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Landscape of X chromosome inactivation across human tissues.
Tukiainen T, Villani AC, Yen A, Rivas MA, Marshall JL, Satija R, Aguirre M, Gauthier L, Fleharty M, Kirby A, Cummings BB, Castel SE, Karczewski KJ, Aguet F, Byrnes A, GTEx Consortium, Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, Enhancing GTEx (eGTEx) groups, NIH Common Fund, NIH/NCI, NIH/NHGRI, NIH/NIMH, NIH/NIDA, Biospecimen Collection Source Site—NDRI, Biospecimen Collection Source Site—RPCI, Biospecimen Core Resource—VARI, Brain Bank Repository—University of Miami Brain Endowment Bank, Leidos Biomedical—Project Management, ELSI Study, Genome Browser Data Integration &Visualization—EBI, Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz, Lappalainen T, Regev A, Ardlie KG, Hacohen N, MacArthur DG
(2017) Nature 550: 244-248
MeSH Terms: Chromosomes, Human, X, Female, Genes, X-Linked, Genome, Human, Genomics, Humans, Male, Organ Specificity, Phenotype, Sequence Analysis, RNA, Single-Cell Analysis, Transcriptome, X Chromosome Inactivation
Show Abstract · Added October 27, 2017
X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals. The extent to which XCI is shared between cells and tissues remains poorly characterized, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression and phenotypic traits. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.
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13 MeSH Terms
Congenital nevi versus metastatic melanoma in a newborn to a mother with malignant melanoma - diagnosis supported by sex chromosome analysis and Imaging Mass Spectrometry.
Alomari AK, Glusac EJ, Choi J, Hui P, Seeley EH, Caprioli RM, Watsky KL, Urban J, Lazova R
(2015) J Cutan Pathol 42: 757-64
MeSH Terms: Adult, Female, Follow-Up Studies, Humans, Infant, Newborn, Male, Mass Spectrometry, Melanoma, Neoplasm Metastasis, Nevus, Pigmented, Placenta, Pregnancy, Pregnancy Complications, Neoplastic, Sentinel Lymph Node Biopsy, Sex Chromosomes, Skin Neoplasms
Show Abstract · Added October 15, 2015
A 37-year-old pregnant woman presented with a 2-cm irregular reddish nodule on her left upper arm during pregnancy. A biopsy from the lesion showed a 2.2-mm thick malignant melanoma with intravascular invasion, 25 mitosis/mm(2) and no ulceration. Following induction of labor, the patient underwent re-excision with sentinel lymph node biopsy. This showed no residual melanoma and no lymph node metastasis. The newborn boy had multiple pigmented lesions on the trunk, some of which were large and irregular. Two were biopsied and histologic examination showed dense dermal proliferation of medium sized melanocytes with multiple mitotic figures and no maturation with their descent into the dermis, raising suspicion of transplacental metastases. Examination of the placenta failed to show metastatic lesions. Multiplex polymerase chain reaction (PCR)-based genotyping, including testing for amelogenin locus for sex chromosome determination, demonstrated the presence of Y chromosome material in the melanocytes of the newborn's lesions excluding maternal origin. A diagnosis of congenital nevi was rendered. Subsequently, Imaging Mass Spectrometric analysis of the mother's lesion showed proteomic signature expression indicative of malignant melanoma, whereas the two lesions in the newborn showed changes indicative of nevi. This case demonstrates the utility of genotyping and Mass Spectrometry analysis in this challenging clinical scenario.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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16 MeSH Terms
Return of individual research results from genome-wide association studies: experience of the Electronic Medical Records and Genomics (eMERGE) Network.
Fullerton SM, Wolf WA, Brothers KB, Clayton EW, Crawford DC, Denny JC, Greenland P, Koenig BA, Leppig KA, Lindor NM, McCarty CA, McGuire AL, McPeek Hinz ER, Mirel DB, Ramos EM, Ritchie MD, Smith ME, Waudby CJ, Burke W, Jarvik GP
(2012) Genet Med 14: 424-31
MeSH Terms: Biomedical Research, Factor V, Genetics, Medical, Genome-Wide Association Study, Homozygote, Humans, Incidental Findings, Klinefelter Syndrome, Medical Informatics, Research Subjects, Sex Chromosome Aberrations, Truth Disclosure, Turner Syndrome
Show Abstract · Added December 10, 2013
PURPOSE - Return of individual genetic results to research participants, including participants in archives and biorepositories, is receiving increased attention. However, few groups have deliberated on specific results or weighed deliberations against relevant local contextual factors.
METHODS - The Electronic Medical Records and Genomics (eMERGE) Network, which includes five biorepositories conducting genome-wide association studies, convened a return of results oversight committee to identify potentially returnable results. Network-wide deliberations were then brought to local constituencies for final decision making.
RESULTS - Defining results that should be considered for return required input from clinicians with relevant expertise and much deliberation. The return of results oversight committee identified two sex chromosomal anomalies, Klinefelter syndrome and Turner syndrome, as well as homozygosity for factor V Leiden, as findings that could warrant reporting. Views about returning findings of HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of electronic medical records suggested that most participants with detected abnormalities were unaware of these findings. Local considerations relevant to return varied and, to date, four sites have elected not to return findings (return was not possible at one site).
CONCLUSION - The eMERGE experience reveals the complexity of return of results decision making and provides a potential deliberative model for adoption in other collaborative contexts.
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13 MeSH Terms
A spatial and temporal map of C. elegans gene expression.
Spencer WC, Zeller G, Watson JD, Henz SR, Watkins KL, McWhirter RD, Petersen S, Sreedharan VT, Widmer C, Jo J, Reinke V, Petrella L, Strome S, Von Stetina SE, Katz M, Shaham S, Rätsch G, Miller DM
(2011) Genome Res 21: 325-41
MeSH Terms: Animals, Caenorhabditis elegans, Computational Biology, Databases, Genetic, Gene Expression Profiling, Gene Expression Regulation, Developmental, Male, Meiosis, Molecular Sequence Data, Oogenesis, Open Reading Frames, Transcription, Genetic, Untranslated Regions, X Chromosome Inactivation
Show Abstract · Added February 21, 2014
The C. elegans genome has been completely sequenced, and the developmental anatomy of this model organism is described at single-cell resolution. Here we utilize strategies that exploit this precisely defined architecture to link gene expression to cell type. We obtained RNAs from specific cells and from each developmental stage using tissue-specific promoters to mark cells for isolation by FACS or for mRNA extraction by the mRNA-tagging method. We then generated gene expression profiles of more than 30 different cells and developmental stages using tiling arrays. Machine-learning-based analysis detected transcripts corresponding to established gene models and revealed novel transcriptionally active regions (TARs) in noncoding domains that comprise at least 10% of the total C. elegans genome. Our results show that about 75% of transcripts with detectable expression are differentially expressed among developmental stages and across cell types. Examination of known tissue- and cell-specific transcripts validates these data sets and suggests that newly identified TARs may exercise cell-specific functions. Additionally, we used self-organizing maps to define groups of coregulated transcripts and applied regulatory element analysis to identify known transcription factor- and miRNA-binding sites, as well as novel motifs that likely function to control subsets of these genes. By using cell-specific, whole-genome profiling strategies, we have detected a large number of novel transcripts and produced high-resolution gene expression maps that provide a basis for establishing the roles of individual genes in cellular differentiation.
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14 MeSH Terms
Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension.
Aldred MA, Comhair SA, Varella-Garcia M, Asosingh K, Xu W, Noon GP, Thistlethwaite PA, Tuder RM, Erzurum SC, Geraci MW, Coldren CD
(2010) Am J Respir Crit Care Med 182: 1153-60
MeSH Terms: Adult, Airway Remodeling, Bone Morphogenetic Protein Receptors, Type II, Cell Proliferation, Child, Chromosome Aberrations, Chromosome Deletion, DNA Copy Number Variations, Endothelial Cells, Female, Gene Rearrangement, Genome-Wide Association Study, Genomic Instability, Germ-Line Mutation, Humans, Hypertension, Pulmonary, In Situ Hybridization, Fluorescence, Lung, Microarray Analysis, Middle Aged, Myocytes, Smooth Muscle, Polymorphism, Single Nucleotide, Pulmonary Artery, Pulmonary Disease, Chronic Obstructive, X Chromosome Inactivation
Show Abstract · Added November 17, 2011
RATIONALE - Vascular remodeling in pulmonary arterial hypertension (PAH) involves proliferation and migration of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Previous studies have indicated that the endothelial cell proliferation is quasineoplastic, with evidence of monoclonality and instability of short DNA microsatellite sequences.
OBJECTIVES - To assess whether there is larger-scale genomic instability.
METHODS - We performed genome-wide microarray copy number analysis on pulmonary artery endothelial cells and smooth muscle cells isolated from the lungs of patients with PAH.
MEASUREMENTS AND MAIN RESULTS - Mosaic chromosomal abnormalities were detected in PAEC cultures from five of nine PAH lungs but not in normal (n = 8) or disease control subjects (n = 5). Fluorescent in situ hybridization analysis confirmed the presence of these abnormalities in vivo in two of three cases. One patient harbored a germline mutation of BMPR2, the primary genetic cause of PAH, and somatic loss of chromosome-13, which constitutes a second hit in the same pathway by deleting Smad-8. In two female subjects with mosaic loss of the X chromosome, methylation analysis showed that the active X was deleted. One subject also showed completely skewed X-inactivation in the nondeleted cells, suggesting the pulmonary artery endothelial cell population was clonal before the acquisition of the chromosome abnormality.
CONCLUSIONS - Our data indicate a high frequency of genetically abnormal subclones within PAH lung vessels and provide the first definitive evidence of a second genetic hit in a patient with a germline BMPR2 mutation. We propose that these chromosome abnormalities may confer a growth advantage and thus contribute to the progression of PAH.
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25 MeSH Terms
Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females.
Marsh E, Fulp C, Gomez E, Nasrallah I, Minarcik J, Sudi J, Christian SL, Mancini G, Labosky P, Dobyns W, Brooks-Kayal A, Golden JA
(2009) Brain 132: 1563-76
MeSH Terms: Adult, Animals, Brain, Child, Child, Preschool, Disease Models, Animal, Electroencephalography, Epilepsy, Female, Genotype, Heterozygote, Homeodomain Proteins, Humans, Infant, Intellectual Disability, Interneurons, Male, Mice, Mice, Knockout, Phenotype, Receptors, Androgen, Spasms, Infantile, Transcription Factors, X Chromosome Inactivation
Show Abstract · Added July 20, 2010
Mutations in the X-linked aristaless-related homeobox gene (ARX) have been linked to structural brain anomalies as well as multiple neurocognitive deficits. The generation of Arx-deficient mice revealed several morphological anomalies, resembling those observed in patients and an interneuron migration defect but perinatal lethality precluded analyses of later phenotypes. Interestingly, many of the neurological phenotypes observed in patients with various ARX mutations can be attributed, in part, to interneuron dysfunction. To directly test this possibility, mice carrying a floxed Arx allele were generated and crossed to Dlx5/6(CRE-IRES-GFP)(Dlx5/6(CIG)) mice, conditionally deleting Arx from ganglionic eminence derived neurons including cortical interneurons. We now report that Arx(-/y);Dlx5/6(CIG) (male) mice exhibit a variety of seizure types beginning in early-life, including seizures that behaviourally and electroencephalographically resembles infantile spasms, and show evolution through development. Thus, this represents a new genetic model of a malignant form of paediatric epilepsy, with some characteristics resembling infantile spasms, caused by mutations in a known infantile spasms gene. Unexpectedly, approximately half of the female mice carrying a single mutant Arx allele (Arx(-/+);Dlx5/6(CIG)) also developed seizures. We also found that a subset of human female carriers have seizures and neurocognitive deficits. In summary, we have identified a previously unrecognized patient population with neurological deficits attributed to ARX mutations that are recapitulated in our mouse model. Furthermore, we show that perturbation of interneuron subpopulations is an important mechanism underling the pathogenesis of developmental epilepsy in both hemizygous males and carrier females. Given the frequency of ARX mutations in patients with infantile spasms and related disorders, our data unveil a new model for further understanding the pathogenesis of these disorders.
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24 MeSH Terms
Conservation of small RNA pathways in platypus.
Murchison EP, Kheradpour P, Sachidanandam R, Smith C, Hodges E, Xuan Z, Kellis M, Grützner F, Stark A, Hannon GJ
(2008) Genome Res 18: 995-1004
MeSH Terms: Animals, Base Sequence, Evolution, Molecular, Male, MicroRNAs, Molecular Sequence Data, Phylogeny, Platypus, RNA Interference, RNA, Small Interfering, X Chromosome
Show Abstract · Added February 15, 2016
Small RNA pathways play evolutionarily conserved roles in gene regulation and defense from parasitic nucleic acids. The character and expression patterns of small RNAs show conservation throughout animal lineages, but specific animal clades also show variations on these recurring themes, including species-specific small RNAs. The monotremes, with only platypus and four species of echidna as extant members, represent the basal branch of the mammalian lineage. Here, we examine the small RNA pathways of monotremes by deep sequencing of six platypus and echidna tissues. We find that highly conserved microRNA species display their signature tissue-specific expression patterns. In addition, we find a large rapidly evolving cluster of microRNAs on platypus chromosome X1, which is unique to monotremes. Platypus and echidna testes contain a robust Piwi-interacting (piRNA) system, which appears to be participating in ongoing transposon defense.
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11 MeSH Terms
Clonality studies in sacral chordoma.
Klingler L, Trammell R, Allan DG, Butler MG, Schwartz HS
(2006) Cancer Genet Cytogenet 171: 68-71
MeSH Terms: Adult, Aged, Cell Proliferation, Chordoma, Chromosomes, Human, X, Clone Cells, DNA Methylation, DNA, Neoplasm, Female, Humans, Middle Aged, Polymerase Chain Reaction, Receptors, Androgen, Sacrum, X Chromosome Inactivation
Show Abstract · Added March 5, 2014
Chordomas are rare, slow-growing, primary malignant skeletal neoplasms. Chromosome analysis, telomere reduction and telomere activity, DNA microsatellite, and loss of heterozygosity studies have been performed on chordomas; however, the clonality status (monoclonal versus polyclonal proliferation) is unknown. The primary purpose of this study was to determine whether sacral chordoma is monoclonal or polyclonal in origin with the use of a polymorphic X-linked gene (AR; alias HUMARA) and X-chromosome inactivation studies. DNA was harvested from tumor and corresponding normal tissue from eight women (37-71 years) with chordoma. Clonality was determined using an X chromosome inactivation protocol and a polymorphic human androgen receptor gene (AR) located on the X chromosome. The procedure required a methylation-specific polymerase chain reaction (PCR) and determination of the ratio of active to inactive X chromosomes. Results were informative for seven of the eight women, with two separate X-linked alleles seen for the AR gene in the normal tissue. Expression of AR gene alleles from each of the two X chromosomes was present in the chordoma tumor, indicating a polyclonal proliferation in all seven women. Most solid tumors and skeletal neoplasms are polyclonal in nature. Our study indicates that chordoma is polyclonal in its pattern of proliferation.
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15 MeSH Terms
The X chromosome in quantitative trait locus mapping.
Broman KW, Sen S, Owens SE, Manichaikul A, Southard-Smith EM, Churchill GA
(2006) Genetics 174: 2151-8
MeSH Terms: Animals, Chromosome Mapping, Female, Genetic Linkage, Genome, Lod Score, Male, Mice, Pedigree, Quantitative Trait Loci, Quantitative Trait, Heritable, X Chromosome
Show Abstract · Added May 19, 2014
The X chromosome requires special treatment in the mapping of quantitative trait loci (QTL). However, most QTL mapping methods, and most computer programs for QTL mapping, have focused exclusively on autosomal loci. We describe a method for appropriate treatment of the X chromosome for QTL mapping in experimental crosses. We address the important issue of formulating the null hypothesis of no linkage appropriately. If the X chromosome is treated like an autosome, a sex difference in the phenotype can lead to spurious linkage on the X chromosome. Further, the number of degrees of freedom for the linkage test may be different for the X chromosome than for autosomes, and so an X chromosome-specific significance threshold is required. To address this issue, we propose a general procedure to obtain chromosome-specific significance thresholds that controls the genomewide false positive rate at the desired level. We apply our methods to data on gut length in a large intercross of mice carrying the Sox10Dom mutation, a model of Hirschsprung disease. We identified QTL contributing to variation in gut length on chromosomes 5 and 18. We found suggestive evidence of linkage to the X chromosome, which would be viewed as strong evidence of linkage if the X chromosome was treated as an autosome. Our methods have been implemented in the package R/qtl.
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12 MeSH Terms
Loss of alpha3/alpha4(IV) collagen from the glomerular basement membrane induces a strain-dependent isoform switch to alpha5alpha6(IV) collagen associated with longer renal survival in Col4a3-/- Alport mice.
Kang JS, Wang XP, Miner JH, Morello R, Sado Y, Abrahamson DR, Borza DB
(2006) J Am Soc Nephrol 17: 1962-9
MeSH Terms: Animals, Collagen Type IV, Disease Models, Animal, Glomerular Basement Membrane, Kidney Glomerulus, Mice, Mice, Transgenic, Nephritis, Hereditary, Protein Isoforms, Survival, X Chromosome
Show Abstract · Added August 21, 2013
Mutations in COL4A3/4/5 genes that affect the normal assembly of the alpha3/4/5(IV) collagen network in the glomerular basement membrane (GBM) cause Alport syndrome. Patients progress to renal failure at variable rates that are determined by the underlying mutation and putative modifier genes. Col4a3(-/-) mice, a model for autosomal recessive Alport syndrome, progress to renal failure significantly slower on the C57BL/6 than on the 129X1/Sv background. Reported here is a novel strain-specific alternative collagen IV isoform switch that is associated with the differential renal survival in Col4a3(-/-) Alport mice. The downregulation or the absence of alpha3/4(IV) collagen chains in the GBM of Lmx1b(-/-) and Col4a3(-/-) mice was found to induce ectopic deposition of alpha5/6(IV) collagen. The GBM deposition of alpha5/6(IV) collagen was abundant in C57BL/6 Col4a3(-/-) mice but almost undetectable in 129X1/Sv Col4a3(-/-) mice. This strain difference was due to overall low expression of alpha6(IV) chain and alpha5/6(IV) protomers in the tissues of 129X1/SvJ mice, a natural Col4a6 knockdown. In (129 x B6)F1 Col4a3(-/-) mice, the amount of alpha5/6(IV) collagen in the GBM was inherited in a mother-to-son manner, suggesting that it is controlled by one or more X-linked loci, possibly Col4a6 itself. Importantly, high levels of ectopic alpha5/6(IV) collagen in the GBM were associated with approximately 46% longer renal survival. These findings suggest that alpha5/6(IV) collagen, the biologic role of which has been hitherto unknown, may partially substitute for alpha3/4/5(IV) collagen. Therapeutically induced GBM deposition of alpha5/6(IV) collagen may provide a novel strategy for delaying renal failure in patients with autosomal recessive Alport syndrome.
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11 MeSH Terms