Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Duplication”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 397 records · Page 22Linked to original sources
PubMed2001

Origin of alternative splicing by tandem exon duplication.

Genes with new functions often evolve by gene duplication. Alternative splicing is another means of evolutionary innovation in eukaryotes, which allows a single gene to encode functionally diverse proteins. We investigate a connection between these two evolutionary phenomena. For approximately 10% of the described cases of substitution alternative splicing, such that either one or another amino acid sequence is included into the protein, evidence of origin by tandem exon duplication was found. This is a conservative estimate because alternative exons are typically short and, on many occasions, duplicates may have diverged beyond recognition. Dating exon duplications through a combination of the available experimental data on alternative splicing in orthologous genes from different species and computational analysis indicates that most of the duplications antedate at least the radiation of mammalian orders or even the radiation of vertebrate classes. At present, tandem exon duplication is the only mechanism of evolution of substitution alternative splicing that can be specifically demonstrated. Along with gene duplication, this could be a major route for generating functional diversity during evolution of multicellular eukaryotes.

Alternative Splicing↗
PubMed2003

Enrichment of segmental duplications in regions of breaks of synteny between the human and mouse genomes suggest their involvement in evolutionary rearrangements.

The sequence of the mouse genome allows one to compare the conservation of synteny between the human and mouse genome and exploration of regions that might have been involved in major rearrangements during the evolution of these two species (evolutionary genome rearrangements). Recent segmental duplications (or duplicons) are paralogous DNA sequences with high sequence identity that account for about 3.5-5% of the human genome and have emerged during the past approximately 35 million years of evolution. These regions are susceptible to illegitimate recombination leading to rearrangements that result in genomic disorders or genomic mutations. A catalogue of several hundred segmental duplications potentially leading to genomic rearrangements has been reported. The authors and others have observed that some chromosome regions involved in genomic disorders are shuffled in orientation and order in the mouse genome and that regions flanked by segmental duplications are often polymorphic. We have compared the human and mouse genome sequences and demonstrate here that recent segmental duplications correlate with breaks of synteny between these two species. We also observed that nine primary regions involved in human genomic disorders show changes in the order or the orientation of mouse/human synteny segments, were often flanked by segmental duplications in the human sequence. We found that 53% of all evolutionary rearrangement breakpoints associate with segmental duplications, as compared with 18% expected in a random location of breaks along the chromosome (P<0.0001). Our data suggest that segmental duplications have participated in the recent evolution of the human genome, as driving forces for evolutionary rearrangements, chromosome structure polymorphisms and genomic disorders.

Animals↗
PubMed2003

Significantly different patterns of amino acid replacement after gene duplication as compared to after speciation.

We have performed a large-scale analysis of amino acid sequence evolution after gene duplication by comparing evolution after gene duplication with evolution after speciation in over 1,800 phylogenetic trees constructed from manually curated alignments of protein domains downloaded from the PFAM database. The site-specific rate of evolution is significantly altered by gene duplication. A significant increase in the proportion of amino acid substitutions at constrained (slowly evolving) sites after duplication was observed. An increase in the proportion of replacements at normally constrained amino acid sites could result from relaxation of purifying selective pressure. However, the proportion of amino acid replacements involving radical changes in amino acid properties after duplication does not appear to be significantly increased by relaxed selective pressure. The increased proportion of replacements at constrained sites was observed over a relatively large range of protein change (up to 25% amino acid replacements per site). These findings have implications for our understanding of the nature of evolution after duplication and may help to shed light on the evolution of novel protein functions through gene duplication.

Algorithms↗
PubMed2003

Using a pericentromeric interspersed repeat to recapitulate the phylogeny and expansion of human centromeric segmental duplications.

Despite considerable advances in sequencing of the human genome over the past few years, the organization and evolution of human pericentromeric regions have been difficult to resolve. This is due, in part, to the presence of large, complex blocks of duplicated genomic sequence at the boundary between centromeric satellite and unique euchromatic DNA. Here, we report the identification and characterization of an approximately 49-kb repeat sequence that exists in more than 40 copies within the human genome. This repeat is specific to highly duplicated pericentromeric regions with multiple copies distributed in an interspersed fashion among a subset of human chromosomes. Using this interspersed repeat (termed PIR4) as a marker of pericentromeric DNA, we recovered and sequence-tagged 3 Mb of pericentromeric DNA from a variety of human chromosomes as well as nonhuman primate genomes. A global evolutionary reconstruction of the dispersal of PIR4 sequence and analysis of flanking sequence supports a model in which pericentromeric duplications initiated before the separation of the great ape species (>12 MYA). Further, analyses of this duplication and associated flanking duplications narrow the major burst of pericentromeric duplication activity to a time just before the divergence of the African great ape and human species (5 to 7 MYA). These recent duplication exchange events substantially restructured the pericentromeric regions of hominoid chromosomes and created an architecture where large blocks of sequence are shared among nonhomologous chromosomes. This report provides the first global view of the series of historical events that have reshaped human pericentromeric regions over recent evolutionary time.

Animals↗
PubMed2006

Functional diversification of B MADS-box homeotic regulators of flower development: Adaptive evolution in protein-protein interaction domains after major gene duplication events.

B-class MADS-box genes have been shown to be the key regulators of petal and stamen specification in several eudicot model species such as Arabidopsis thaliana, Antirrhinum majus, and Petunia hybrida. Orthologs of these genes have been found across angiosperms and gymnosperms, and it is thought that the basic regulatory function of B proteins is conserved in seed plant lineages. The evolution of B genes is characterized by numerous duplications that might represent key elements fostering the functional diversification of duplicates with a deep impact on their role in the evolution of the floral developmental program. To evaluate this, we performed a rigorous statistical analysis with B gene sequences. Using maximum likelihood and Bayesian methods, we estimated molecular substitution rates and determined the selective regimes operating at each residue of B proteins. We implemented tests that rely on phylogenetic hypotheses and codon substitution models to detect significant differences in substitution rates (DSRs) and sites under positive adaptive selection (PS) in specific lineages before and after duplication events. With these methods, we identified several protein residues fixed by PS shortly after the origin of PISTILLATA-like and APETALA3-like lineages in angiosperms and shortly after the origin of the euAP3-like lineage in core eudicots, the 2 main B gene duplications. The residues inferred to have been fixed by positive selection lie mostly within the K domain of the protein, which is key to promote heterodimerization. Additionally, we used a likelihood method that accommodates DSRs among lineages to estimate duplication dates for AP3-PI and euAP3-TM6, calibrating with data from the fossil record. The dates obtained are consistent with angiosperm origins and diversification of core eudicots. Our results strongly suggest that novel multimer formation with other MADS proteins could have been crucial for the functional divergence of B MADS-box genes. We thus propose a mechanism of functional diversification and persistence of gene duplicates by the appearance of novel multimerization capabilities after duplications. Multimer formation in different combinations of regulatory proteins can be a mechanistic basis for the origin of novel regulatory functions and a gene regulatory mechanism for the appearance of morphological innovations.

Amino Acid Sequence↗
PubMed2002

Extent of gene duplication in the genomes of Drosophila, nematode, and yeast.

We conducted a detailed analysis of duplicate genes in three complete genomes: yeast, Drosophila, and Caenorhabditis elegans. For two proteins belonging to the same family we used the criteria: (1) their similarity is > or =I (I = 30% if L > or = 150 a.a. and I = 0.01n + 4.8L(-0.32(1 + exp(-L/1000))) if L < 150 a.a., where n = 6 and L is the length of the alignable region), and (2) the length of the alignable region between the two sequences is > or = 80% of the longer protein. We found it very important to delete isoforms (caused by alternative splicing), same genes with different names, and proteins derived from repetitive elements. We estimated that there were 530, 674, and 1,219 protein families in yeast, Drosophila, and C. elegans, respectively, so, as expected, yeast has the smallest number of duplicate genes. However, for the duplicate pairs with the number of substitutions per synonymous site (K(S)) < 0.01, Drosophila has only seven pairs, whereas yeast has 58 pairs and nematode has 153 pairs. After considering the possible effects of codon usage bias and gene conversion, these numbers became 6, 55, and 147, respectively. Thus, Drosophila appears to have much fewer young duplicate genes than do yeast and nematode. The larger numbers of duplicate pairs with K(S) < 0.01 in yeast and C. elegans were probably largely caused by block duplications. At any rate, it is clear that the genome of Drosophila melanogaster has undergone few gene duplications in the recent past and has much fewer gene families than C. elegans.

Animals↗
PubMed2002

Nucleotide variation of the duplicated amylase genes in Drosophila kikkawai.

We examined levels and patterns of the nucleotide polymorphism of the Amylase genes with a head-to-head duplication in Drosophila kikkawai. The levels of variation in D. kikkawai were comparable to those in Drosophila melanogaster. Tajima's test, Fu and Li's test, HKA test, and MK test did not show significant departure from neutrality. We found an excess of replacement changes in the within-locus class, representing polymorphism in one of the duplicated genes, compared with the between-locus class, representing polymorphism shared between the duplicated genes. Most replacement changes in the within-locus class were singletons. These results suggest that most replacement changes are deleterious. A contrasting evolutionary pattern, involving concerted evolution in the coding regions but differential evolution in the 5'-flanking regions, was observed. However, unlike the duplicated Amy genes of D. melanogaster, the coding regions of the duplicated genes in D. kikkawai tended to diverge. Using Ohta's model of the small multigene family, we found that recombination (interchromosomal equal crossing-over) rate was one order higher than gene conversion (unequal crossing-over) rate, resulting in a considerable but incomplete homogenization of the duplicated coding regions. Linkage disequilibria were found in the intron as well as within and around the regulatory cis-element sequences of one of the duplicated genes (Amy1). The possible causes of these linkage disequilibria were discussed.

Amino Acid Sequence↗
PubMed2026

Prenatal diagnosis and genetic counseling of a de novo 10q11.22q11.23 duplication associated with a normal development at 12 months of age.

BACKGROUND: Copy number variants are an important source of genomic variations, ranging from pathogenic to benign. The 10q11.22q11.23 region contains complex low-copy repeats that predispose to recurrent deletions and duplications via nonallelic homologous recombination. While some reports associate duplications of this region with developmental delay, intellectual disability, and autism spectrum disorders, emerging evidence suggests that such duplications may also be observed in phenotypically normal individuals, indicating incomplete penetrance and variable expressivity. CASE PRESENTATION: A 35-year-old pregnant woman with an unremarkable obstetric history underwent amniocentesis at 20 weeks of gestation. Conventional karyotyping and copy number variation sequencing (CNV-seq) were performed. CNV-seq revealed a de novo 4.56&#x2009;Mb duplication at 10q11.22q11.23. The duplication was classified as a variant of uncertain significance. After extensive genetic counseling, the parents elected to continue the pregnancy. At 40 weeks of gestation, a female infant was delivered by cesarean section with normal birth parameters. A comprehensive physical examination at birth revealed no abnormalities. At the 12-month follow-up, the infant demonstrated normal growth parameters and age-appropriate neurodevelopmental milestones, with no evidence of dysmorphic features, developmental delay, or other clinical concerns. CONCLUSION: This report describes a prenatal case of a de novo 10q11.22q11.23 duplication with a normal development at 12 months of age. Our findings contribute to the growing body of literature suggesting that duplications in this pericentromeric region may exhibit incomplete penetrance and variable expressivity, and in some cases, may represent benign familial or de novo variants without apparent clinical consequences.

10q11.22q11.23 duplication↗
PubMed2003

Divergence in the spatial pattern of gene expression between human duplicate genes.

Microarray gene expression data provide a wealth of information for elucidating the mode and tempo of molecular evolution. In the present study,we analyze the spatial expression pattern of human duplicate gene pairs by using oligonucleotide microarray data,and study the relationship between coding sequence divergence and expression divergence. First,we find a strong positive correlation between the proportion of duplicate gene pairs with divergent expression (as presence or absence of expression in a tissue) and both synonymous (K(S)) and nonsynonymous divergence (K(A)). The divergence of gene expression between human duplicate genes is rapid, probably faster than that between yeast duplicates in terms of generations. Second,we compute the correlation coefficient (R) between the expression levels of duplicate genes in different tissues and find a significant negative correlation between R and K(S). There is also a negative correlation between R and K(A), when K(A) <or= 0.2. These results indicate that protein sequence divergence and divergence of spatial expression pattern are initially coupled. Finally,we compare the functions of those duplicate genes that show rapid divergence in spatial expression pattern with the functions of those duplicate genes that show no or little divergence in spatial expression.

Computational Biology↗
PubMed2003

A sensitive method for detecting variation in copy numbers of duplicated genes.

Gene duplications are common in the vertebrate genome, and duplicated loci often show a variation in copy number that may have important phenotypic effects. Here we describe a powerful method for quantification of duplicated copies based on pyrosequencing. A reliable quantification was obtained by amplification of the duplication break-point and a corresponding nonduplicated sequence in a competitive PCR assay. A comparison with an independent method for quantification based on the Invader technology revealed an excellent correlation between the two methods. The pyrosequencing-based method was evaluated by analyzing variation in copy number at the duplicated KIT/Dominant white locus in pigs. We were able to distinguish haplotypes at this locus by combining the duplication breakpoint test with a diagnostic test for a functionally important splice mutation in the duplicated gene. An extensive allelic variation, including the presence of a new allele carrying a single KIT copy expected to encode a truncated KIT receptor, was revealed when analyzing white pigs from commercial lines.

Algorithms↗
PubMed2001

Partitioning of tissue expression accompanies multiple duplications of the Na+/K+ ATPase alpha subunit gene.

Vertebrate genomes contain multiple copies of related genes that arose through gene duplication. In the past it has been proposed that these duplicated genes were retained because of acquisition of novel beneficial functions. A more recent model, the duplication-degeneration-complementation hypothesis (DDC), posits that the functions of a single gene may become separately allocated among the duplicated genes, rendering both duplicates essential. Thus far, empirical evidence for this model has been limited to the engrailed and sox family of developmental regulators, and it has been unclear whether it may also apply to ubiquitously expressed genes with essential functions for cell survival. Here we describe the cloning of three zebrafish alpha subunits of the Na(+),K(+)-ATPase and a comprehensive evolutionary analysis of this gene family. The predicted amino acid sequences are extremely well conserved among vertebrates. The evolutionary relationships and the map positions of these genes and of other alpha-like sequences indicate that both tandem and ploidy duplications contributed to the expansion of this gene family in the teleost lineage. The duplications are accompanied by acquisition of clear functional specialization, consistent with the DDC model of genome evolution.

Amino Acid Sequence↗
PubMed2004

Segmental duplications flank the multiple sclerosis locus on chromosome 17q.

Large chromosomal rearrangements, duplications, and inversions are relatively common in mammalian genomes. Here we report interesting features of DNA strands flanking a Multiple Sclerosis (MS) susceptibility locus on Chromosome 17q24. During the positional cloning process of this 3-Mb locus, several markers showed a radiation hybrid clone retention rate above the average (1.8-fold), suggestive for the existence of duplicated sequences in this region. FISH studies demonstrated multiple signals with three of the tested regional BACs, and 24 BACs out of 187 showed evidence for duplication in shotgun sequence comparisons of the 17q22-q24 region. Specifically, the MS haplotype region proved to be flanked by palindromic sequence stretches and by long segmental intrachromosomal duplications in which highly homologous DNA sequences (>96% identity) are present at both ends of the haplotype. Moreover, the 3-Mb DNA segment, flanked by the duplications, is inverted in the mouse genome when compared with the orientation in human and chimp. The segmental duplication architecture surrounding the MS locus raises the possibility that a nonallelic homologous recombination between duplications could affect the biological activity of the regional genes, perhaps even contributing to the genetic background of MS.

Animals↗
PubMed2005

Punctuated duplication seeding events during the evolution of human chromosome 2p11.

Primate genomic sequence comparisons are becoming increasingly useful for elucidating the evolutionary history and organization of our own genome. Such studies are particularly informative within human pericentromeric regions--areas of particularly rapid change in genomic structure. Here, we present a systematic analysis of the evolutionary history of one approximately 700-kb region of 2p11, including the first autosomal transition from pericentromeric sequence to higher-order alpha-satellite DNA. We show that this region is composed of segmental duplications corresponding to 14 ancestral segments ranging in size from 4 kb to approximately 115 kb. These duplicons show 94%-98.5% sequence identity to their ancestral loci. Comparative FISH and phylogenetic analysis indicate that these duplicons are differentially distributed in human, chimpanzee, and gorilla genomes, whereas baboon has a single putative ancestral locus for all but one of the duplications. Our analysis supports a model where duplicative transposition events occurred during a narrow window of evolution after the separation of the human/ape lineage from the Old World monkeys (10-20 million years ago). Although dramatic secondary dispersal events occurred during the radiation of the human, chimpanzee, and gorilla lineages, duplicative transposition seeding events of new material to this particular pericentromeric region abruptly ceased after this time period. The multiplicity of initial duplicative transpositions prior to the separation of humans and great-apes suggests a punctuated model for the formation of highly duplicated pericentromeric regions within the human genome. The data further indicate that factors other than sequence are important determinants for such bursts of duplicative transposition from the euchromatin to pericentromeric regions.

Animals↗
PubMed2006

Ancient duplicated conserved noncoding elements in vertebrates: a genomic and functional analysis.

Fish-mammal genomic comparisons have proved powerful in identifying conserved noncoding elements likely to be cis-regulatory in nature, and the majority of those tested in vivo have been shown to act as tissue-specific enhancers associated with genes involved in transcriptional regulation of development. Although most of these elements share little sequence identity to each other, a small number are remarkably similar and appear to be the product of duplication events. Here, we searched for duplicated conserved noncoding elements in the human genome, using comparisons with Fugu to select putative cis-regulatory sequences. We identified 124 families of duplicated elements, each containing between two and five members, that are highly conserved within and between vertebrate genomes. In 74% of cases, we were able to assign a specific set of paralogous genes with annotation relating to transcriptional regulation and/or development to each family, thus removing much of the ambiguity in identifying associated genes. We find that duplicate elements have the potential to up-regulate reporter gene expression in a tissue-specific manner and that expression domains often overlap, but are not necessarily identical, between family members. Over two thirds of the families are conserved in duplicate in fish and appear to predate the large-scale duplication events thought to have occurred at the origin of vertebrates. We propose a model whereby gene duplication and the evolution of cis-regulatory elements can be considered in the context of increased morphological diversity and the emergence of the modern vertebrate body plan.

Animals↗
PubMed1999

CAGGG repeats and the pericentromeric duplication of the hominoid genome.

Gene duplication is one of the primary forces of evolutionary change. We present data from three different pericentromeric regions of human chromosomes, which indicate that such regions of the genome have been sites of recent genomic duplication. This form of duplication has involved the evolutionary movement of segments of genomic material, including both intronic and exonic sequence, from diverse regions of the genome toward the pericentromeric regions. Sequence analyses of the target sites of duplication have identified a novel class of interspersed GC-rich repeats located precisely at the boundaries of duplication. Estimates of the evolutionary age of these duplications indicate that they have occurred between 10 and 25 mya. In contrast, comparative analyses confirm that the GC-rich pericentromeric repeats have existed within the pericentromeric regions of primate chromosomes before the divergence of the cercopithecoid and hominoid lineages ( approximately 30 mya). These data provide molecular evidence for considerable interchromosomal duplication of genic segments during the evolution of the hominoid genome and strongly implicate GC-rich repeat elements as playing a direct role in the pericentromeric localization of these events

Animals↗
PubMedDate not supplied

Duplication events and the evolution of segmental identity.

Duplication of genes, genomes, or morphological structures (or some combination of these) has long been thought to facilitate evolutionary change. Here we focus on studies of the teleost fishes to consider the conceptual similarities in the evolutionary potential of these three different kinds of duplication events. We review recent data that have confirmed the occurrence of a whole-genome duplication event in the ray-finned fish lineage, and discuss whether this event may have fuelled the radiation of teleost fishes. We then consider the fates of individual duplicated genes, from both a theoretical and an experimental viewpoint, focusing on our studies of teleost Hox genes and their functions in patterning the segmented hindbrain. Finally, we consider the duplication of morphological structures, once again drawing on our experimental studies of the hindbrain, which have revealed that experimentally induced duplicated neurons can produce functionally redundant neural circuits. We posit that the availability of duplicated material, independent of its nature, can lead to functional redundancy, which in turn enables evolutionary change.

Animals↗
PubMed2002

Vertebrate phylogenomics: reconciled trees and gene duplications.

Ancient gene duplication events have left many traces in vertebrate genomes. Reconciled trees represent the differences between gene family trees and the species phylogeny those genes are sampled from, allowing us to both infer gene duplication events and estimate a species phylogeny from a sample of gene families. We show that analysis of 118 gene families yields a phylogeny of vertebrates largely in agreement with other data. We formulate the problem of locating episodes of gene duplication as a set cover problem: given a species tree in which each node has a set of gene duplications associated with it, the smallest set of species nodes whose union includes all gene duplications specifies the locations of gene duplication episodes. By generating a unique mapping from this cover set we can determine the minimal number of such episodes at each location. When applied to our data, this method reveals a complex history of gene duplications in vertebrate evolution that does not conform to the "2R" hypothesis.

Animals↗
PubMedDate not supplied

Duplication dup(1)(q32q44) detected by comparative genomic hybridization (CGH): further delineation of trisomies 1q.

Partial trisomy 1q is rare and mostly the result of an abnormal segregation of parental translocation chromosomes and their homologues. Only 31 cases have been described with pure partial trisomy 1q. In the fetus presented, chromosome analysis after amniocentesis had shown an unbalanced male karyotype with an aberrant chromosome 1. A de novo terminal duplication of the long arm was suspected but could not be verified by FISH in 1994. Five years after fetal death, retrospective identification of the additional material in 1q could finally be achieved by comparative genomic hybridization (CGH) using DNA extracted from formalin-fixed and paraffin-embedded fetal tissues. A direct duplication dir dup (1)(pter-->q44::q32.1-->qter) was found. Only 6 other individuals with duplication of this segment have been described so far. Comparative delineation of a dup1q phenotype with regard to size and origin of the dup (1q) segment evidenced that large duplications as well as proximal and interstitial duplications coincide with more severe visceral malformations, severe mental retar- dation and a short life span. Terminal duplications (1q32-->qter) concur with less severe malformations and longer periods of survival, but marked mental retardation. With small terminal duplications (1q42-->qter) dysmorphisms are usually mild and intellectual performance is mostly in the normal range.

Adult↗