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PubMed2006

Duplication of 5q15-q23.2: case report and literature review.

BACKGROUND: Pure partial trisomy of chromosome 5q is rare and cases have ranged over the entire region, making it difficult to describe a good phenotypic correlation to the cytogenetic duplication. CASE: We present a 4.5-year-old girl with a de novo direct duplication of chromosome 5q15-q23.2. She has moderate developmental delay with lack of speech, microcephaly, and subtle dysmorphic features including prominent forehead, bulbous nose, epicanthic folds, protruding tongue, and slightly posteriorly-rotated ears. CONCLUSIONS: A comparison is made with other similar duplication cases reported in the literature and a general description of a proximal 5q duplication phenotype is given, with lack of speech as the principal feature.

Chromosome Mapping↗
PubMed2003

Genome duplication, subfunction partitioning, and lineage divergence: Sox9 in stickleback and zebrafish.

Teleosts are the most species-rich group of vertebrates, and a genome duplication (tetraploidization) event in ray-fin fish appears to have preceded this remarkable explosion of biodiversity. What is the relationship of the ray-fin genome duplication to the teleost radiation? Genome duplication may have facilitated lineage divergence by partitioning different ancestral gene subfunctions among co-orthologs of tetrapod genes in different teleost lineages. To test this hypothesis, we investigated gene expression patterns for Sox9 gene duplicates in stickleback and zebrafish, teleosts whose lineages diverged early in Euteleost evolution. Most expression domains appear to have been partitioned between Sox9a and Sox9b before the divergence of stickleback and zebrafish lineages, but some ancestral expression domains were distributed differentially in each lineage. We conclude that some gene subfunctions, as represented by lineage-specific expression domains, may have assorted differently in separate lineages and that these may have contributed to lineage diversification during teleost evolution.

Animals↗
PubMed2005

The melanoma-associated 24 base pair duplication in p16INK4a is functionally impaired.

Melanoma-associated germline mutations affecting the tumor suppressor and cyclin-dependent kinase (CDK) inhibitor, CDKN2A/p16INK4a, have been identified in over 100 melanoma-prone families worldwide. To predict the melanoma risk for carriers of specific mutations, mutant p16INK4a can be tested in biochemical and cellular assays. In most cases, p16INK4a mutations with predicted disease relation, due to segregation with melanoma, are functionally impaired in such assays. The N-terminal 24 base pair duplication of CDKN2A, however, encodes a p16INK4a variant previously shown to have wild-type function, despite segregating with melanoma in at least 5 melanoma families. To clarify whether the duplication mutation has a cell cycle regulatory defect or behaves like wild-type p16INK4a, we reanalyzed the cell cycle-inhibitory activity of this mutation. Stable cell clones of the p16-null WMM1175 melanoma cell line inducible for ectopic p16INK4a were used in this study. In these cells, p16INK4a expression can be controlled at physiologic levels. Our results show that in comparison to wild-type p16INK4a, the duplication mutant induced weaker S-phase inhibition and cells expressing this mutant form of p16INK4a retained colony formation ability. We also show that the cell cycle-regulatory defect of the p16INK4a duplication mutant was associated with decreased inhibition of pRb phosphorylation even though it retained significant binding to CDK4.

Base Pairing↗
PubMed2005

Prenatal detection of a de novo terminal inverted duplication 4p in a fetus with the Wolf-Hirschhorn syndrome phenotype.

OBJECTIVES: To present the prenatal diagnosis of a de novo terminal inversion duplication of the short arm of chromosome 4 and a review of the literature. CASE: An amniocentesis for chromosome analysis was performed at 33 weeks' gestation because ultrasound examination showed a female fetus with multiple abnormalities consisting of severe intrauterine growth retardation, microcephaly, a cleft lip and renal hypoplasia. RESULTS: Cytogenetic analysis and FISH studies of the cultured amniocytes revealed a de novo terminal inversion duplication of the short arm of chromosome 4 characterized by a duplication of 4p14-p16.1 chromosome region concomitant with a terminal deletion 4p16.1-pter. The karyotype was thus: 46,XX, inv dup del (4)(:p14-->p16.1::p16.1-->qter). The parents opted to terminate the pregnancy. Fetopathological examination showed dysmorphic features and abnormalities consistent with a Wolf-Hirschhorn syndrome (WHS) diagnosis, clinical manifestations of partial 4p trisomy being mild. CONCLUSION: Although relatively rare, inverted duplications have been reported repeatedly in an increasing number of chromosomes. Only two previous cases with de novo inv dup del (4p) and one with tandem dup 4p have been reported, all of them associated with a 4pter deletion. We report the first case diagnosed prenatally. Breakpoints are variable, resulting in different abnormal phenotype. In our case, clinical manifestations resulted in a WHS phenotype.

Abnormalities, Multiple↗
PubMed2004

Duplication of 9 p11.2-p13.1: a benign cytogenetic variant.

The detection of very rare variants in prenatal diagnosis often causes counseling difficulties and anxiety in parents. We describe a duplication of the proximal region of chromosome 9 short arm in two cases of prenatal diagnosis and in one young woman, with evidence that such rearrangement is an uncommon variant. The duplication was investigated using Fluorescence in situ hybridization (FISH). Although the cytogenetic findings were indicative of a 'duplication 9p syndrome' associated with mental and developmental retardation, we were able to demonstrate that the rearrangement was a heteromorphism with no phenotypic consequence. We also determined the breakpoint regions of the rearrangement and identified the BAC probes that precisely define the duplicated region devoid of risk of phenotypic effects.

Adult↗
PubMed1999

Gene duplications in early metazoan evolution.

Major increases in complexity during animal evolution occurred at the transition from a unicellular protozoan to a multicellular metazoan, the evolution of Bilateria from diploblasts (possibly the Cambrian explosion) and during early vertebrate evolution. A role for gene duplication in the third event has been widely discussed. Here I examine the possible role of gene duplications and domain shuffling in the first two events. There is evidence for a wave of gene duplications and shuffling which may have paved the way for multicellularity; there are also examples of gene duplications that may have facilitated the transition from diploblasts to Bilateria.

Animals↗
PubMed1998

Sponge Pax cDNA related to Pax-2/5/8 and ancient gene duplications in the Pax family.

Members of the Pax gene family encode transcription factors containing a DNA-binding paired domain which is involved in developmental control and the formation of the central nervous system (CNS). The family members are classified into six classes or subfamilies, depending on the presence or absence of paired-type homeobox and octapeptide. To obtain rough estimates of times when the different classes of the Pax family diverged by gene duplication, we cloned and sequenced a Pax-related cDNA, sPax-2/5/8, from Ephydatia fluviatilis, a freshwater sponge, which encodes a paired-type homeobox and an octapeptide, in addition to a paired domain. A phylogenetic tree based on the paired domain sequences suggest that sPax-2/5/8 is a homologue of vertebrate Pax-2/5/8. It was also suggested that the majority of gene duplications that gave rise to distinct classes has been completed in the very early evolution of animals before the parazoan-eumetazoan split. Long after the ancient gene duplications, further gene duplications that gave rise to members in each subfamily occurred on the chordate lineages and completed before the fish-tetrapod split. This suggests that the major classes of the Pax genes involved in the formation of CNS characteristic of triploblasts had already existed long before the Cambrian explosion of triploblasts, and there is no direct link between the creation of new genes with novel functions and the Cambrian explosion. The pattern of gene diversification found in the Pax family is similar to those in five gene families involved in the signal transduction analyzed by us. Furthermore, the evolutionary rates of the Pax proteins have been shown to decrease with increasing organismal complexity during animal evolution.

Amino Acid Sequence↗
PubMed1999

Phylogenies of developmentally important proteins do not support the hypothesis of two rounds of genome duplication early in vertebrate history.

It has been proposed that two rounds of duplication of the entire genome (polyploidization) occurred early in vertebrate history (the 2R hypothesis); and the observation that certain gene families important in regulating development have four members in vertebrates, as opposed to one in Drosophila, has been adduced as evidence in support of this hypothesis. However, such a pattern of relationship can be taken as support of the 2R hypothesis only if (1) the four vertebrate genes can be shown to have diverged after the origin of vertebrates, and (2) the phylogeny of the four vertebrate genes (A-D) exhibits a topology of the form (AB) (CD), rather than (A) (BCD). In order to test the 2R hypothesis, I constructed phylogenies for nine protein families important in development. Only one showed a topology of the form (AB) (CD), and that received weak statistical support. In contrast, four phylogenies showed topologies of the form (A) (BCD) with statistically significant support. Furthermore, in two cases there was significant support for duplication of the vertebrate genes prior to the divergence of deuterostomes and protostomes: in one case there was significant support for duplication of the vertebrate genes at least prior to the divergence of vertebrates and urochordates, and in one case there was weak support for duplication of the vertebrate genes prior to the divergence of deuterostomes and protostomes. Taken together with other recently published phylogenies of developmentally important genes, these results provide strong evidence against the 2R hypothesis.

Animals↗
PubMed1999

Pervasiveness of gene conservation and persistence of duplicates in cellular genomes.

In this work detailed statistics on ancestral gene duplication and gene conservation in completely sequenced cellular genomes are presented. Analysis of open reading frame (ORF) products having simultaneous matches in several distinct organisms showed a significant correlation between duplication and conservation. Systematic comparisons of predicted proteomes of 23 organisms (including 20 that have been completely sequenced), have allowed us to quantify the degree of ancestral duplication within each genome and the level of conservation between genomes, using threshold values calculated for individual organisms. Statistical analysis of various gene proportions revealed interesting trends in gene structure and evolution, such as that (a) more than one-quarter (25%-66%) of the predicted ORF products of the surveyed organisms are not unique, indicating a high level of ancestral duplications; (b) levels of exclusive conservation within Bacteria are higher than those within the eukaryal or archaeal domains; and (c) at least one-half (47-99%) of the total predicted ORF products in the surveyed genomes have one or several highly significant matches in another genome. Significant matches are based on simulations taking into account the mean size of ORF products and the composition of each target organism's proteome. The methodology we have developed ensures stability and comparability of our results as the number of completely sequenced genomes increases.

Base Sequence↗
PubMed2003

Lectin-related resistance factors against bruchids evolved through a number of duplication events.

Abundant lectin-related proteins found in common beans ( Phaseolus vulgaris L.) have been shown to confer resistance against the larvae of a number of bruchid species. Genes encoding for these proteins are members of the lectin multigene family, the most representative components being arcelins, phytohemagglutinins and alpha-amylase inhibitors. Arcelins have been described in seven variants, some of which are resistance factors against the Mexican bean weevil ( Zabrotes subfasciatus), a major bean predator. In this study the isolation and sequencing of arcelin genes from wild P. vulgaris genotypes, containing Arc3 and Arc7 variants, is reported, and similarities and evolutionary relationships among the seven known arcelins are described. The evolutionary analysis shows that arcelins 3 and 4 cluster together and are the most-ancient variants. A duplication event gave rise to two additional clusters, one comprising arcelins 1, 2 and 6 and separated from the cluster of arcelins 5 and 7. A multiple number of arcelin genes were found in arcelin 3 and 4 genotypes indicating that more than one type of arcelin gene may be present in the same locus. Some of these sequences are reminiscent of ancient duplication events in arcelin evolution demonstrating that arcelins have evolved through multiple duplications. A further aim of this paper was to better understand and describe the evolution of the entire lectin multigene family. Beside arcelins, a number of other types of sequences, such as putative lectins and sequences not easily classifiable, were found in genotypes containing Arc3 and Arc4. These results, together with the evolutionary analysis, indicate that lectin loci are quite complex and confirm their origin by multiple duplication events.

Amino Acid Sequence↗
PubMed2003

Evolution of vertebrate voltage-gated ion channel alpha chains by sequential gene duplication.

Phylogenetic analysis of alpha chains of voltage-gated ion channels revealed that extensive gene duplication has occurred among both Ca(2+) and Na(+)-channels since the origin of vertebrates. Rather than showing a pattern of gene duplication consistent with the hypothesis of polyploidization early in vertebrate history, both Ca(2+) and Na(+) channels showed patterns of sequential gene duplication associated with specialization of the gene products. In the case of Na(+) channels, the phylogeny supported the hypothesis that the ancestral vertebrate gene had an expression pattern including both central and peripheral nervous system cells and that duplication of vertebrate Na(+) channel genes has repeatedly been followed by specialization for the central nervous system, the peripheral nervous system, or muscle cells. Thus, cephalization in vertebrate evolution has been accompanied by specialization of this important family of neuromuscular proteins along the central-peripheral axis.

Animals↗
PubMed2003

Retention of a duplicate gene through changes in subcellular targeting: an electron transport protein homologue localizes to the golgi.

Cytochrome c oxidase (COX), the terminal enzyme complex of the electron transport chain, contains 13 subunits, 3 encoded by mitochondrial DNA and 10 by nuclear. Several of the nuclear subunits, including subunit VIIa, are known to have two tissue- and development-specific isoforms in mammals. A recently identified third member of the gene family, COX7AR, encodes a protein previously thought to function in mitochondria. However, observation of fluorescent pCOX7AR C-terminal fusion proteins in HeLa cells showed that pCOX7AR is localized to the Golgi apparatus. Sequence analyses indicate that the duplication of COX7AR occurred prior to the origin of the Euteleostomi (bony vertebrates) and that pCOX7AR is more highly conserved than the two other isoforms. These results indicate that, after gene duplication and modification of the mitochondrial targeting signal, pCOX7AR was evolutionarily altered to a new and apparently important function in the Golgi. These results also suggest that predictions of function from homology can be misleading and show that specialization and modification of subcellular localization are similar to cis-element subfunctionalization. In cis-element subfunctionalization, complementary null mutations occur to the cis-elements of the descendents of a gene duplication, causing both descendent genes to be obligate. In the process described in this paper, which could be termed subcellular subfunctionalization, complementary null mutations can occur to the subcellular localization signals of the descendants of a gene duplication, causing both descendent genes to be similarly obligate. Noncomplementary null mutations could also uncover an alternate localization, which is the more likely case for pCOX7AR.

Electron Transport Complex IV↗
PubMed2001

Characterization of two alcohol dehydrogenase (Adh) loci from the olive fruit fly, Bactrocera (Dacus) oleae and implications for Adh duplication in dipteran insects.

We report the cloning and structural characterization of two Adh loci of the olive fruit fly, Bactrocera oleae. Each of the two genes, named Adh1 and Adh2, consists of three exons and two introns for a total length of 1981 and 988 nucleotides, respectively. Their deduced amino acid sequences of 257 and 258 residues exhibit a 77% identity and display the characteristics of the insect ADH enzymes, which belong to the short-chain dehydrogenases/reductases family. The Adh genes of B. oleae are compared to the two genes of the Mediterranean fly, Ceratitis capitata, the only other species of the Tephritidae family in which the Adh genes have been studied. On the basis of amino acid divergence the four genes form two clusters each containing one gene from each species, as expected if there was one duplication event before speciation. On the basis of nucleotide sequence the four sequences form two clusters each containing the two sequences from the same species, as expected if there was a separate duplication event in each species. To help decide between the two alternatives, we compared at both the amino acid and DNA level the Adh genes of five Drosophila species that are known to carry two such genes and observed that, with only one exception at the amino acid level, conspecific loci cluster together. We conclude that the information we have at present does not allow a firm choice between the hypothesis of a single duplication event that occurred before the split of Bactrocera and Ceratitis from their common ancestor and the hypothesis of two independent duplication events, one in each of the two genera.

Alcohol Dehydrogenase↗
PubMed2005

Tandem organization of independently duplicated homeobox genes in the basal cnidarian Acropora millepora.

A number of examples of independently duplicated regulatory genes have been identified in cnidarians, but the extent of this phenomenon and organization of these duplicated genes are unknown. Here we describe the identification of three pairs of independently duplicated homeobox genes in the anthozoan cnidarian, Acropora millepora. In each case, the pairs of paralogous genes are tightly linked, but the extent of sequence divergence implies that these do not reflect recent duplication events. The phenomenon is likely to be more general, as the examples reported here represent most of the limited number of Acropora homeobox genes for which genomic data are yet available.

Amino Acid Sequence↗
PubMed1999

Exon duplication from a fork head to a homeodomain protein.

The evolution of complex organisms such as animals requires a large expansion of the number of genes controlling developmental events. In addition, it is thought that domains are shuffled between genes to further increase the complexity and generate new types of genes and functions. Working with the Caenorhabditis elegans homeobox gene ceh-43, the orthologue of fly Distal-less (Dll), we observed sequence similarity to the C. elegans gene fkh-1. Now, with the complete genomic sequence available, we examined this similarity in detail. The region of similarity is confined essentially to one exon in the carboxy terminus of the two genes. Based on the gene structure, we think that an exon of fkh-1 was duplicated to the carboxy terminus of ceh-43, where it was incorporated as the last exon. This duplication event seems to have happened recently since the similarity on the nucleotide level is higher than the sequence similarity between fkh-1 of C. elegans and C. briggsae. Potentially the duplication event was mediated via a short region of sequence similarity between the two open reading frames of the genes. This duplication event clear shows that a part of a gene can successfully be juxtaposed to another gene. These events may perhaps not be rare.

Amino Acid Sequence↗
PubMed2001

A 1.1-kb duplication in the p67-phox gene causes chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency that is caused by a functional defect of the NADPH oxidase of phagocytes, and that leads to severe recurrent infections. CGD results from the absence or the dysfunction of various components of NADPH oxidase, and autosomal recessive CGD with the lack of p67-phox (A67 CGD) is the rarest form of the disease. Identifying familiar mutations in subjects with A67 CGD provides the most reliable method of detecting carriers and is the basis for prenatal diagnosis. In the present study, we report the detailed characterization of the first duplication in the p67-phox gene identified in a 30-year-old patient affected by systemic aspergillosis attributable to p67-phox deficiency. We show that this new mutation involving exons 9 and 10 is the result of a tandem duplication of approximately 1.1 kb, which resulted from the juxtaposition of intron 8 to intron 10. We have sequenced both the junction fragment of this duplication and the corresponding wild-type regions and have found that the breakpoint regions in intron 8 and in intron 10 show limited homology. Our result suggests that this interchange arose as an illegitimate recombination event. As in other non-homologous rearrangements previously reported, the duplication breakpoints are located within the sequence motif 5'-CCAG-3' and its complement 5'-CTGG-3'.

Adult↗
PubMed2001

Identification of duplicated genes in 17q11.2 using FISH on stretched chromosomes and DNA fibers.

Recent evidence has been provided that links duplicons (REP-P and REP-M) in 17q11.2 flanking the neurofibromatosis type 1 (NF1) gene to the breakpoints of the NF1 microdeletion syndrome. The physical mapping and structural definition of duplicated regions is often impossible by conventional approaches, and so we have used high resolution fluorescence in situ hybridization (FISH) with locus-specific probes of limited size on chromosomes stretched to different degrees to identify novel duplicated genes and expressed sequence tags (ESTs) mapping to 17q11.2. This approach has allowed us to detect and map duplications of the BLMH and GOS28 genes, with one copy lying centromeric and one telomeric to the NF1 gene, and an SHGC30113 transcript with one copy being adjacent and the other distal to the NF1 3' untranslated region. Double-color FISH with a BLMH-specific probe on stretched chromosomes showed that the telomeric BLMH repeat lacked the 5' end of the gene and was 0.8 Mb from its centromeric copy. The distance between the SHGC30113 repeats was estimated as being 500 kb by double-color FISH on highly stretched chromosomes and DNA fibers. The latter approach revealed adjacent SHGC30113-BLMH-specific signals relating to the incomplete BLMH copy. The use of FISH on stretched chromosomes and, where applicable DNA fibers, is a powerful tool for identifying and finely characterizing duplicated regions whose mapping by the classical physical mapping approach is often precluded.

Chromosomes, Artificial, Yeast↗
PubMed2001

Duplication and transposition of the NF1 pseudogene regions on chromosomes 2, 14, and 22.

Numerous NF1 pseudogenes have been identified in the human genome. Those in 2q21, 14q11, and 22q11 form a subset with a similar genomic organization and a high sequence homology. We have studied, by polymerase chain reaction and fluorescence in situ hybridization, the extent of homology of the regions surrounding these NF1 pseudogenes. Our analyses have demonstrated that a fragment of at least 640 kb is homologous between the three regions. Based on previous studies and these new findings, we propose a model for the spreading of the NF1 pseudogene-containing regions. A fragment of approximately 640 kb was first duplicated in chromosome region 2q21 and transposed to 14q11. Subsequently, this fragment was duplicated in 14q11 and transposed to 22q11. A part of the 640-kb fragment in 14q11, with a length of about 430 kb, was further duplicated to a variable extent in 14q11. In addition, we have identified sequences that may facilitate the duplication and transposition of the 640-kb and 430-kb fragments.

Animals↗