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At least 703 records · Page 39Linked to original sources
PubMed2006

Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease.

OBJECTIVE: Recently, genomic multiplications of alpha-synuclein gene (SNCA) have been reported to cause hereditary early-onset parkinsonism. The objective of this study was to assess the frequency of SNCA multiplications among autosomal dominant hereditary Parkinson's disease (ADPD). METHODS: We screened 113 ADPD probands and 200 sporadic PD cases by quantitative polymerase chain reaction and confirmed SNCA multiplications by fluorescence in situ hybridization (FISH) and comparative genomic hybridization array. RESULTS: Two families (two patients from Family A and one from Family B) with SNCA duplication were identified among ADPD patients. Even though they had the same SNCA duplication, one patient had dementia. Because there was exactly the same difference between the regions originated from each patient, the finding suggests that the phenotype of SNCA multiplication may be also influenced by the range of duplication region. We also detected asymptomatic carriers in the families of both patients. Interestingly, the penetrance ratio was 33.3% (2/6) in one kindred, indicating that the ratio was very much lower than expected. INTERPRETATION: These two newly identified Japanese patients with SNCA duplication and the five previously identified American and European families with SNCA triplication or duplication mutations indicate that the incidence of SNCA multiplication may be more frequent than previously estimated.

Aged↗
PubMed2001

Duplication or amplification of chromosome band 11q23, including the unrearranged MLL gene, is a recurrent abnormality in therapy-related MDS and AML, and is closely related to mutation of the TP53 gene and to previous therapy with alkylating agents.

Gene amplification is a rare phenomenon in acute leukemia, but recently amplification of specific chromosome bands containing genes rearranged in leukemia-specific balanced chromosome translocations has been reported in a few cases. We detected duplication or amplification of chromosome band 11q23 with 3-7 copies of the MLL gene by fluorescence in situ hybridization in 12 out of 70 unselected patients with therapy-related myelodysplasia or acute myeloid leukemia (17%). In all but one case, the supernumerary copies of MLL were located to previously unidentified marker chromosomes or unbalanced translocations. In 4 of the 12 patients, 2-6 copies were located together on the same chromosome arm representing amplification, 7 patients had single, extra duplicated copies of MLL, whereas both amplification and duplication were observed in the same cell in 1 patient. Comparative genomic hybridization demonstrated gain of varying, often large parts of 11q in five patients. The MLL gene was shown to be unrearranged in all 12 patients. Seven out of eight patients with duplication or amplification of MLL had mutations of TP53. Patients with supernumerary copies of MLL were in general older (P = 0.007) and had a shorter survival (P < 0.001) compared to other patients. Duplication or amplification of MLL was significantly associated with a complex karyotype (P = 0.002), with deletion or loss of 5q (P = 0.001), and with prior therapy with alkylating agents. These results support the existence of a specific genetic pathway in t-MDS and t-AML with many previously unidentified chromosome aberrations demonstrated to represent extra copies of parts of 11q, including the unrearranged MLL gene.

Acute Disease↗
PubMed2006

Gene duplications in 21-hydroxylase deficiency: the importance of accurate molecular diagnosis in carrier detection and prenatal diagnosis.

BACKGROUND: The detection of 21-OH deficiency (21OHD) carriers in the general population requires that misinterpretations of apparently severe mutations in alleles carrying duplicated genes be avoided. Prenatal treatment prevents virilization in female fetuses and genetic counseling may be offered to couples in which one partner is either a patient or a carrier. This paper proposes a semiquantitative PCR method involving primer extension that distinguishes the severe point mutation Q318X in single gene copy alleles from the normal/nondeficient variant in gene-duplicated alleles. SAMPLES AND METHODS: DNA from 65 individuals carrying Q318X variants, that of 85 partners of 21OHD carriers or patients, and one fetal sample (as well as the DNA of his family) were analyzed. 21OHD alleles were studied by gene-specific PCR/allele-specific oligonucleotides hybridization for common mutations, Southern analysis, complementary direct sequencing and microsatellite typing. Primer extension analysis of the Q318X variants using fluorescent dideoxynucleotides was performed on CYP21A2 gene-specific PCR-amplified DNA samples from controls, patients, potential carriers and prenatal samples. RESULTS: Different fluorescence patterns were seen for the severe mutation (single gene copy) and the nondeficient (gene-duplicated) alleles carrying Q318X. The normal/mutant fluorescence peak (N/M) ratio was < 1 in all heterozygous carriers (mean 0.83; min. 0.70; max. 0.95). In all normal individuals carrying the gene-duplicated Q318X normal variant, the N/M ratio was > 1 (mean 1.69; min. 1.44; max. 2.02). CONCLUSION: The proposed method discriminated between the severe Q318X mutation and the normal Q318X variant in gene duplication, and could be a useful complementary tool in prenatal diagnosis and carrier detection.

Adrenal Hyperplasia, Congenital↗
PubMed2002

A 3-Mb map of a large Segmental duplication overlapping the alpha7-nicotinic acetylcholine receptor gene (CHRNA7) at human 15q13-q14.

Several neuropsychiatric disorders map to human 15q13-q14, which contains a strong candidate in the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7) and is partly duplicated, complicating further genetic analysis. We have shown that the partial duplication is in a hybrid (CHRFAM7A)between CHRNA7 and one of many copies of a novel gene (FAM7A). We have constructed a 3-Mb map of 15q13-q14 showing that CHRFAM7A is part of a large segmental duplication in the opposite orientation to CHRNA7 and revealing several other duplications. The data support a model of recent evolutionary events including duplications, at least one large deletion, and an inversion. We have identified two individuals with a structure that lacks CHRFAM7A and therefore predates many steps in this model, suggesting an unstable region with other intermediates possibly still in existence. This instability may be relevant to the many neuropsychiatric disorders that map in this region.

Adult↗
PubMed2002

Ancient duplications of the human proglucagon gene.

The human proglucagon gene (GCG) is encoded within a finished 576-kb DNA sequence generated by the Human Genome Project. GCG is flanked by 18 kb and 65 kb of DNA, 5' and 3', respectively, that do not encode genes. The genomic sequence that includes GCG was found to have a long history of gene duplication events. Some members of the glucagon-like family of genes, GCG on chromosome 2 and GIP on chromosome 17, may be products of ancient genome duplications on the early vertebrate lineage. A large genomic tandem duplication event that included DPP4-like and GCG genes occurred before the amphibian-mammal divergence, but one of the duplicated copies of GCG has been lost on the human lineage. Recently, a processed pseudogene of the X-chromosome-linked gene TIMM8A was inserted downstream of GCG. Some ancient duplicates of GCG may retain physiological functions in other vertebrates.

Animals↗
PubMed1999

Evolution of the archaeal rhodopsins: evolution rate changes by gene duplication and functional differentiation.

The amino acid sequences of 25 archaeal retinal proteins from 13 different strains of extreme halophiles were analyzed to establish their molecular phylogenetic relationship. On the basis of amino acid sequence similarity, these proteins apparently formed a distinct family designated as the archaeal rhodopsin family (ARF), which was not related to other known proteins, including G protein-coupled receptors. The archaeal rhodopsin family was further divided into four clusters with different functions; H+ pump (bacteriorhodopsin), Cl- pump (halorhodopsin), and two kinds of sensor (sensory rhodopsin and phoborhodopsin). These four rhodopsin clusters seemed to have occurred by gene duplication(s) before the generic speciation of halophilic archaea, based on phylogenetic analysis. Therefore, the degrees of differences in amino acid sequences within each cluster simply reflected the divergent evolution of halophilic archaea. By comparing the branch lengths after speciation points of the reconstituted tree, we calculated the relative evolution rates of the four archaeal rhodopsins bacteriorhodopsin:halorhodopsin:sensory rhodopsin: phoborhodopsin to be 5:4:3:10. From these values, the degrees of functional and structural restriction of each protein can be inferred. The branching topology of four clusters grouped bacteriorhodopsin and halorhodopsin versus sensory rhodopsin and phoborhodopsin by likelihood mapping. Using bacteriorhodopsin (and halorhodopsin) as an outgroup, the gene duplication point of sensory rhodopsin/phoborhodopsin was determined. By calculating the branch lengths between the gene duplication point and each halophilic archaea speciation point, we could speculate upon the relative evolution rate of pre-sensory rhodopsin and pre-phoborhodopsin. The evolution rate of pre-sensory rhodopsin was fivefold faster than that of pre-phoborhodopsin, which suggests that the original function of the ancestral sensor was similar to that of phoborhodopsin, and that sensory rhodopsin evolved from pre-sensory rhodopsin by the accumulation of mutations. The changes in evolution rate by gene duplication and functional differentiation were demonstrated in the archaeal rhodopsin family using the gene duplication date and halobacterial speciation date as common time stamps.

Amino Acid Sequence↗
PubMed1999

Gene duplication: past, present and future.

Gene duplication is of central interest to evolutionary developmental biology, having been implicated in evolutionary increases in complexity. These ideas stem principally from the Lewis model for the evolution of the BX-C and Ohno's proposal for genome duplications during chordate evolution. Here I revisit these models and show how recent data have confirmed their essential features, but forced some important revisions. These include revised dates for homeotic gene duplications and for widespread gene duplication in vertebrate evolution. I also outline the major unresolved questions in the study of gene duplication, and its relevance to evolution and development.

Animals↗
PubMed2004

Duplicate marker loci can result in incorrect locus orders on linkage maps.

Genetic linkage maps, constructed from multi-locus recombination data, are the basis for many applications of molecular markers. For the successful employment of a linkage map, it is essential that the linear order of loci on a chromosome is correct. The objectives of this theoretical study were to (1) investigate the occurrence of incorrect locus orders caused by duplicate marker loci, (2) develop a statistical test for the detection of duplicate markers, and (3) discuss the implications for practical applications of linkage maps. We derived conditions, under which incorrect locus orders do or do not occur with duplicate marker loci for the general case of n markers on a chromosome in a BC(1) mapping population. We further illustrated these conditions numerically for the special case of four markers. On the basis of the extent of segregation distortion, an exact test for the presence of duplicate marker loci was suggested and its power was investigated numerically. Incorrect locus orders caused by duplicate marker loci can (1) negatively affect the assignment of target genes to chromosome regions in a map-based cloning experiment, (2) hinder indirect selection for a favorable allele at a quantitative trait locus, and (3) decrease the efficiency of reducing the length of the chromosome segment attached to a target gene in marker-assisted backcrossing.

Chromosome Mapping↗
PubMed2003

Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study.

OBJECTIVE: Recent studies have revealed that genetic polymorphisms of cytochrome P(450) 2D6 (CYP2D6) are among the factors that determine the interindividual differences in the metabolism and response to antidepressants. We investigated the relationship between persistent mood disorders and the duplication of the CYP2D6 gene, which encodes an enzyme with increased activity. METHODS: We screened the prevalence of the CYP2D6 genotypes in 108 patients with persistent mood disorders using long polymerase chain reaction (PCR) and the real-time PCR methods. Clinical correlates with the genotypes were also analyzed. RESULTS: Among the 108 patients, 81 had failed to respond to antidepressants shown to be metabolized by CYP2D6. Of those 81, 8 had a CYP2D6 gene duplication (9.9%, 95% confidence interval 3.4-16.4%) which was higher than the 0.8-1.0% incidence previously observed in healthy Nordic Caucasians. The worst week scores of the Hamilton Depression Rating Scale were higher in the patients with the duplication compared with those without the duplication ( P=0.026, student's t-test). CONCLUSION: These results suggest that the CYP2D6 gene duplication is a possible factor that influences the development of persistence in patients with mood disorders probably by ultrarapid drug metabolism.

Antidepressive Agents↗
PubMed2002

The evolutionary history of prosaposin: two successive tandem-duplication events gave rise to the four saposin domains in vertebrates.

Prosaposin is a multifunctional protein encoded by a single-copy gene. It contains four saposin domains (A, B, C, and D) occurring as tandem repeats connected by linker sequences. Because the saposin domains are similar to one another, it is deduced that they were created by sequential duplications of an ancestral domain. There are two types of evolutionary scenarios that may explain the creation of the four-domain gene: (1) two rounds of tandem internal gene duplication and (2) three rounds of duplications. An evolutionary and phylogenetic analysis of saposin DNA and amino acid sequences from human, mouse, rat, chicken, and zebrafish indicates that the first evolutionary scenario is the most likely. Accordingly, an ancestral saposin-unit duplication produced a two-domain gene, which, subsequently, underwent a second complete tandem duplication to give rise to the present four-domain structure of the prosaposin gene.

Amino Acid Sequence↗
PubMed2003

Evolutionary dynamics of large numts in the human genome: rarity of independent insertions and abundance of post-insertion duplications.

We determined the phylogenetic positions of 82 large nuclear pseudogenes of mitochondrial origin (numts) within the human genome. For each numt, two possibilities pertaining to its origin were considered: (1) independent insertion from the mitochondria into the nucleus, or (2) genomic duplication subsequent to the insertion. A significant increase in the rate of numt accumulation is seen after the divergence of Platyrrhini (New World monkeys) from the Catarrhini (Old World monkeys, apes and humans). By using pairwise phylogenetic analyses, we were able to demonstrate that this peak in numt accumulation is mostly the result of duplication of preexisting nuclear numts rather than the result of an increase in mitochondrial-sequence insertion. In fact, only about a third of all the numt repertoire in the human nuclear genome is due to insertions of mitochondrial sequences, the rest originated as duplications of preexisting numts. Hence, we conclude that numt insertion occurs at a much lower rate than previously reported. As expected under the assumption that genomic duplications occur at rates that are uninfluenced by content, older numts were found to be duplicated more times than recently inserted ones.

DNA Transposable Elements↗
PubMed2003

Evolutionary dynamics of duplicated microsatellites shared by sex chromosomes.

Segmental duplications on sex chromosomes constitute an important proportion of recent duplications (approximately 30%). Among those, the evolution of duplicated noncoding DNA is still poorly investigated. We focus our work on repeated DNA sequences extensively used in population genetics and evolution: microsatellites. Six duplicated (CA), microsatellite loci, located on the homologous region of human sex chromosomes, were studied at the intraspecific level in Homo sapiens and by an orthologous comparison in eight primate species. At the intraspecific level, we evaluated the congruence in paralogous divergence between the flanking sequences of the six microsatellites and the approximately 2.2-kb surrounding sequences and observed that both phylogenies are congruent. At the interspecific level (8 species of primates: 54 individuals), we analyzed the sequence polymorphism and divergence of each orthologous locus for both the flanking sequence and the microsatellite. The results showed a lower divergence of flanking sequences than expected in noncoding DNA and a relative stability of the first nucleotides close to the microsatellite. The location of each CAIII locus in a Low Copy Repeated element containing duplicated VCX/Y genes (approximately 1 kb) suggested that direct or indirect selection could explain these results. Moreover, the substitution rates in the flanking sequences and in the microsatellites were correlated. Thus, the evolutionary dynamics of microsatellites seems closely linked to the variation of spontaneous mutations in the surrounding regions.

Animals↗
PubMed2004

Novel neuropeptide Y Y2-like receptor subtype in zebrafish and frogs supports early vertebrate chromosome duplications.

The Y receptors comprise a family of G-protein coupled receptors with neuropeptide Y-family peptides as endogenous ligands. The Y receptor family has five members in mammals and evolutionary data suggest that it diversified in the two genome duplications proposed to have occurred early in vertebrate evolution. If this theory holds true, it allows for additional family members to be present. We describe here the cloning, pharmacological characterization, tissue distribution, and chromosomal localization of a novel subtype of the Y-receptor family, named Y7, from the zebrafish. We also present Y7 sequences from rainbow trout and two amphibians. The new receptor is most similar to Y2, with 51-54% identity. As Y2 has also been cloned from some of these species, there clearly are two separate Y2-subfamily genes. Chromosomal mapping in zebrafish supports origin of Y7 as a duplicate of Y2 by chromosome duplication in an early vertebrate. Y7 has probably been lost in the lineage leading to mammals. The pharmacological profile of the zebrafish Y7 receptor is different from mammalian Y2, as it does not bind short fragments of NPY with a high affinity. The Y7 receptor supports the theory of early vertebrate genome duplications and suggests that the Y family of receptors is a result of these early genome duplications.

Amino Acid Sequence↗
PubMed2004

Higher gene duplicabilities for metabolic proteins than for nonmetabolic proteins in yeast and E. coli.

Although the evolutionary significance of gene duplication has long been appreciated, it remains unclear what factors determine gene duplicability. In this study we investigated whether metabolism is an important determinant of gene duplicability because cellular metabolism is crucial for the survival and reproduction of an organism. Using genomic data and metabolic pathway data from the yeast (Saccharomyces cerevisiae) and Escherichia coli, we found that metabolic proteins indeed tend to have higher gene duplicability than nonmetabolic proteins. Moreover, a detailed analysis of metabolic pathways in these two organisms revealed that genes in the central metabolic pathways and the catabolic pathways have, on average, higher gene duplicability than do other genes and that most genes in anabolic pathways are single-copy genes.

Computational Biology↗
PubMed2005

Natural selection during functional divergence to LMP7 and proteasome subunit X (PSMB5) following gene duplication.

The LMP7 and PSMB5 genes were created through an ancient gene duplication event of their ancestral locus. These proteins contain an active site of proteolysis, and LMP7 replaces PSMB5 as a component of the 20S proteasome after stimulation of cells by interferon-gamma. Replacement of PSMB5 by LMP7 changes the profile of the products of 20S proteasome processing, predisposing digested peptides for transport to and display by the immune system. The purpose of this study is to investigate evolutionary forces influencing functional divergence between LMP7 and PSMB5 following duplication. Levels of synonymous and nonsynonymous substitution rates are estimated to infer differences in levels of natural selection. Estimates of substitution rates indicate that natural selection elevated rates of nonsynonymous substitution in LMP7 following gene duplication, whereas PSMB5 experienced an increase in substitution rate that was not likely due to diversifying natural selection following duplication. Following initial divergence, nearly neutral mutations have dominated gene evolution in both lineages. The LMP7 gene locus provides a rare example of a protein with specialized function arising from duplication and divergence of a housekeeping protein by way of natural selection.

Animals↗
PubMed2004

Phylogenetic timing of the fish-specific genome duplication correlates with the diversification of teleost fish.

For many genes, ray-finned fish (Actinopterygii) have two paralogous copies, where only one ortholog is present in tetrapods. The discovery of an additional, almost-complete set of Hox clusters in teleosts (zebrafish, pufferfish, medaka, and cichlid) but not in basal actinopterygian lineages ( Polypterus) led to the formulation of the fish-specific genome duplication hypothesis. The phylogenetic timing of this genome duplication during the evolution of ray-finned fish is unknown, since only a few species of basal fish lineages have been investigated so far. In this study, three nuclear genes ( fzd8, sox11, tyrosinase) were sequenced from sturgeons (Acipenseriformes), gars (Semionotiformes), bony tongues (Osteoglossomorpha), and a tenpounder (Elopomorpha). For these three genes, two copies have been described previously teleosts (e.g., zebrafish, pufferfish), but only one orthologous copy is found in tetrapods. Individual gene trees for these three genes and a concatenated dataset support the hypothesis that the fish-specific genome duplication event took place after the split of the Acipenseriformes and the Semionotiformes from the lineage leading to teleost fish but before the divergence of Osteoglossiformes. If these three genes were duplicated during the proposed fish-specific genome duplication event, then this event separates the species-poor early-branching lineages from the species-rich teleost lineage. The additional number of genes resulting from this event might have facilitated the evolutionary radiation and the phenotypic diversification of the teleost fish.

Animals↗
PubMed2005

Gene duplication and the properties of biological networks.

Patterns of network connection of members of multigene families were examined for two biological networks: a genetic network from the yeast Saccharomyces cerevisiae and a protein-protein interaction network from Caenorhabditis elegans. In both networks, genes belonging to gene families represented by a single member in the genome ("singletons") were disproportionately represented among the nodes having large numbers of connections. Of 68 single-member yeast families with 25 or more network connections, 28 (44.4%) were located in duplicated genomic segments believed to have originated from an ancient polyploidization event; thus, each of these 28 loci was thus presumably duplicated along with the genomic segment to which it belongs, but one of the two duplicates has subsequently been deleted. Nodes connected to major "hubs" with a large number of connections, tended to be relatively sparsely interconnected among themselves. Furthermore, duplicated genes, even those arising from recent duplication, rarely shared many network connections, suggesting that network connections are remarkably labile over evolutionary time. These factors serve to explain well-known general properties of biological networks, including their scale-free and modular nature.

Animals↗
PubMed2006

En bloc duplications, mutation rates, and densities of amino acid changes clarify the evolution of vertebrate alpha-1,3/4-fucosyltransferases.

Numerous vertebrates have four alpha-1,3/4-fucosyltransferase genes (FUT9, FUT7, FUT4, and FUT Lewis) belonging to the same family. Until now, studies on the evolution of this family have mainly focused on Lewis genes but how the other alpha-1,3/4-fucosyltransferases have emerged from a common ancestor is not well known. In order to define the respective roles of duplications and mutations, we have compared amino acid sequences representative of bony fish (Takifugu rubripes), amphibians (Xenopus laevis), birds (Gallus gallus), and mammals (Bos taurus). The FUT tree has two fundamental branches, each split into two subfamilies. We found evidence for two duplication events, dated around 710-760 Myr and 590-640 Myr, respectively, compatible with the hypothesis of two rounds of whole genome duplications in chordate genomes, before the emergence of bony vertebrates. Based on the Homo sapiens (human) physical map, we identified blocks of paralogues belonging to regions of FUT9 (6q16), FUT4 (11q21), FUT7 (9q34), and FUT Lewis (19p13) and to a region on HSA1p that is devoid of any FUT. In zebrafish (Danio rerio), an orthologue region of HSA1 harbors an FUT9 specific to bony fish, showing that duplications are not restricted to a single FUT gene but involve blocks of paralogues. In addition, sets of genes within each block clarify the order of duplication events and, as a result, the order of alpha-1,3/4-fucosyltransferase gene emergence. We have also determined the mutation rates and the density of amino acid changes along protein sequences in each alpha-1,3/4-fucosyltransferase subfamily during the main vertebrate transitions. After the emergence of tetrapods, the mutation rate of FUT9 decreased dramatically, suggesting the early acquisition of a crucial fucosyltransferase activity in the first stages of development. The FUT7 mutation rate, which in tetrapod ancestors is about half that in amniote ancestors, may be related to the role of this gene in immune systems. In contrast to other subfamilies, we found a constant mutation rate in FUT Lewis and a rather homogeneous amino acid density change, independently of the vertebrate transition, suggesting that hitherto Lewis epitopes have dispensable functions.

Ambystoma↗