematically analyzed all overlapping genes in the genomes of two closely related species: Mycoplasma genitalium and Mycoplasma pneumoniae. Careful comparisons were made for homologous genes that are overlapped in one species but not in the other. This comparative analysis allows us to propose a model of how overlapping genes emerged in the course of evolution. It was found that overlapping genes were generated primarily due to the loss of a stop codon in either gene, in many cases, the absence of which resulted in elongation of the 3' end of the gene's coding region. More specifically, the loss of the stop codon took place as a result of the following events: deletion of the stop codon (64.4%), point mutation at the stop codon (4.4%), and frame shift at the end of the coding region (6.7%). Overlapping genes, in a sense, can be thought of as the results of evolutionary pressure to minimize genome size. However, our analysis indicates that many overlapping genes, at least in the genomes of M.genitalium and M.pneumoniae, are due to incidental elongation of the coding regions.

Genes, Bacterial↗

PubMed1999

The 5' region of the COX4 gene contains a novel overlapping gene, NOC4.

We identified a novel human gene, NOC4 (Neighbor Of COX4), located 5' to COX4, the gene for cytochrome c oxidase subunit IV, on Chr 16q32-ter. Transcripts from this gene were identified among human expressed sequence tags. A full-length, 1.06-kb human retinal NOC4 cDNA encoded a 24-kDa, 210-amino acid hypothetical protein of unknown function. Northern hybridization analysis of human RNAs from various tissues detected NOC4 transcripts of 2.2 and 1.4 kb in all tissues examined, suggesting that NOC4 expression is ubiquitous. Transcription of both the COX4 and NOC4 genes initiates within a 250-bp intergenic promoter and occurs in opposite directions. The bidirectional promoter is G + C-rich, lacks TATA and CCAAT elements, and contains multiple potential binding sites for Sp1 and NRF-2/GABP. Two of the NRF-2/GABP sites are located within 14-bp direct repeats, a conserved feature of mammalian COX4 promoters. The NOC4 and COX4 genes are also linked in the rat, mouse, and bovine genomes. A NOC4-GFP fusion protein is located in both the nucleus and the cytoplasm, including the mitochondria.

Amino Acid Sequence↗