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PubMed1997

Duplication of seven exons in the lysyl hydroxylase gene is associated with longer forms of a repetitive sequence within the gene and is a common cause for the type VI variant of Ehlers-Danlos syndrome.

The type VI variant of the Ehlers-Danlos syndrome (EDS) is a recessively inherited connective tissue disorder which, in most families, is due to a deficiency in lysyl hydroxylase activity. We have recently characterized a homozygous duplication of 8.9 kb in the lysyl hydroxylase gene (PLOD) in two EDS VI families. The duplication is caused by a homologous recombination of Alu sequences in introns 9 and 16. Using PCR, we have analyzed 26 additional EDS VI families from various countries and found that 7 of them have this duplication. Our data has shown a frequency of 19.1% for this mutant allele among 35 EDS VI families studied by us so far. Our haplotype analysis shows a variation in the sequence of DNA region surrounding the duplication. There is an association between a particular allele size class, the long form, at the dinucleotide repeat within intron 16 and the duplication mutation in PLOD. Screening of a general population revealed one positive finding among 582 alleles tested. An abnormal sequence in exon 17 of the gene, which generated a stop codon in the exon sequence and aberrant mRNA processing, was responsible for the nonfunctionality of the other allele in one of the compound heterozygous patients.

Alleles↗

PubMed1997

[Difference of new mutation rates in dystrophin gene between deletion and duplication mutation in Duchenne and Becker muscular dystrophy].

To clarify new mutational rates in the dystrophin gene between deletion and duplication mutations, carrier diagnosis was performed on 123 mothers of probands suffered from Duchenne (DMD) and Becker (BMD) muscular dystrophy. Quantitative Southern blot analysis with cDNA probes was applied in this study. Out of 108 mothers of DMD/BMD patients with deletion mutation in dystrophin gene, 69 were carriers and 39 were non-carriers. On the other hands, all of 15 mothers of probands with duplication mutation were carriers. The fact that no new mutation occurred in oogenesis in the families with duplication mutations in dystrophin gene indicates that duplications arise in spermatogenesis. The risk of the mother of an isolated case of DMD/BMD with duplication mutation of being a carrier is significantly higher than the estimated risk based on the equality of new mutation in oogenesis and spermatogenesis.

Dystrophin↗

PubMed2026

Tandem Duplication-Driven Neofunctionalization of UDP-Glycosyltransferases Shapes the Diversification of Triterpenoid Saponins in the Cucurbitaceae.

Tandem duplication of tailoring enzymes allows evolutionary innovation that diversifies plant specialized metabolism. Here, we present an interesting example of how tandem duplicated UDP-glycosyltransferases undergo neofunctionalization and shape the chemical diversity of triterpenoid saponins in the Cucurbitaceae family. A chromosome-level genome of Siraitia grosvenorii was assembled and aligned with multiple cucurbit genomes, revealing a specific UGT73AM tandem duplication responsible for regio-selective glycosylation (e.g. the rare 1,4-linked disaccharide) of diverse saponins such as mogrosides, ginsenosides, and momordicines. Comparative genomics depicted the evolutionary trajectory of a universal saponin-biosynthesizing UGT73 tandem arrays syntenously preserved across core eudicots, where lineage-specific UGT copies contribute to distinct metabolic phenotypes. A crystal structure of SgUGT73AM30 (mogrol 25-O-glycosyltransferase) in complex with UDP and mogrol was obtained to elucidate the molecular basis of the regio-specific decoration on vicinal diol of the substrates. Altogether, these findings provide insights into tandem duplication-driven diversification of glycosyltransferases and lay the foundation for engineered glycosylation of valuable triterpenoid saponins.

Saponins↗

PubMed2002

Gene duplication and gene conversion shape the evolution of archaeal chaperonins.

Chaperonins are multi-subunit double-ring complexes that mediate the folding of nascent or denatured proteins. Gene duplication has been a potent force in the evolution of chaperonins in Archaea. Here we show that gene conversion has also been an important factor. We utilized a novel maximum likehood-based phylogenetic method for scanning DNA sequence alignments for regions of anomalous phylogenetic signal, such as those affected by gene conversion. Our results suggest that in crenarchaeotes, where an ancient gene duplication producing alpha and beta subunits took place in the common ancestor of the Pyrodictium, Aeropyrum, Pyrobaculum and Sulfolobus lineages, multiple independent gene conversions have occurred between the alpha and beta genes independently in each of these groups. Significantly, the conversions have repeatedly homogenized the region of the gene encoding the substrate-binding domain. This suggests that while the alpha and beta subunits in crenarchaeotes share only 50-60% overall amino acid sequence identity, they do not possess distinct roles in the binding of substrate. Cryptic gene conversion between distantly related paralogs may be more common than is currently appreciated, and could be a significant factor in slowing the functional differentiation of proteins encoded by duplicate genes long after their duplication.

Amino Acid Sequence↗

PubMed2026

Genome-wide cyclin gene evolution in Arabidopsis and Brassica reveals polyploidization-driven duplication and flowering-time associations.

Cyclin genes are plant cell cycle regulators that play essential roles in growth, development, and reproduction. However, the evolutionary dynamics and genomic organization of cyclin genes across the Brassicaceae family remain poorly understood, particularly in the context of allotetraploid genome evolution. Here, we investigated the diversity, expansion mechanisms, and potential functional diversification of cyclin genes across ten Brassicaceae genomes, including four Arabidopsis and six Brassica species. A total of 1087 cyclin genes representing 23 cyclin types were identified. Comparative genomic analyses revealed that cyclin gene expansion was strongly influenced by polyploidization in Brassica species, with 1845 duplication events involving 1063 genes. Whole-genome duplication was the predominant mechanism driving expansion, while both inter- and intra-genomic duplications contributed to gene retention in tetraploid Brassica species, with the highest duplication frequency observed in Brassica juncea. Across genomes, 120 physical gene clusters were identified, including homogeneous and heterogeneous types. Ortholog analysis between progenitor and allotetraploid species identified 852 orthologous pairs involving 366 genes, indicating extensive conservation following allotetraploid formation. Phylogenetic analysis resolved cyclins into three major clades, while expression-based clustering in Brassica napus grouped genes into four major clusters, suggesting functional diversification. Integration of pan-genomic and flowering-time QTL analyses further identified two cyclin genes, Bna21cycA2 and Bna113cycD4, which contain amino acid polymorphisms and represent putative candidate variations potentially associated with flowering-time variation across multiple genomes. These findings provide new insights into the evolutionary expansion, retention, and potential functional divergence of cyclin genes in Brassicaceae and highlight candidate loci for future functional studies and crop improvement.

Evolution, Molecular↗

PubMed2004

Developmental constraint on gene duplicability in fruit flies and nematodes.

A previous study in nematodes suggested that developmental constraint reduces the duplicability of genes involved in early development. Recent large-scale gene expression studies of fly development enabled us to conduct a more detailed study of this issue. We found that the average duplicability of genes involved in embryonic development is indeed lower than that of genes involved in larval development but not significantly lower than that of genes involved in later stages of development. Moreover, in both flies and nematodes genes with multiple expression peaks do not seem to have a lower duplicability than do genes with a single expression peak. Thus, although developmental constraint does appear to reduce gene duplicability, the effect seems weak or at best moderate.

Animals↗

PubMed2004

Shotgun sequence assembly and recent segmental duplications within the human genome.

Complex eukaryotic genomes are now being sequenced at an accelerated pace primarily using whole-genome shotgun (WGS) sequence assembly approaches. WGS assembly was initially criticized because of its perceived inability to resolve repeat structures within genomes. Here, we quantify the effect of WGS sequence assembly on large, highly similar repeats by comparison of the segmental duplication content of two different human genome assemblies. Our analysis shows that large (> 15 kilobases) and highly identical (> 97%) duplications are not adequately resolved by WGS assembly. This leads to significant reduction in genome length and the loss of genes embedded within duplications. Comparable analyses of mouse genome assemblies confirm that strict WGS sequence assembly will oversimplify our understanding of mammalian genome structure and evolution; a hybrid strategy using a targeted clone-by-clone approach to resolve duplications is proposed.

Animals↗

PubMed2001

A cascade of complex subtelomeric duplications during the evolution of the hominoid and Old World monkey genomes.

Subtelomeric duplications of an obscure tubulin "genic" segment located near the telomere of human chromosome 4q35 have occurred at different evolutionary time points within the last 25 million years of the catarrhine (i.e., hominoid and Old World monkey) evolution. The analyses of these segments reported here indicate an exceptional level of evolutionary instability. Substantial intra- and interspecific differences in copy number and distribution are observed among cercopithecoid (Old World monkey) and hominoid genomes. Characterization of the hominoid duplicated segments reveals a strong positional bias within pericentromeric and subtelomeric regions of the genome. On the basis of phylogenetic analysis from predicted proteins and comparisons of nucleotide-substitution rates, we present evidence of a conserved b-tubulin gene among the duplications. Remarkably, the evolutionary conservation has occurred in a nonorthologous fashion, such that the functional copy has shifted its positional context between hominoids and cercopithecoids. We propose that, in a chimpanzee-human common ancestor, one of the paralogous copies assumed the original function, whereas the ancestral copy acquired mutations and eventually became silenced. Our analysis emphasizes the dynamic nature of duplication-mediated genome evolution and the delicate balance between gene acquisition and silencing.

Animals↗

PubMed2025

Tandem gene duplication facilitates intertidal adaptation in atypical mangrove plants.

Mangrove plants, originating from inland ancestors, have independently adapted to extreme intertidal zones characterized by salt and hypoxia stress. While typical mangroves exhibit specialized phenotypes, like viviparous seeds and salt secretion, atypical clades that have thrived without such traits are particularly suitable for exploring the molecular and physiological basis underlying plant adaptation to intertidal zones. We assembled a chromosome-level genome of an atypical mangrove, Scyphiphora hydrophylacea, the only mangrove species in Gentianales. Similar to other mangroves, S. hydrophylacea colonized intertidal zones during climatic optimum periods of sea-level rise. Despite lacking recent whole-genome duplications (WGDs), its genome acquired extensive tandem gene duplications (TDs), leading to the rapid expansion of key salt- and hypoxia-related genes. Transcriptome data further corroborated that TD-driven gene expansions contribute to stress tolerance. Specifically, the expansion of genes involved in cation transmembrane transport, osmotic regulation, and oxidative stress response may enhance salinity tolerance, and the expansion of signal transduction and energy metabolism genes in hypoxia-response pathways may confer waterlogging tolerance. Therefore, in the absence of large-scale gene duplication, the rapid expansion of core genes involved in salt and hypoxia tolerance through tandem duplication may represent a key force driving the adaptation of atypical mangroves. These findings also provide valuable insights for crop improvement strategies aimed at enhancing environmental resilience while maintaining phenotypic stability.

Gene Duplication↗

PubMed1999

De novo direct duplication of 15q15-->q24 in a newborn boy with mild manifestations.

Duplication of distal 15q results in a recognizable clinical phenotype. We report here on a 25-day-old boy with a de novo interstitial duplication of chromosome region 15q15-q24. The manifestations in this patient are milder than those of previously described patients and include minor facial anomalies, velopharyngeal insufficiency, branchial cleft cyst, and hydronephrosis. Fluorescence in situ hybridization (FISH) using a chromosome 15 painting probe confirmed that the extra material is of chromosome 15 origin. Further analysis with the SNRPN probe demonstrated that the duplication is telomeric to the Prader-Willi/Angelman syndrome critical region. This case delineates a broader spectrum for patients with duplication 15q syndrome.

Abnormalities, Multiple↗

PubMed1998

The fate of duplicated genes: loss or new function?

Gene duplication events are important sources of novel gene functions. However, more often than not, a duplicate gene may lose its function and become a pseudogene. What is the relative frequency of these two scenarios: functional divergence versus gene loss? Given that most non-neutral mutations are deleterious, gene loss should be far more frequent than divergence. However, a recent empirical study suggests that about 50% of all gene duplications will lead to functional divergence. The study infers the frequency of functional divergence from the size distribution of gene families produced by two successive genome duplications early in vertebrate evolution. Reasons for this unexpectedly high frequency of functional divergence are discussed.

Animals↗

PubMed2001

De novo partial duplication of chromosome 7p in a male with autistic disorder.

We describe a de novo partial duplication of 7p in a 25-year-old male with autistic disorder (AD). High-resolution chromosome analysis revealed an extra segment added to the proximal short arm of chromosome 7. The G-band pattern was consistent with an inverted duplication of 7p11.2-p14.1. Fluorescent in situ hybridization (FISH), using a whole chromosome 7 DNA probe (Cytocell, Inc., UK), confirmed that the extra chromosome material is derived from chromosome 7, indicating that the patient is partially trisomic for a region of the short arm of chromosome 7. Partial duplication of the short arm of chromosome 7 is uncommon with little more than 30 cases in the literature. This is the first report of an individual with a 7p duplication who also has AD.

Adult↗

PubMed2002

Association studies of the HOPA dodecamer duplication variant in different subtypes of autism.

The HOPA gene in Xq13 is coding for a protein involved in a nuclear thyroid receptor complex. Previous studies suggested association of the dodecamer duplication in the OPA-repeat region in exon 43 (according to the genomic database sequence) with autism, mental retardation, and schizophrenia/hypothyroidism. We determined the frequency of this 12 bp duplication variant in a sample of 155 patients divided in different subtypes of autism, 278 parents of those patients, and 157 control individuals. The allele frequency of the duplication variant was not significantly different between autistic patients, their parents, and the control group. Therefore, it is unlikely that this 12 bp duplication variant of the HOPA gene has major relevance to the susceptibility to different subtypes of autism at least in this German patient sample. In addition, we identified a third variant with a 15 bp deletion in the OPA-repeat region, recently described by another group, in one autistic patient. This third allele was also present in the patient's nonautistic mother and sister, who are heterozygous for this variant, but could not be detected in any other individual genotyped in this study. Expression analysis revealed transcription of all three allelic variants in lymphoblastoid cell lines. Furthermore, we identified a new splice variant that utilizes an additional 9 bp of the 3' intron subsequent to exon 39. Both alternative transcripts are coexpressed in all fetal and adult tissues examined.

Alternative Splicing↗

PubMed2003

Routine cytogenetic and FISH studies for 17p11/15q11 duplications and subtelomeric rearrangement studies in children with autism spectrum disorders.

To assess the frequency of cytogenetic abnormalities in children with autism spectrum disorders (ASDs), routine G-banded cytogenetic analyses and FISH studies to rule out 15q11.2 and 17p11.2 duplications were performed on 49 children with ASDs. Blood samples were further studied using a complete set of subtelomeric FISH probes. Routine chromosome study showed that one child had a small duplication of chromosome 5: 46,XY,dup(5)(p?14.2p?15.1). Another child had an interstitial duplication of the Prader-Willi and Angelman syndrome critical region of chromosome 15, detected by FISH analysis. The detection of these two cases underscores the importance of obtaining routine chromosome and 15q11-q13 FISH analyses in children with ASDs. No instance of 17p11.2 duplication was observed. Subtelomeric analysis did not reveal abnormalities in any of the subjects.

Adolescent↗

PubMed2003

Genetic and clinical characterization of patients with an interstitial duplication 15q11-q13, emphasizing behavioral phenotype and response to treatment.

The clinical significance of an interstitial duplication of (15)(q11-q13) remains unclear and controversial. The reported phenotypes vary widely and appear to be influenced by the parent of origin of the duplication. Aside from cases of dup(15) reported with autism, the behavioral phenotype of individuals with dup(15) has not been described. We present three families, two with intrachromosomal duplication (15)(q11-q13) ascertained because of developmental delay in a relative. Two families show clear evidence of multigenerational maternal inheritance. The individuals discussed in this paper have minor anomalies and developmental delays. In addition, we describe a behavioral phenotype which often includes attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder. Responses to medications used to manage these behaviors are also described, including a positive response to methylphenidate and a poor response to fluoxetine. The duplication in each presenting individual, and available family members, was investigated utilizing cytogenetic and molecular techniques including high resolution cytogenetics, fluorescence in situ hybridization (FISH), DNA methylation studies, and quantitative fluorescence PCR. High resolution cytogenetic techniques alone missed some cases, demonstrating the need to confirm results with other methods.

Child↗

PubMed2003

Inv dup del(4)(:p14 --> p16.3::p16.3 --> qter) with manifestations of partial duplication 4p and Wolf-Hirschhorn syndrome.

An 8-year-old girl with a combination of clinical manifestations of partial duplication 4p and the Wolf-Hirschhorn syndrome was studied. Chromosomal G-banding and FISH analyses showed a 33.2-Mb segment of inverted duplication at 4p14-p16.3 and a 2.8-Mb segment of deletion at 4p16.3-pter (including the Wolf-Hirschhorn syndrome critical region). The chromosomes of the parents were normal. Her karyotype was thus 46,XX, inv dup del(4)(:p14 --> p16.3::p16.3 --> qter) de novo. The inverted duplication deletion was assumed to have arisen through chromatid breakage at 4p16.3, U-type reunion at the breakpoints to produce a dicentric intermediate, breakage of the dicentric to result in a monocentric, and telomere capture/healing of the broken end. Olfactory receptor gene clusters at 4p16.3 were ruled out as an intermediary of the duplication deletion process.

Abnormalities, Multiple↗

PubMed2005

Array comparative genomic hybridization analysis of a familial duplication of chromosome 13q: a recognizable syndrome.

We report on a family with six persons in three generations who have mild mental retardation, behavioral problems, seizures, hearing loss, strabismus, dental anomalies, hypermobility, juvenile hallux valgus, and mild dysmorphic features. Classical cytogenetic analysis showed a partial duplication of chromosome 13q, array comparative genomic hybridization showed the duplication to span approximately 21 Mb, ranging from chromosome band 13q21.31 to 13q31.1. The relatively mild presentation of this large duplication may be explained by the relative paucity of genes in the chromosome region involved. Genotype-phenotype correlations in patients with similar partial 13q duplications are inconsistent. Emerging cytogenetic techniques will allow more reliable genotype-phenotype correlations.

Abnormalities, Multiple↗

PubMed2006

Array-based genomic delineation of a familial duplication 11q14.1-q22.1 associated with recurrent depression.

Detection of abnormal karyotypes with associated clinical manifestations is an important tool for the identification of genes that confer susceptibility to genetic disorders. We present a family with a duplication 11q14.1-q22.1 resulting from an unbalanced familial insertion, associated with a mild dysmorphic phenotype and mood disorders, mainly major depression. This relatively large duplication of a segment from chromosome 11 is associated with a surprisingly little physical phenotypic effect in this family. The finding of mood disorders in adult members of the family who carry the insertion supports the view that the duplication may be important for the identification of contributing gene(s) to mood disorders. Major depression is considered to be a complex trait with multiple genetic alterations interacting with environmental factors. Array-based comparative genome hybridization (array CGH) analysis with a 1 Mb genomic array, defined the duplication region that extended over 16 Mb from 11q14.1 to 11q22.1. Brain-expressed genes that map within this 16 Mb region, are considered worthy of further investigation as gene(s) contributing to the etiology of major depression.

Adolescent↗