Reciprocal uniparental disomy in yeast.
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ABSTRACT:
SUBMITTER: Andersen SL
PROVIDER: S-EPMC3382553 | biostudies-other | 2012 Jun
REPOSITORIES: biostudies-other
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Project description:Robertsonian translocations (ROBs) are whole arm rearrangements involving the acrocentric chromosomes 13-15 and 21-22 and carriers are at increased risk for aneuploidy and thus uniparental disomy (UPD). Chromosomes 14 and 15 are imprinted with expression of genes dependent on the parental origin of the chromosome. Correction of a trisomic or monosomic conceptus for chromosomes 14 or 15 would lead to one of the established UPD 14mat/pat or UPD 15 (Prader-Willi/Angelman) syndromes (PWS/AS). In view of this, prenatal UPD testing should be considered for balanced carriers of a ROB, fetuses with a familial or de novo balanced ROB that contains chromosome 14 or 15 or with a normal karyotype when a parent is a carrier of a balanced ROB with a 14 or 15. Individuals with congenital anomalies and an abnormal phenotype and carry a ROB involving the two imprinted chromosomes should also be UPD tested.
| S-EPMC4729106 | biostudies-literature
Project description:Uniparental disomy (UPD) is often considered as an event to be characterized exclusively by molecular genetic or epigenetic approaches. This review shows that at least one third of UPD cases emerge in connection with or due to a chromosomal rearrangement. Thus, additional (molecular) cytogenetic characterization of UPD cases is essential. Up to now > 1,100 UPD cases detected in clinical, non-tumor cases are reported in the literature. Recently, these cases were summarized in a regularly updated, freely available online database http://www.med.uni-jena.de/fish/sSMC/00START-UPD.htm. Based of this, here the presently known imprinting syndromes, the chromosomal contribution to UPD phenomenon, and the cytogenetic subgroups of UPD, including cases with normal, abnormal balanced or unbalanced karyotype (like e.g. small supernumerary marker chromosomes and Robertsonian translocations) and segmental UPD are reviewed. Furthermore, chromosome fragmentation as a possible mechanism of trisomic rescue is discussed, which might help to explain the observed 1:9 rate of maternal versus paternal UPD present in cases with original trisomic karyotypes. Overall, as UPD is more but an interesting rarity, the genetic background of each "UPD-patient" needs to be characterized besides by molecular methods, also by molecular cytogenetics in detail.
| S-EPMC2853554 | biostudies-literature
Project description:Hemimegalencephaly (HME) is a heterogeneous cortical malformation characterized by enlargement of one cerebral hemisphere. Somatic variants in mammalian target of rapamycin (mTOR) regulatory genes have been implicated in some HME cases; however, ∼70% have no identified genetic etiology. Here, we screened two HME patients to identify disease-causing somatic variants. DNA from leukocytes, buccal swabs, and surgically resected brain tissue from two HME patients were screened for somatic variants using genome-wide genotyping arrays or sequencing of the protein-coding regions of the genome. Functional studies were performed to evaluate the molecular consequences of candidate disease-causing variants. Both HME patients evaluated were found to have likely disease-causing variants in DNA extracted from brain tissue but not in buccal swab or leukocyte DNA, consistent with a somatic mutational mechanism. In the first case, a previously identified disease-causing somatic single nucleotide in MTOR was identified. In the second case, we detected an overrepresentation of the alleles inherited from the mother on Chromosome 16 in brain tissue DNA only, indicative of somatic uniparental disomy (UPD) of the p-arm of Chromosome 16. Using methylation analyses, an imprinted locus on 16p spanning ZNF597 was identified, which results in increased expression of ZNF597 mRNA and protein in the brain tissue of the second case. Enhanced mTOR signaling was observed in tissue specimens from both patients. We speculate that overexpression of maternally expressed ZNF597 led to aberrant hemispheric development in the patient with somatic UPD of Chromosome 16p possibly through modulation of mTOR signaling.
| S-EPMC5593155 | biostudies-literature
Project description:Analysis of the molecular etiologies of SCID has led to important insights into the control of immune cell development. Most cases of SCID result from either X-linked or autosomal recessive inheritance of mutations in a known causative gene. However, in some cases, the molecular etiology remains unclear. To identify the cause of SCID in a patient known to lack the protein-tyrosine phosphatase CD45, we used SNP arrays and whole-exome sequencing. The patient's mother was heterozygous for an inactivating mutation in CD45 but the paternal alleles exhibited no detectable mutations. The patient exhibited a single CD45 mutation identical to the maternal allele. Patient SNP array analysis revealed no change in copy number but loss of heterozygosity for the entire length of chromosome 1 (Chr1), indicating that disease was caused by uniparental disomy (UPD) with isodisomy of the entire maternal Chr1 bearing the mutant CD45 allele. Nonlymphoid blood cells and other mesoderm- and ectoderm-derived tissues retained UPD of the entire maternal Chr1 in this patient, who had undergone successful bone marrow transplantation. Exome sequencing revealed mutations in seven additional genes bearing nonsynonymous SNPs predicted to have deleterious effects. These findings are unique in representing a reported case of SCID caused by UPD and suggest UPD should be considered in SCID and other recessive disorders, especially when the patient appears homozygous for an abnormal gene found in only one parent. Evaluation for alterations in other genes affected by UPD should also be considered in such cases.
| S-EPMC3387083 | biostudies-literature
Project description:The systematic application of new genome-wide single nucleotide polymorphism arrays has demonstrated that somatically acquired regions of loss of heterozygosity without changes in copy number frequently occur in many types of cancer. Until recently, the ubiquity of this type of chromosomal defect had gone unrecognized because it cannot be detected by routine cytogenetic technologies. Random and recurrent patterns of copy-neutral loss of heterozygosity, also referred to as uniparental disomy, can be found in specific cancer types and probably contribute to clonal outgrowth owing to various mechanisms. In this review we explore the types, topography, genesis, pathophysiological consequences, and clinical implications of uniparental disomy.
| S-EPMC3523887 | biostudies-other
Project description:Uniparental disomy (UPD) gives a description of the inheritance of both homologues of a chromosome pair from the same parent. The consequences of UPD depend on the specific chromosome/segment involved and its parental origin.We report prenatal phenotypes of 2 rare cases of UPD.The prenatal phenotype of case 1 included sonographic markers such as enlarged nuchal translucency (NT), absent nasal bone, short femur and humerus length, and several structural malformations involving Dandy-Walker malformation and congenital heart defects. The prenatal phenotype of Case 2 are sonographic markers, including enlarged NT, thickened nuchal fold, ascites, and polyhydramnios without apparent structural malformations.Conventional G-band karyotype appears normal in case 1, while it shows normal chromosomes with a small supernumerary marker chromosome (sSMC) in case 2. Genetic etiology was left unknown until single-nucleotide polymorphism-based array (SNP-array) was performed, and segmental paternal UPD 22 was identified in case 1 and segmental paternal UPD 14 was found in case 2.The parents of case 1 chose termination of pregnancy. The neonate of case 2 was born prematurely with a bellshaped small thorax and died within a day.UPD cases are rare and the phenotypes are different, which depend on the origin and affected chromosomal part. If a fetus shows multiple anomalies that cannot be attributed to a common aneuploidy or a genetic syndrome, or manifests some features possibly related to an UPD syndrome, such as detection of sSMC, SNP-array should be considered.
| S-EPMC5690727 | biostudies-literature
Project description: Not available
| S-EPMC6592828 | biostudies-literature
Project description:PurposeData on the clinical prevalence and spectrum of uniparental disomy (UPD) remain limited. Trio exome sequencing (ES) presents a comprehensive method for detection of UPD alongside sequence and copy-number variant analysis.MethodsWe analyzed 32,067 ES trios referred for diagnostic testing to create a profile of UPD events and their disease associations. ES single-nucleotide polymorphism (SNP) and copy-number data were used to identify both whole-chromosome and segmental UPD and to categorize whole-chromosome results as isodisomy, heterodisomy, or mixed.ResultsNinety-nine whole-chromosome and 13 segmental UPD events were identified. Of these, 29 were associated with an imprinting disorder, and 16 were associated with a positive test result through homozygous sequence variants. Isodisomy was more commonly observed in large chromosomes along with a higher rate of homozygous pathogenic variants, while heterodisomy was more frequent in chromosomes associated with imprinting or trisomy mosaicism (14, 15, 16, 20, 22).ConclusionWhole-chromosome UPD was observed in 0.31% of cases, resulting in a diagnostic finding in 0.14%. Only three UPD-positive cases had a diagnostic finding unrelated to the UPD. Thirteen UPD events were identified in cases with prior normal SNP chromosomal microarray results, demonstrating the additional diagnostic value of UPD detection by trio ES.
| S-EPMC8187148 | biostudies-literature
Project description:BackgroundUniparental disomy (UPD) is well-known to be closely intermingled with imprinting disorders. Besides, UPD can lead to a disease by 'activation' of a recessive gene mutation or due to incomplete (cryptic) trisomic rescue. Corresponding to all common theories how UPD forms, it takes place as a consequence of a "chromosomic problem", like an aneuploidy or a chromosomal rearrangement. Nonetheless, UPD is rarely considered as a cytogenetic, but most often as a molecular genetic problem.ResultsHere a review on the ~ 4900 published UPD-cases is provided, and even though being biased as discussed in the paper, the following insights have been given from that analysis: (1) the rate of maternal to paternal UPD is 2~3 to 1; (2) at most only ~ 0.03% of the available UPD cases are grasped scientifically, yet; (3) frequencies of single whole-chromosome UPDs are non-random, with UPD(16) and UPD(15) being most frequent in clinically healthy and diseased people, respectively; (4) there is a direct correlation of UPD frequency and known frequent first trimester trisomies, except for chromosomes 1, 5, 11 and 18 (which can be explained); (5) heterodisomy is under- and UPD-mosaicism is over-represented in recent reports; and (6) cytogenetics is not considered enough when a UPD is identified.ConclusionsAs UPD is diagnosed using molecular genetic approaches, and thus by specialists considering chromosomes at best as a whim of nature, most UPD reports lack the chromosomal aspect. Here it is affirmed and substantiated by corresponding data that UPD is a chromosomic disorder in the first place and cytogenetic analyses is indicated in each diagnosed UPD-case.
| S-EPMC8851757 | biostudies-literature
Project description:Uniparental disomy (UPD), in which an individual contains a pair of homologous chromosomes originating from only one parent, is a frequent phenomenon that is linked to congenital disorders and various cancers. UPD is thought to result mostly from pre- or post-zygotic chromosome missegregation. However, the factors that drive UPD remain unknown. Here we use the fission yeast Schizosaccharomyces pombe as a model to investigate UPD, and show that defects in the RNA interference (RNAi) machinery or in the YTH domain-containing RNA elimination factor Mmi1 cause high levels of UPD in vegetative diploid cells. This phenomenon is not due to defects in heterochromatin assembly at centromeres. Notably, in cells lacking RNAi components or Mmi1, UPD is associated with the untimely expression of gametogenic genes. Deletion of the upregulated gene encoding the meiotic cohesin Rec8 or the cyclin Crs1 suppresses UPD in both RNAi and mmi1 mutants. Moreover, overexpression of Rec8 is sufficient to trigger UPD in wild-type cells. Rec8 expressed in vegetative cells localizes to chromosomal arms and to the centromere core, where it is required for localization of the cohesin subunit Psc3. The centromeric localization of Rec8 and Psc3 promotes UPD by uniquely affecting chromosome segregation, causing a reductional segregation of one homologue. Together, these findings establish the untimely vegetative expression of gametogenic genes as a causative factor of UPD, and provide a solid foundation for understanding this phenomenon, which is linked to diverse human diseases.
| S-EPMC5567995 | biostudies-literature