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PubMed1998

[Further genetic study of tandem duplication formation in the region of the deo operon in the process of Escherichia coli K-12 conjugational recombination].

The formation of heterozygous duplications in the region of the deo operon was studied in conjugational matings (male) HfrH deoC deoD thr::Tn9 thyA x HfrH deoA deoB::Tn5 thyA. When recombinants that inherited the donor marker thr::Tn9 (Cml r) were selected on a medium containing thymine and chloramphenicol, but not threonine, more than 80% of the offspring were heterozygous tandem duplications extending to the region of the deo operon. In matings with a thymidine-dependent HfrH deoA deoB::Tn5 thyA strain as a recipient, when recombinants were selected on a medium containing thymine, i.e., under conditions of thymine starvation of merozygotes, the recombinogenic effect was observed. However, this effect did not change the frequency of duplication formation. The integration of genetic markers via homologous recombination into the chromosomal regions adjacent to duplications occurred at a lower frequency. An analysis of the formation of haploid segregants by duplications showed that, in most cases of duplication formation, the proximal segment of the donor chromosome is integrated into the distal position, i.e., after the homologous segment of the recipient chromosome.

Conjugation, Genetic↗
PubMed2005

Do disparate mechanisms of duplication add similar genes to the genome?

Gene duplication is the fundamental source of new genes. Biases in duplication have profound implications for the dynamics of gene content during evolution. In this article, we compare genes arising from whole gene duplication (WGD), smaller scale duplication (SSD) and singletons in Saccharomyces cerevisiae. Our results demonstrate that genes duplicated by WGD and SSD are similarly biased with respect to codon bias and evolutionary rate, although differing significantly in their functional constituency.

Codon↗
PubMed2001

Genome duplication, divergent resolution and speciation.

What are the evolutionary consequences of gene duplication? One answer is speciation, according to a model initially called Reciprocal Silencing and recently expanded and renamed Divergent Resolution. This model shows how the loss of different copies of a duplicated gene in allopatric populations (divergent resolution) can promote speciation by genetically isolating these populations should they become reunited. Genome duplication events produce thousands of duplicated genes. Therefore, lineages with a history of genome duplication might have been especially prone to speciation via divergent resolution.

Animals↗
PubMed2006

Global trends of whole-genome duplications revealed by the ciliate Paramecium tetraurelia.

The duplication of entire genomes has long been recognized as having great potential for evolutionary novelties, but the mechanisms underlying their resolution through gene loss are poorly understood. Here we show that in the unicellular eukaryote Paramecium tetraurelia, a ciliate, most of the nearly 40,000 genes arose through at least three successive whole-genome duplications. Phylogenetic analysis indicates that the most recent duplication coincides with an explosion of speciation events that gave rise to the P. aurelia complex of 15 sibling species. We observed that gene loss occurs over a long timescale, not as an initial massive event. Genes from the same metabolic pathway or protein complex have common patterns of gene loss, and highly expressed genes are over-retained after all duplications. The conclusion of this analysis is that many genes are maintained after whole-genome duplication not because of functional innovation but because of gene dosage constraints.

Animals↗
PubMed2003

Structural divergence of chromosomal segments that arose from successive duplication events in the Arabidopsis genome.

Using the extensive segmental duplications of the Arabidopsis thaliana genome, a comparative study of homoeologous segments occurring in chromosomes 1, 2, 4 and 5 was performed. The gene-by-gene BLASTP approach was applied to identify duplicated genes in homoeologues. The levels of synonymous substitutions between duplicated coding sequences suggest that these regions were formed by at least two rounds of duplications. Moreover, remnants of even more ancient duplication events were recognised by a whole-genome study. We describe a subchromosomal organisation of genes, including the tandemly repeated genes, and the distribution of transposable elements (TEs). In certain cases, evidence of the possible mechanisms of structural rearrangements within the segments could be found. We provide a probable scenario of the rearrangements that took place during the evolution of the homoeologous regions. Furthermore, on the basis of the comparative analysis of the chromosomal segments in the Columbia and Landsberg erecta accessions, an additional structural variation in the A.thaliana genome is described. Analysis of the segments, spanning 7 Mb or 5.6% of the genome, permitted us to propose a model of evolution at the subchromosomal level.

Arabidopsis↗
PubMed2004

Simulating evolution by gene duplication of protein features that require multiple amino acid residues.

Gene duplication is thought to be a major source of evolutionary innovation because it allows one copy of a gene to mutate and explore genetic space while the other copy continues to fulfill the original function. Models of the process often implicitly assume that a single mutation to the duplicated gene can confer a new selectable property. Yet some protein features, such as disulfide bonds or ligand binding sites, require the participation of two or more amino acid residues, which could require several mutations. Here we model the evolution of such protein features by what we consider to be the conceptually simplest route-point mutation in duplicated genes. We show that for very large population sizes N, where at steady state in the absence of selection the population would be expected to contain one or more duplicated alleles coding for the feature, the time to fixation in the population hovers near the inverse of the point mutation rate, and varies sluggishly with the lambda(th) root of 1/N, where lambda is the number of nucleotide positions that must be mutated to produce the feature. At smaller population sizes, the time to fixation varies linearly with 1/N and exceeds the inverse of the point mutation rate. We conclude that, in general, to be fixed in 10(8) generations, the production of novel protein features that require the participation of two or more amino acid residues simply by multiple point mutations in duplicated genes would entail population sizes of no less than 10(9).

Amino Acids↗
PubMed2002

Recent segmental duplications in the human genome.

Primate-specific segmental duplications are considered important in human disease and evolution. The inability to distinguish between allelic and duplication sequence overlap has hampered their characterization as well as assembly and annotation of our genome. We developed a method whereby each public sequence is analyzed at the clone level for overrepresentation within a whole-genome shotgun sequence. This test has the ability to detect duplications larger than 15 kilobases irrespective of copy number, location, or high sequence similarity. We mapped 169 large regions flanked by highly similar duplications. Twenty-four of these hot spots of genomic instability have been associated with genetic disease. Our analysis indicates a highly nonrandom chromosomal and genic distribution of recent segmental duplications, with a likely role in expanding protein diversity.

Alleles↗
PubMed2002

Organisation of the pericentromeric region of chromosome 15: at least four partial gene copies are amplified in patients with a proximal duplication of 15q.

Clinical cytogenetic laboratories frequently identify an apparent duplication of proximal 15q that does not involve probes within the PWS/AS critical region and is not associated with any consistent phenotype. Previous mapping data placed several pseudogenes, NF1, IgH D/V, and GABRA5 in the pericentromeric region of proximal 15q. Recent studies have shown that these pseudogene sequences have increased copy numbers in subjects with apparent duplications of proximal 15q. To determine the extent of variation in a control population, we analysed NF1 and IgH D pseudogene copy number in interphase nuclei from 20 cytogenetically normal subjects by FISH. Both loci are polymorphic in controls, ranging from 1-4 signals for NF1 and 1-3 signals for IgH D. Eight subjects with apparent duplications, examined by the same method, showed significantly increased NF1 copy number (5-10 signals). IgH D copy number was also increased in 6/8 of these patients (4-9 signals). We identified a fourth pseudogene, BCL8A, which maps to the pericentromeric region and is coamplified along with the NF1 sequences. Interphase FISH ordering experiments show that IgH D lies closest to the centromere, while BCL8A is the most distal locus in this pseudogene array; the total size of the amplicon is estimated at approximately 1 Mb. The duplicated chromosome was inherited from either sex parent, indicating no parent of origin effect, and no consistent phenotype was present. FISH analysis with one or more of these probes is therefore useful in discriminating polymorphic amplification of proximal pseudogene sequences from clinically significant duplications of 15q.

Adult↗
PubMed1999

Syndromal obesity due to paternal duplication 6(q24.3-q27).

The likelihood of a paternally expressing imprinted gene in chromosome region 6(q23-24) has been highlighted by cases of transient neonatal diabetes mellitus (TNDM) in which paternal uniparental disomy (UPD) for chromosome 6 or paternal duplication 6(q23-qter) was detected. We present the case of a 38-year-old man with moderate to severe intellectual delay, short stature, small hands and feet, eye abnormality, small mouth, and obesity (without hyperphagia) beginning in mid-childhood. The perinatal and neonatal histories were normal. The patient had a duplication within 6q. Fluorescence in situ hybrisation studies were performed with single and dual hybridisations using a chromosome 6 library probe, short and long arm subregional probes, 6q23-24, 6q25.3-6qter locus-specific probes, and a 6q telomere probe. The hybridisation results defined an inverted duplication of 6q24.3 to 6q27. DNA studies with microsatellite markers from 6p and 6q showed regular biparental inheritance of chromosome 6 and confirmed that the duplication was paternal in origin. Our patient appears to be the first one known to have paternal duplication of chromosome area 6(q24-q27) who did not have TNDM as an infant. He has remained nondiabetic, although obesity, without hyperphagia, has been a constant problem since its onset in mid-childhood.

Adult↗
PubMed1999

Autosomal XX sex reversal caused by duplication of SOX9.

SOX9 is one of the genes that play critical roles in male sexual differentiation. Mutations of SOX9 leading to haploinsufficiency can cause campomelic dysplasia and XY sex reversal. We report here evidence supporting that SOX9 duplication can cause XX sex reversal. A newborn infant was referred for genetic evaluation because of abnormal male external genitalia. The infant had severe penile/scrotal hypospadias. Gonads were palpable. Cytogenetic analysis demonstrated a de novo mosaic 46,XX,dup(17)(q23.1q24.3)/46, XX karyotype. Fluorescent in situ hybridization (FISH) with a BAC clone containing the SOX9 gene demonstrated that the SOX9 gene is duplicated on the rearranged chromosome 17. The presence of SRY was ruled out by FISH with a probe containing the SRY gene and polymerase chain reaction with SRY-specific primers. Microsatellite analysis with 13 markers on 17q23-24 determined that the duplication is maternal in origin and defined the boundary of the duplication to be approximately 12 centimorgans (cM) proximal and 4 cM distal to the SOX9 gene. Thus, SOX9 duplication is the most likely cause for the sex reversal in this case because it plays an important role in male sex determination and differentiation. This study suggests that extra dose of SOX9 is sufficient to initiate testis differentiation in the absence of SRY. Other SRY-negative XX sex-reversed individuals deserve thorough investigation of SOX9 gene.

Chromosomes, Human, Pair 17↗
PubMed2002

Duplication of 8p23.2: a benign cytogenetic variant?

We describe a duplication of the 8p23.2 band in seven individuals from four families. The duplication was recognizable as an enlarged 8p23.2 band on G-banded chromosomes at the 550 band level. It was transmitted from a parent to offspring in three of the four families in which both parents were karyotyped. Each proband in the four families had the enlarged band and showed various phenotypic abnormalities, but the abnormalities were inconsistent. Chromosomal and interphase fluorescence in situ hybridization (FISH) analysis of the enlarged band region defined a 2.5-Mb duplicated segment common to all seven individuals studied. Interphase FISH analysis of peripheral blood lymphocytes from 50 unrelated normal individuals showed the duplication in three individuals. In view of these findings, it is most likely that the 8p23.2 duplication we described is a normal variant.

Child↗
PubMed2002

Partial duplication 4q and deletion 1p36 in monozygotic twins with discordant phenotypes.

We report on monozygotic (MZ) twins with a de novo chromosome abnormality consisting of a partial duplication of chromosome 4 (q25-qter) and deletion of chromosome 1p36. These infants had dysmorphic facial features and other clinical manifestations similar to those described with the previously delineated duplication 4q and deletion 1p36 phenotypes and two other reported cases of combined partial duplication 4q and deletion 1p36. However, the twins were discordant for a number of congenital anomalies. The discordant phenotypes described in these genetically identical infants demonstrate that nongenetic factors may play a significant role in the phenotypic differences in patients with recognized chromosome duplication and deletion syndromes, which are usually attributed to the individual genotypic differences in the duplicated and/or deleted chromosome segments.

Abnormalities, Multiple↗
PubMed2001

Direct duplication of 8p21.3-->p23.1: a cytogenetic anomaly associated with developmental delay without consistent clinical features.

We report six cases in two families and a sporadic case with a direct duplication of region 8p21.3-->23.1. In one family, the duplication started in the mother and was transmitted to one son and one daughter. In the second family, the father was mosaic for the anomaly that was transmitted to his two daughters. The cytogenetic anomaly was initially described as an 8p+ with banding analysis and then delineated with fluorescence in situ hybridization (FISH) using whole-chromosome 8 painting, 8p specific painting, and 8p or 8p/8q subtelomeric probes. Deletion was not detected in the subtelomeric region of the abnormal chromosome 8 examined in one family and in the sporadic case. The phenotypic picture varies from normal to moderate mental retardation in the affected individuals. No consistent minor anomalies or congenital defects were observed among these cases. After comparing the chromosome region involved in our cases with those in others having direct or inverted duplications of 8p, it is thought that the segment 8p21.1-->21.3 might be the critical region for an 8p duplication syndrome. The parental origin of the duplication does not seem to impact its clinical significance.

Chromosome Aberrations↗
PubMed2004

A girl with duplication 17p10-p12 associated with a dicentric chromosome.

We report a 7 1/2-year-old girl with an approximately 9.5 Mb duplication of proximal 17p. Her clinical features include moderately severe developmental delay, absence of speech, talipes, congenital dislocation of the hips, premature adrenarche, dysmorphic facial features, deep palmar creases, and signs and symptoms of peripheral neuropathy consistent with Charcot-Marie-Tooth disease type 1A (CMT1A). Chromosome analysis revealed a partially duplicated 17p with two centromeres on the derivative chromosome. Fluorescence in situ hybridization (FISH) analysis demonstrated the tandemly duplicated segment spans 17p10-p12, including the entire Smith-Magenis syndrome (SMS) critical region and a portion of the CMT1A critical region. One breakpoint mapped within the centromere and the second breakpoint mapped within the CMT1A critical region, distal to the PMP22 gene. Microsatellite polymorphism studies showed that the duplicated chromosome is of maternal origin. We compare the clinical features of our patient to those of individuals with partial trisomy of proximal 17p to further delineate the genotype-phenotype correlation associated with segmental duplication of this chromosomal region.

Centromere↗
PubMed2005

Duplication of Xq26.2-q27.1, including SOX3, in a mother and daughter with short stature and dyslalia.

Duplications of the distal long arm of the X chromosome are rare and carrier females are usually phenotypically normal. We report on a 14-year-old short statured (height and weight <3rd centile) girl with dup(X)(q26.2q27.1) inherited from a short mother. The proband has minor dysmorphic features, lordosis, lack of menarche, late signs of puberty, low prepuberal levels of gonadotrophins and steroids, but borderline low IGF-1 and normal IGF-Bp3 serum levels. Both the proposita and her mother have severe speech problems with stuttering and dyslalia. The 44-year-old mother with a strikingly aged face and a prominent nose, had menarche at 15 years. Both maternal sisters and the grandmother of the proposita are also short. Karyotyping revealed an additional band at Xq26 in all metaphases from the proband, her mother, and two maternal aunts. Molecular cytogenetic investigations revealed an Xq26.2-q27.1 direct duplication of approximately 7.5 Mb that encompasses or disrupts the SOX3 gene, which maps at the distal border of the duplicated segment. A similar chromosomal duplication was reported recently in five families and in each was associated with an abnormal phenotype in males with short stature [Hol et al., 2000; Solomon et al., 2002, 2004]. Using an androgen-receptor (HUMARA) gene methylation assay and FISH, we show that despite preferential inactivation of the dup(Xq) chromosome a significant proportion of lymphocytes in both mother and daughter carry an active duplicated X chromosome. Our findings further suggest that a dosage effect of SOX3 may to be responsible for a speech disorder in addition to short stature secondary to hypopituitarism.

Abnormalities, Multiple↗
PubMed2006

Pure direct duplication (12)(q24.1-->q24.2) in a child with Marcus Gunn phenomenon and multiple congenital anomalies.

Partial trisomy of the region 12q24.1-->q24.2 is rare and usually associated with other rearrangements. We report on the clinical and cytogenetic findings in a girl with a pure de novo direct duplication dup(12)(q24.1-->q24.2). She had developmental and growth retardation, facial dysmorphism with upslanting palpebral fissures, wide downturned mouth, short neck, and Marcus Gunn phenomenon. She also had single transverse creases, hypoplasia of the corpus callosum, and cardiac malformations consisting of a bicuspid aortic valve, multiple ventricular septal defects, and kinking of the aorta. The size of the duplication was characterized by molecular cytogenetics and comparative genomic hybridization (CGH) to be 11.5 Mb in size and extended from the BAC probe RP11-256L11 loci (108.2 Mb) +/- 1 Mb to the BAC probe RP11-665J20 loci (119.7 Mb) +/- 1 Mb. No such pure 12q24 duplication was detected out of the 23 patients reported in the literature with duplications in 12q region. Comparison with these reported 12q trisomies suggests the duplication dup(12)(q24.1-->q24.2) is associated with a recognizable phenotype consisting of characteristic facial dysmorphism, growth retardation, and cardiac malformation.

Abnormalities, Multiple↗
PubMed2007

Prevalence of duplications and deletions of the 22q11 DiGeorge syndrome region in a population-based sample of infants with cleft palate.

The prevalence of duplications and deletions of the 22q11.2 (DiGeorge syndrome) region was studied among babies born in Norway with open cleft palate without cleft lip (cleft palate only, CPO). During a 5-year period (1996-2001), there were 245 live births with CPO that were referred for surgery. DNA was available from 174 cases with overt cleft palate. DNA copy number was analyzed with the multiplex ligation-dependent probe amplification (MLPA) technique, and an unambiguous result was obtained in 169 (97%) of the samples. We found no 22q11.2 duplications, and one known, and two previously undiagnosed cases with 22q11.2 deletions. All three del22q11-syndrome cases also had heart malformations, which represent one-third of the 10 babies with heart malformations in our study population. The prevalence of del22q11-syndrome among babies with cleft palate with or without additional malformations was 1 of 57 (1.8%). Because the prevalence of CPO in the 35 22q11.2 duplication cases published was 20%, we also investigated if dup22q11-testing was warranted in this group. However, no 22q11.2 duplications were found, indicating that the duplication cases ascertained so far might not be representative of the dup22q11-group as a whole. We conclude that neither del22q11 nor dup22q11 testing is warranted in babies with overt cleft palate as the only finding.

Chromosome Deletion↗
PubMed2001

Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement.

A submicroscopic duplication that contains the entire proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease, an X-linked central nervous system dysmyelinating disorder. Previous studies have demonstrated that carrier females for the duplication are usually asymptomatic. We describe 2 unrelated female patients who present with mild Pelizaeus-Merzbacher disease or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results have improved dramatically over a 10-year period. The other patient, who presented with spastic diplegia and was initially diagnosed with cerebral palsy, has also shown clinical improvement. Interphase fluorescent in situ hybridization identified a proteolipid protein gene duplication in both patients. Interphase fluorescent in situ hybridization analyses of the family members indicated that the duplication in both patients occurred as de novo events. Neither skewing of X inactivation in the peripheral lymphocytes nor proteolipid protein gene coding alterations were identified in either patient. These findings indicate that, occasionally, females with a proteolipid protein gene duplication can manifest an early-onset neurological phenotype. We hypothesize that the remarkable clinical improvement is a result of myelin compensation by oligodendrocytes expressing one copy of proteolipid protein gene secondary to selection for a favorable X inactivation pattern. These findings indicate plasticity of oligodendrocytes in the formation of central nervous system myelin and suggest a potential role for stem cell transplantation therapies.

Brain↗