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PubMed2006

On the paucity of duplicated genes in Caenorhabditis elegans operons.

Spliced leader trans-splicing is an mRNA maturation process used by a small set of eukaryotes, including the nematode C. elegans, to cap the downstream genes of operons. We analyzed the frequency of duplication of operonic genes in C. elegans and confirmed that they are duplicated less often in the genome than monocistronic genes. Because operons account for about 15% of the genes in C. elegans, this lower duplication frequency might place a large constraint on the plasticity of the genome. Further analyses suggest that this paucity of duplicated genes results from operon organization hindering specific types of gene duplication.

Animals↗
PubMed2005

Interchromosomal duplication of major histocompatibility complex class I regions in rainbow trout (Oncorhynchus mykiss), a species with a presumably recent tetraploid ancestry.

Salmonid fishes are among the few animal taxa with a probable recent tetraploid ancestor. The present study is the first to compare large (>100 kb) duplicated genomic sequence fragments in such species. Two contiguous stretches with major histocompatibility complex (MHC) class I genes were detected in a rainbow trout BAC library, mapped and sequenced. The MHC class I duplicated regions, mapped by fluorescence in situ hybridization (FISH), were shown to be located on different metaphase chromosomes, Chr 14 and 18. Gene organization in both duplications is similar to that in other fishes, in that the class I loci are tightly linked with the PSMB8, PSMB9, PSMB10 and ABCB3 genes. Whereas one region, Onmy-IA, has a classical MHC class I locus (UBA), Onmy-IB encodes only non-classical class Ib proteins. The nucleotide diversity between the Onmy-IA and Onmy-IB noncoding regions is about 14%. This suggests that the MHC class I duplication event has occurred about 60 mya close to the time of an hypothesized ancestral tetraploid event. The present article is the first convincing report on the co-existence of two closely related MHC class I core regions on two different chromosomes. The interchromosomal duplication and the homology levels are supportive of the tetraploid model.

Amino Acid Sequence↗
PubMed2002

Characterization of a partial duplication of the aflatoxin gene cluster in Aspergillus parasiticus ATCC 56775.

A partial duplication of the complete aflatoxin gene cluster containing homologues of aflR-aflJ-adhA-estA-norA-ver1and omtB was identified from Aspergillus parasiticus ATCC 56775. The genes, verA-avnA-verB-avfA, between ver1 and omtB in the complete gene cluster, however, were not found. One-hybrid assays showed that the duplicated aflRgene ( aflR2) encoded a protein that could activate transcription just as that encoded by aflR1,the aflR gene in the complete gene cluster. Two-hybrid assays showed that AFLR2 also interacted with a putative coactivator, AFLJ1, at comparable levels to AFLR1. Deletion of aflR1 resulted in the loss of production of aflatoxin precursors, which suggested that aflR2could not completely replace the function of aflR1. Point mutations found in adhA2, pre-termination in ver1B and norA2,and a large deletion in omtB2 probably render these duplicated genes to become nonfunctional. A close examination of the history of isolates reported to have a partial duplication suggested that duplication of the aflatoxin cluster is not a prevalent event.

Aflatoxins↗
PubMed2002

P element-mediated duplications of genomic regions in Drosophila melanogaster.

Previously we have described highly unstable yellow mutations induced by chimeric elements that consist of genomic sequences originating from different regions of the X chromosome flanked by identical copies of an internally deleted 1.2 kb P element. To study further the origin and the mechanism of formation of chimeric mobile elements, we analyzed complex y-sc mutations, induced by inversions between P elements located in the neighboring yellow and scute loci. The breakpoints of the inversions are flanked by two P elements in head-to-head orientation on one side and by one P element on the other side. Such an arrangement of P elements leads to frequent duplication into the site between the two P element copies located in head-to-head orientation of the yellow sequences adjacent to the single P element. The duplicated yellow sequences either partly replace the sequence of one of the P elements or are inserted between the conserved head-to-head oriented P elements. In some cases two copies of the yellow sequence are duplicated between the P elements in inverted tail-to-tail orientation. The structure of the P elements at the place of duplication and of the P element- yellow junction suggests that the described duplications, which form chimeric mobile elements, are generated through the previously proposed synthesis-dependent strand annealing mechanism.

Animals↗
PubMed2002

Molecular characterisation of t(17;22)(q11.2;q11.2) is not consistent with NF1 gene duplication.

A tandem duplication of the NF1 gene in 17q11.2 has recently been detected by high-resolution fluorescence in situ hybridisation (FISH) on stretched chromosomes and DNA fibres. These findings suggest not only that, in the 17q11.2 region, the NF1 gene is surrounded by NF1 low-copy repeats on each side of the gene, but also that the NF1 gene and its directly flanking regions are duplicated structures. However, if the NF1 gene is duplicated at 17q11.2, this should be observed by FISH analysis on metaphase chromosomes of relevant translocation carriers with the probes originally used to identify the duplication, since hybridisation signals of some of the probes would be expected on both derivative chromosomes, the der(17) and the der(22). We have only been able to obtain signals on the one or the other derivative of a female translocation carrier. Therefore, our results do not support the hypothesis of a duplication of the NF1 gene and its immediately flanking regions at 17q11.2 as had been previously postulated. Rather, our findings suggest that there is one NF1 gene in the 17q11.2 region.

Chromosomes, Human, Pair 17↗
PubMed2000

Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers-Danlos syndrome type VII.

Type I collagen is the most abundant structural protein in the mammalian body. It exists as a heterotrimer of two subunits in the form [alpha1(I)]2alpha2(I). Pathogenic mutations in COL1A1 and COL1A2, the genes that encode the two subunits, cause a range of phenotypes including mild to lethal forms of osteogenesis imperfecta and a restricted set of Ehlers-Danlos syndrome phenotypes. Lethal mutations usually result from missense mutations that disrupt the normal triple helical structure of the molecule. Multi-exon duplication or deletion in type I collagen genes has rarely been observed and has generally resulted in a lethal or severe phenotype. We report a partial duplication in the COLIA2 gene that causes a relatively mild phenotype, despite the addition of 477 amino acids to the triple helical domain of the proalpha2(I) chain. The abnormal molecule is synthesized and secreted by cultured dermal fibroblasts in a normal fashion. Electron microscopy of dermal tissue reveals small but otherwise near normal collagen fibrils. The gene duplication occurred by mitotic sister chromatid exchange in the mother who is mosaic for the duplication allele. Examination of the abnormal sequence suggests a means by which the duplicated molecule could be processed and properly incorporated into mature collagen fibrils.

Base Sequence↗
PubMed2001

SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens.

The spinal muscular atrophy (SMA) region on chromosome 5q13 contains an inverted duplication of about 500 kb, and deleterious mutations in the survival motor neuron 1 (SMN1) gene cause SMA, a common lethal childhood neuropathy. We have used a number of approaches to probe the evolutionary history of these genes and show that SMN gene duplication and the appearance of SMN2 occurred at very distinct evolutionary times. Molecular fossil and molecular clock data suggest that this duplication may have occurred as recently as 3 million years ago in that the position and identity repetitive elements are identical for both human SMN genes and overall sequence divergence ranged from 0.15% to 0.34%. However, these approaches ignore the possibility of sequence homogenization by means of gene conversion. Consequently, we have used quantitative polymerase chain rection and analysis of allelic variants to provide physical evidence for or against SMN gene duplication in the chimpanzee, mankind's closest relative. These studies have revealed that chimpanzees have 2-7 copies of the SMN gene per diploid genome; however, the two nucleotides diagnostic for exons 7-8 and the SMNdelta7 mRNA product of the SMN2 gene are absent in non-human primates. In contrast, the SMN2 gene has been detected in all extant human populations studied to date, including representatives from Europe, the Central African Republic, and the Congo. These data provide conclusive evidence that SMN gene duplication occurred more than 5 million years ago, before the separation of human and chimpanzee lineages, but that SMN2 appears for the first time in Homo sapiens.

Alleles↗
PubMed2005

Epigenetic changes and repositioning determine the evolutionary fate of duplicated genes.

Consideration of epigenetic silencing, perhaps by DNA methylation, led to an epigenetic complementation (EC) model for evolution by gene duplication (Rodin and Riggs (2003) J. Mol. Evol., 56, 718-729). This and subsequent work on genome-wide analyses of gene duplicates in several eukaryotic species pointed to a fundamental link between localization in the genome, epigenetic regulation of expression, and the evolutionary fate of new redundant gene copies, which can be either non- or neo-functionalization. Our main message in this report is that repositioning of a new duplicate to an ectopic site epigenetically alters its expression pattern, and concomitantly the rate and direction of mutations. Furthermore, comparison of syntenic vs. non-syntenic pairs of gene duplicates of different age unambiguously indicates that repositioning saves redundant gene duplicates from pseudogenization and hastens their evolution towards a new development-time and tissue-specific pattern of function.

Animals↗
PubMed2006

MLPA analysis for a panel of syndromes with mental retardation reveals imbalances in 5.8% of patients with mental retardation and dysmorphic features, including duplications of the Sotos syndrome and Williams-Beuren syndrome regions.

MLPA analysis for a panel of syndromes with mental retardation (MRS-MLPA) was used for investigation of 258 mentally retarded and dysmorphic patients with normal conventional karyotypes (P064 probe set, MRC-Holland, for detection of (micro)deletions associated with 1p36-deletion, Sotos, Williams-Beuren, Prader-Willi, Angelman, Miller-Dieker, Smith-Magenis, and 22q11-deletion syndromes). Patients were initially referred for HR-CGH analysis and MRS-MLPA was performed retrospectively. MRS-MLPA analysis revealed imbalances in 15/258 patients (5.8%). Ten deletions were identified, including deletions of 1p36, 5q35 (Sotos syndrome), 7q11 (Williams-Beuren syndrome), 17p11 (Smith-Magenis syndrome), 15q11 (Angelman syndrome) and 22q11. Duplications were detected in 5q35, 7q11, 17p13, 17p11 and 22q11. We reviewed another 170 patients referred specifically for MRS-MLPA analysis. Eighty of these patients were referred with a clinical suspicion of a specific syndrome, which was confirmed in 17 patients (21.3%). The remaining 90 patients were referred because of mental retardation and dysmorphism but without suspicion of a specific syndrome. Seven imbalances, including four duplications, were detected in these 90 patients (7.8%). Clinical data regarding three patients investigated by MRS-MLPA are presented. The imbalances carried by these patients include a small interstitial 1p36 deletion, a small duplication of 5q35 (encompassing the NSD1 gene, which is deleted/mutated in Sotos syndrome) and a duplication of 7q11 (reciprocal of the Williams-Beuren syndrome deletion), respectively. MRS-MLPA allows testing for a number of micro-deletions/-duplications in a single experiment, thereby filling a gap between array techniques and single locus techniques. MRS-MLPA combined with Subtelomeric MLPA represents an attractive first test in a clinical algorithm for mental retardation.

Adult↗
PubMed2005

Identification of three duplicated Spin genes in medaka (Oryzias latipes).

Gene and genomic duplications are very important and frequent events in fish evolution, and the divergence of duplicated genes in sequences and functions is a focus of research on gene evolution. Here, we report the identification and characterization of three duplicated Spindlin (Spin) genes from medaka (Oryzias latipes): OlSpinA, OlSpinB, and OlSpinC. Molecular cloning, genomic DNA Blast analysis and phylogenetic relationship analysis demonstrated that the three duplicated OlSpin genes should belong to gene duplication. Furthermore, Western blot analysis revealed significant expression differences of the three OlSpins among different tissues and during embryogenesis in medaka, and suggested that sequence and functional divergence might have occurred in evolution among them.

Amino Acid Sequence↗
PubMed2005

The mitochondrial genome of the Japanese freshwater crab, Geothelphusa dehaani (Crustacea: Brachyura): evidence for its evolution via gene duplication.

The translocation of tRNA genes has occurred frequently among multiple independent arthropod lineages. However, the mechanisms of such gene rearrangement are still unclear. In this study we sequenced the nearly complete mitochondrial genome of the Japanese freshwater crab, Geothelphusa dehaani (Decapoda, Brachyura, Potamidae). Its size is relatively large (app. 24 kb) for higher animal mtDNA and is due to the presence of many intergenic noncoding sequences (IGNs), one of which is a large repeat region (>7.0 kb). Excluding the repeat region and the putative control region (514 bp), the total size of IGNs (1953 bp) is still the largest reported in arthropods. In comparison to the proposed ancestral arrangement for the insect-crustacean clade, G. dehaani displays changes in the positional order for three tRNA genes (trnQ, trnL(uur) and trnH). At the putative former and current locations for trnQ and trnH, there are IGNs with high similarities to corresponding sequences in the ancestral arrangement. This suggests the occurrence of partial duplication, followed by a loss of function for one copy of these two duplicated genes in G. dehaani. Furthermore, three trnLs (one trnL(uur) and two trnL(cun)s) are found in G. dehaani; their sequences are highly similar to each other (70.8-82.5%) and similar to the trnL(cun) of other arthropods. This suggests that duplication of trnL(cun) occurred at least twice, and the current trnL(uur) of G. dehaani arose by a subsequent anticodon alternation. These observations provide direct evidence for the "duplication-random loss" model for mtDNA gene rearrangement. Comparisons with other available Brachyuran data(http://www.ncbi.nlm.nih.gov/genomes/ORGANELLES/6657.html) suggest that two of the three tRNA translocations are unique in G. dehaani. For G. dehaani, where duplications have occurred but deletion of extra sequences is incomplete, the IGNs found at the ancestral or trans-locations are likely to be footprints of relatively recent mitochondrial genome evolution.

Animals↗
PubMed2005

Comparison of different techniques for detecting 17p12 duplication in CMT1A.

Charcot-Marie-Tooth type 1A is caused by a 1.5Mb DNA duplication in the 17p12 chromosomal region encompassing the peripheral myelin protein 22 gene. In the present study, we compared the Real-Time PCR with the other methods currently used for the diagnosis of Charcot-Marie-Tooth. By using a combination of junction fragment PCR, analysis of microsatellite markers, and pulsed field gel electrophoresis, we identified 76 unrelated patients with 17p12 duplication. In these patients, junction fragment PCR detected 63% of cases of duplication, the microsatellite markers method revealed 74%, while the combined use of microsatellite markers and junction fragment PCR revealed 91% of cases of Charcot-Marie-Tooth type 1A. Pulsed field gel electrophoresis detected 100% of the cases with duplication, even in presence of atypical 17p12 duplication. Real-Time PCR detected 100% of the cases with Charcot-Marie-Tooth type 1A and was comparable to pulsed field gel electrophoresis. However, in contrast to pulsed field gel electrophoresis, Real-Time PCR does not need fresh blood, minimizes diagnosis time and cost, and thus can be easily used for the molecular diagnosis of Charcot-Marie-Tooth type 1A.

Blotting, Southern↗
PubMed2005

Expression divergence between duplicate genes.

A general picture of the role of expression divergence in the evolution of duplicate genes is emerging, thanks to the availability of completely sequenced genomes and functional genomic data, such as microarray data. It is now clear that expression divergence, regulatory-motif divergence and coding-sequence divergence all increase with the age of duplicate genes, although their exact interrelationships remain to be determined. It is also clear that gene duplication increases expression diversity and enables tissue or developmental specialization to evolve. However, the relative roles of subfunctionalization and neofunctionalization in the retention of duplicate genes remain to be clarified, especially for higher eukaryotes. In addition, the relationship between gene duplication and evolution of transcriptional regulatory networks is largely unexplored.

Evolution, Molecular↗
PubMed2001

Origin of the duplicated regions in the yeast genomes.

The genome of Saccharomyces cerevisiae contains several duplicated regions. The recent sequencing results of several yeast species suggest that the duplicated regions found in the modern Saccharomyces species are probably the result of a single gross duplication, as well as a series of sporadic independent short-segment duplications. The gross duplication might coincide with the origin of the ability to grow under anaerobic conditions.

Animals↗
PubMed2002

Gene duplication and divergence in the early evolution of vertebrates.

The duplication-degeneration-complementation model of duplicate gene preservation by subfunctionalisation is currently the best explanation for the high level of retention of duplicate genes in early vertebrate evolution. But a direct test of the applicability of this model to such ancient evolutionary events may be difficult. More likely, recent duplications in other lineages will allow us to establish general principles concerning the fate of genes of different types that are duplicated in different ways. These principles may be then extrapolated to understanding the early evolution of the vertebrates.

Animals↗
PubMed1999

Molecular and clinical characterization of a patient with duplication of 1p36.3 and metopic synostosis.

Chromosome 1p duplications are rare. There have been only 11 reported cases of isolated 1p duplication, all of which were proximal, interstitial duplications. We present a patient with a terminal duplication of 1p (1p36.3). To our knowledge, this is the first such reported case. Our patient presented with metopic synostosis, rectal stenosis, atrial septal defect, and mildly delayed gross motor development. Molecular characterization using microsatellite marker analysis and fluorescence in situ hybridization (FISH) revealed an area of duplication between p58 and D1S2893, approximately 13 cM in size. We compare our patient's clinical findings with the clinical phenotype found in patients with the corresponding deletion of 1p36.3 and discuss the role of gene dosage in other deletion/duplication syndromes.

Child, Preschool↗
PubMed2005

Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication.

Human subtelomeres are polymorphic patchworks of interchromosomal segmental duplications at the ends of chromosomes. Here we provide evidence that these patchworks arose recently through repeated translocations between chromosome ends. We assess the relative contribution of the principal mechanisms of ectopic DNA repair to the formation of subtelomeric duplications and find that non-homologous end-joining predominates. Once subtelomeric duplications arise, they are prone to homology-based sequence transfers as shown by the incongruent phylogenetic relationships of neighbouring sections. Interchromosomal recombination of subtelomeres is a potent force for recent change. Cytogenetic and sequence analyses reveal that pieces of the subtelomeric patchwork have changed location and copy number with unprecedented frequency during primate evolution. Half of the known subtelomeric sequence has formed recently, through human-specific sequence transfers and duplications. Subtelomeric dynamics result in a gene duplication rate significantly higher than the genome average and could have both advantageous and pathological consequences in human biology. More generally, our analyses suggest an evolutionary cycle between segmental polymorphisms and genome rearrangements.

Animals↗
PubMed2002

Evidence of en bloc duplication in vertebrate genomes.

It has been 30 years since it was first proposed that the vertebrate genome evolved through several rounds of genome-wide duplications (polyploidizations). Despite rapid advances in genetics, including sequencing of the complete genomes of several divergent species, this hypothesis has not been tested rigorously and is still a matter of debate. If polyploidizations occurred during chordate evolution, there should be a network of paralogous regions in the present-day jawed vertebrate (Gnathostomata) genomes. Here we present an investigation of the major histocompatibility complex (MHC) paralogous regions, which we accomplished by characterizing the corresponding region in amphioxus by identifying nine anchor genes and sequencing both the anchor genes and the regions that flank them (a total of 400 kb). Phylogenetic analysis of 31 genes (including the anchor genes) in these regions shows that duplications occurred after the divergence of cephalochordates and vertebrates but before the Gnathostomata radiation. The distribution of human and amphioxus orthologs in their respective genomes and the relationship between these distributions support the en bloc duplication events. Our analysis represents the first step towards demonstrating that the human ancestral genome has undergone polyploidization. Moreover, reconstruction of the pre-duplicated region indicates that one of the duplicated regions retains the ancestral organization.

Animals↗