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1.
Nat Commun ; 10(1): 3009, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285442

RESUMO

Quantitative genetics theory predicts that X-chromosome dosage compensation (DC) will have a detectable effect on the amount of genetic and therefore phenotypic trait variances at associated loci in males and females. Here, we systematically examine the role of DC in humans in 20 complex traits in a sample of more than 450,000 individuals from the UK Biobank and 1600 gene expression traits from a sample of 2000 individuals as well as across-tissue gene expression from the GTEx resource. We find approximately twice as much X-linked genetic variation across the UK Biobank traits in males (mean h2SNP = 0.63%) compared to females (mean h2SNP = 0.30%), confirming the predicted DC effect. Our DC estimates for complex traits and gene expression are consistent with a small proportion of genes escaping X-inactivation in a trait- and tissue-dependent manner. Finally, we highlight examples of biologically relevant X-linked heterogeneity between the sexes that bias DC estimates if unaccounted for.


Assuntos
Genes Ligados ao Cromossomo X/genética , Loci Gênicos/genética , Variação Genética/genética , Herança Multifatorial/genética , Inativação do Cromossomo X/genética , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Modelos Genéticos , Fenótipo , Fatores Sexuais
2.
J Dermatol ; 46(8): 731-733, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31241787

RESUMO

Hypohidrotic ectodermal dysplasia (HED) is a rare hereditary disorder that affects tissues derived from the ectoderm including hair, teeth and sweat glands. EDA is the major causative gene of HED. This study recruited a Chinese family with HED, including a male proband and his mother with a fetus. The proband had typical clinical features of HED and the mother had identical but milder features. Interestingly, some phenotypes of the mother appeared asymmetrically between the right and left side of the body that were not reported in previous studies. Targeted sequencing was performed in the proband and a novel frame-shift mutation (NM_001399.4: c.381_382delinsG, p.Q128Rfs*9) in EDA was found. Sanger sequencing validated the mutation and identified the same mutation in the mother. Our study expands the clinical and genetic spectrum of EDA-related disorders and reports new asymmetrical phenotypes in a female.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas/genética , Genes Ligados ao Cromossomo X/genética , Fenótipo , Adulto , Criança , Análise Mutacional de DNA , Displasia Ectodérmica Anidrótica Tipo 1/diagnóstico , Feminino , Mutação da Fase de Leitura , Aconselhamento Genético , Hemizigoto , Heterozigoto , Humanos , Masculino
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(6): 561-565, 2019 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-31055805

RESUMO

OBJECTIVE: To summarize clinical manifestations, inheritance pattern and mutations of NR0B1 gene in 7 children with X-linked adrenal dysplasia congenita (XL-AHC). METHODS: Clinical data of the 7 children was collected. Next-generation sequencing was carried out to detect potential mutations in the coding regions of adrenal gland-related genes. Suspected mutations were verified with Sanger sequencing. RESULTS: In all of the children, the initial symptom was adrenocortical insufficiency. Five cases had neonatal onset, while the remaining two developed it at the age of 2. Three cases (42.9%) had a short stature and 1 showed growth retardation (14.3%). Of the 7 cases, 6 (85.7%) had mutations occurring in exon 1, and 1 (14.3%) had it occurring in exon 2. Four cases (57.1%) were frameshift mutations, 2 cases (28.6%) were nonsense mutations and 1 case (14.3%) was missense mutation. Two mutations were known to be pathogenic, and 5 had not been reported previously. Maternal inheritance was found in 6 cases. Three children had a maternal uncle died of unexplained causes. The mothers of 2 children had a history of spontaneous abortions. One child had a brother died of unexplained reason. CONCLUSION: Male children with primary adrenal insufficiency should be routinely checked for NR0B1 mutations, especially those with a family history. mutations of NR0B1 gene occur mostly in exon 1, with frameshift mutations being the most common type. The development of all patients with XL-AHC should be closely monitored during follow-up.


Assuntos
Insuficiência Adrenal , Criança , Receptor Nuclear Órfão DAX-1 , Análise Mutacional de DNA , Genes Ligados ao Cromossomo X , Humanos , Hipoadrenocorticismo Familiar , Masculino , Mutação
4.
Nat Commun ; 10(1): 2164, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092820

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21. We propose that expression is amplified through modification of promoter and 3'-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner.


Assuntos
Cromossomos Humanos X/genética , Genes Ligados ao Cromossomo X/genética , Interferon Tipo I/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lúpus Eritematoso Sistêmico/genética , Regiões 3' não Traduzidas/genética , Adulto , Fatores Etários , Estudos de Casos e Controles , Feminino , Genes Ligados ao Cromossomo X/imunologia , Predisposição Genética para Doença , Humanos , Interferon Tipo I/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Regiões Promotoras Genéticas/genética , Fatores Sexuais , Receptor 7 Toll-Like/genética
6.
Gynecol Obstet Invest ; 84(4): 412-416, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30965333

RESUMO

INTRODUCTION: X-linked recessive mutations predominantly affect male fetuses with milder or no abnormalities in female siblings. Most reports show only one affected member in the family. We are reporting a family affected with hydrocephalus, stenosis of the aqueduct of Sylvius, dysgenesis of the corpus callosum, and Xp22.33 microduplication. CASE PRESENTATION: Eighteen-year-old patient was evaluated for her 2 pregnancies; the first was a male fetus with severe hydrocephalus and the second a female fetus with mild hydrocephalus. Postnatal MRI evaluation of the male neonate revealed stenosis of the aqueduct of Sylvius, dysgenesis of the corpus callosum, and severe hydrocephalus requiring ventriculoperitoneal shunt. Postnatal MRI evaluation of the female neonate revealed mild hydrocephalus, stenosis of the aqueduct of Sylvius, and mild dysgenesis of the corpus callosum. The female baby did not require surgical intervention. Genetic testing of the mother and the 2 children revealed a 439 Kb duplication of Xp22.33. DISCUSSION: This family demonstrates typical X-linked recessive heritability. X-inactivation is a compensatory mechanism that explains the mild symptoms of the female child and the severe symptoms of the male child. This familial case shows the importance of prenatal testing and genetic counseling and testing, including karyotype and chromosomal microarray.


Assuntos
Agenesia do Corpo Caloso/genética , Duplicação Cromossômica/genética , Hidrocefalia/genética , Aberrações dos Cromossomos Sexuais , Adolescente , Agenesia do Corpo Caloso/patologia , Aqueduto do Mesencéfalo/patologia , Constrição Patológica/genética , Feminino , Genes Recessivos/genética , Genes Ligados ao Cromossomo X/genética , Humanos , Hidrocefalia/patologia , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Mutação , Gravidez
7.
Mol Med Rep ; 19(5): 4419-4424, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942463

RESUMO

Nance­Horan syndrome (NHS) is a rare X­linked disorder with various clinical manifestations. The present study aimed to identify the pathogenic mutation causing NHS in a three­generation Chinese family with 4 individuals presenting primarily with congenital cataracts. The genomic DNA of 5 individuals was collected, and family history and clinical information were recorded. Whole exome sequencing was performed on the proband, and candidate mutations were filtered by a series of screening processes and validated by Sanger sequencing. The identified pathogenic mutation was confirmed by co­segregation analysis. Finally, a novel frameshift mutation (NM_001291867.1: c.302dupA; p.Ala102fs) was identified in the NHS actin remodeling regulator (NHS) gene, which co­segregated with congenital cataracts in this family. Carrier females exhibited similar but milder clinical symptoms compared with the affected male. These clinical symptoms were consistent with the phenotypic features of the NHS­associated disease, NHS. In summary, the present study identified a novel NHS mutation in a Chinese family with atypical NHS; the results broaden the known pathogenic mutation spectrum of NHS and will aid in the genetic counseling of patients with NHS. The data from the present study also suggest that genetic analysis may be required for the diagnosis of this disease.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Catarata/congênito , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas Nucleares/genética , Anormalidades Dentárias/genética , Adulto , Catarata/genética , Catarata/patologia , Pré-Escolar , Feminino , Mutação da Fase de Leitura , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Linhagem , Anormalidades Dentárias/patologia , Sequenciamento Completo do Exoma
8.
Int J Mol Sci ; 20(8)2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-31013990

RESUMO

Methyl CpG binding protein-2 (MeCP2) isoforms (E1 and E2) are important epigenetic regulators in brain cells. Accordingly, MeCP2 loss- or gain-of-function mutation causes neurodevelopmental disorders, including Rett syndrome (RTT), MECP2 duplication syndrome (MDS), and autism spectrum disorders (ASD). Within different types of brain cells, highest MeCP2 levels are detected in neurons and the lowest in astrocytes. However, our current knowledge of Mecp2/MeCP2 regulatory mechanisms remains largely elusive. It appears that there is a sex-dependent effect in X-linked MeCP2-associated disorders, as RTT primarily affects females, whereas MDS is found almost exclusively in males. This suggests that Mecp2 expression levels in brain cells might be sex-dependent. Here, we investigated the sex- and cell type-specific expression of Mecp2 isoforms in male and female primary neurons and astrocytes isolated from the murine forebrain. Previously, we reported that DNA methylation of six Mecp2 regulatory elements correlated with Mecp2 levels in the brain. We now show that in male brain cells, DNA methylation is significantly correlated with the transcript expression of these two isoforms. We show that both Mecp2 isoforms are highly expressed in male neurons compared to male astrocytes, with Mecp2e1 expressed at higher levels than Mecp2e2. Our data indicate that higher DNA methylation at the Mecp2 regulatory element(s) is associated with lower levels of Mecp2 isoforms in male astrocytes compared to male neurons.


Assuntos
Astrócitos/metabolismo , Metilação de DNA , Proteína 2 de Ligação a Metil-CpG/metabolismo , Neurônios/metabolismo , Animais , Astrócitos/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Ilhas de CpG , Modelos Animais de Doenças , Feminino , Genes Ligados ao Cromossomo X , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Neurônios/citologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
9.
EBioMedicine ; 42: 470-480, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30878599

RESUMO

BACKGROUND: The heterotrimeric GTP-binding protein eIF2 forms a ternary complex with initiator methionyl-tRNA and recruits it to the 40S ribosomal subunit for start codon selection and thereby initiates protein synthesis. Mutations in EIF2S3, encoding the eIF2γ subunit, are associated with severe intellectual disability and microcephaly, usually as part of MEHMO syndrome. METHODS: Exome sequencing of the X chromosome was performed on three related males with normal head circumferences and mild learning difficulties, hypopituitarism (GH and TSH deficiencies), and an unusual form of glucose dysregulation. In situ hybridisation on human embryonic tissue, EIF2S3-knockdown studies in a human pancreatic cell line, and yeast assays on the mutated corresponding eIF2γ protein, were performed in this study. FINDINGS: We report a novel hemizygous EIF2S3 variant, p.Pro432Ser, in the three boys (heterozygous in their mothers). EIF2S3 expression was detectable in the developing pituitary gland and pancreatic islets of Langerhans. Cells lacking EIF2S3 had increased caspase activity/cell death. Impaired protein synthesis and relaxed start codon selection stringency was observed in mutated yeast. INTERPRETATION: Our data suggest that the p.Pro432Ser mutation impairs eIF2γ function leading to a relatively mild novel phenotype compared with previous EIF2S3 mutations. Our studies support a critical role for EIF2S3 in human hypothalamo-pituitary development and function, and glucose regulation, expanding the range of phenotypes associated with EIF2S3 mutations beyond classical MEHMO syndrome. Untreated hypoglycaemia in previous cases may have contributed to their more severe neurological impairment and seizures in association with impaired EIF2S3. FUND: GOSH, MRF, BRC, MRC/Wellcome Trust and NIGMS funded this study.


Assuntos
Fator de Iniciação 2 em Eucariotos/genética , Genes Ligados ao Cromossomo X , Glucose/metabolismo , Hipopituitarismo/etiologia , Hipopituitarismo/metabolismo , Fenótipo , Substituição de Aminoácidos , Apoptose , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Linhagem Celular , Pré-Escolar , Fator de Iniciação 2 em Eucariotos/química , Fator de Iniciação 2 em Eucariotos/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Hipopituitarismo/diagnóstico , Hibridização In Situ , Lactente , Imagem por Ressonância Magnética , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único , Biossíntese de Proteínas
10.
BMC Med Genet ; 20(1): 41, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890130

RESUMO

BACKGROUND: Congenital nystagmus (CN) and congenital cataracts are distinct eye diseases and are usually isolated. Cases with CN and congenital cataracts caused by different genes in one family have been rarely reported. CASE PRESENTATION: A 27-year-old man presented with CN and congenital cataracts and he underwent cataract extraction 2 weeks after birth. Three years later, he had posterior chamber intraocular lens implantation. The proband's mother was only afflicted by bilateral lens opacities. Lensectomy was performed in both eyes at age 15. The proband's daughter had bilateral central cataracts and no nystagmus. She had undergone cataract extraction when she was two months old. In this family, 8 affected individuals were affected by bilateral cataracts, and three of them presented with CN. The genetic analysis was performed using a specific Hereditary Ophthalmological Disease Gene Panel on proband and his parents (one of which was a patient). PCR and Sanger sequencing verified the presence of these variants in all members of the family. The novel mutation, c.498-3C > T, in FRMD7 explains why X-Linked recessive inheritance of CN was found in a subset of patients. A heterozygous mutation of the GJA8 gene (c.139G > C), was identified in all patients and thus explains the autosomal dominant pattern of inheritance of congenital cataracts within the family. CONCLUSIONS: This is the first time that FRMD7 and GJA8 gene mutations have been linked to the pathogenesis of a family with both CN and congenital cataracts. The phenomenon of two different genetic patterns coexisting in one family is rare.


Assuntos
Catarata/congênito , Conexinas/genética , Proteínas do Citoesqueleto/genética , Proteínas de Membrana/genética , Nistagmo Congênito/genética , Análise de Sequência de DNA/métodos , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Catarata/genética , China , Comorbidade , Feminino , Genes Ligados ao Cromossomo X , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Adulto Jovem
11.
Science ; 363(6432): 1210-1213, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30872523

RESUMO

We report the reproductive strategy of the nematode Mesorhabditis belari This species produces only 9% males, whose sperm is necessary to fertilize and activate the eggs. However, most of the fertilized eggs develop without using the sperm DNA and produce female individuals. Only in 9% of eggs is the male DNA utilized, producing sons. We found that mixing of parental genomes only gives rise to males because the Y-bearing sperm of males are much more competent than the X-bearing sperm for penetrating the eggs. In this previously unrecognized strategy, asexual females produce few sexual males whose genes never reenter the female pool. Here, production of males is of interest only if sons are more likely to mate with their sisters. Using game theory, we show that in this context, the production of 9% males by M. belari females is an evolutionary stable strategy.


Assuntos
Óvulo/fisiologia , Partenogênese , Rhabditoidea/fisiologia , Razão de Masculinidade , Animais , Evolução Biológica , Feminino , Teoria do Jogo , Genes Ligados ao Cromossomo X/fisiologia , Genes Ligados ao Cromossomo Y/fisiologia , Masculino , Interações Espermatozoide-Óvulo/fisiologia , Espermatozoides/fisiologia
12.
Proc Natl Acad Sci U S A ; 116(13): 6250-6259, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30760597

RESUMO

There is great interest in being able to spread beneficial traits throughout wild populations in ways that are self-sustaining. Here, we describe a chromosomal selfish genetic element, CleaveR [Cleave and Rescue (ClvR)], able to achieve this goal. ClvR comprises two linked chromosomal components. One, germline-expressed Cas9 and guide RNAs (gRNAs)-the Cleaver-cleaves and thereby disrupts endogenous copies of a gene whose product is essential. The other, a recoded version of the essential gene resistant to cleavage and gene conversion with cleaved copies-the Rescue-provides essential gene function. ClvR enhances its transmission, and that of linked genes, by creating conditions in which progeny lacking ClvR die because they have no functional copies of the essential gene. In contrast, those who inherit ClvR survive, resulting in an increase in ClvR frequency. ClvR is predicted to spread to fixation under diverse conditions. To test these predictions, we generated a ClvR element in Drosophila melanogaster ClvR tko is located on chromosome 3 and uses Cas9 and four gRNAs to disrupt melanogaster technical knockout (tko), an X-linked essential gene. Rescue activity is provided by tko from Drosophila virilis ClvR tko results in germline and maternal carryover-dependent inactivation of melanogaster tko (>99% per generation); lethality caused by this loss is rescued by the virilis transgene; ClvR tko activities are robust to genetic diversity in strains from five continents; and uncleavable but functional melanogaster tko alleles were not observed. Finally, ClvR tko spreads to transgene fixation. The simplicity of ClvR suggests it may be useful for altering populations in diverse species.


Assuntos
Drosophila melanogaster/genética , Tecnologia de Impulso Genético/métodos , Genes Essenciais/genética , Sequências Repetitivas de Ácido Nucleico , Alelos , Animais , Comportamento Animal , Proteína 9 Associada à CRISPR/genética , Feminino , Técnicas de Inativação de Genes , Genes Ligados ao Cromossomo X , Genética Populacional , Genótipo , Células Germinativas , Masculino , Modelos Genéticos , Fenótipo , Dinâmica Populacional , RNA Guia/genética , RNA Guia/metabolismo , Transgenes , Cromossomo X
13.
Reprod Domest Anim ; 54(3): 580-584, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30597663

RESUMO

Chromosomal abnormalities are a major cause of infertility and reproductive problems in equids. Nowadays, their detection is rising due to the use of new diagnostic tools based on molecular markers instead of karyotyping. Reports of this kind of genetic aberrations in domestic donkeys (Equus asinus) are extremely scarce, despite their importance in human activities. In the present study, we analysed the implementation of a short-tandem-repeat (STR)-based molecular method initially developed for horses, as a diagnostic tool to detect chromosomal abnormalities in donkeys. The frequency of five X-linked (LEX003, LEX026, TKY38, TKY270 and UCEDQ502) and one Y-linked (ECAYM2) molecular markers and one Y-linked gene (sex-determining region Y, SRY) was characterized in 121 donkeys from two diverse breeds, the Spanish Andalusian and the African Moroccan breeds. The molecular panel showed 100% sensitivity and 99.67% specificity in detecting 10 different chromosomal abnormalities in the species. In conclusion, this methodology is a valid, rapid and low-cost tool for the detection and characterization of chromosomal abnormalities in domestic donkeys.


Assuntos
Equidae/genética , Testes Genéticos/veterinária , Infertilidade/veterinária , Aberrações dos Cromossomos Sexuais , Animais , Cruzamento , Feminino , Genes Ligados ao Cromossomo X , Genes Ligados ao Cromossomo Y , Testes Genéticos/métodos , Infertilidade/diagnóstico , Infertilidade/genética , Cariotipagem , Masculino , Repetições de Microssatélites , Marrocos , Espanha
14.
Mol Biol Evol ; 36(4): 663-678, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649414

RESUMO

MicroRNAs (miRNAs) are important posttranscriptional regulators of gene expression. However, comprehensive expression profiles of miRNAs during mammalian spermatogenesis are lacking. Herein, we sequenced small RNAs in highly purified mouse spermatogenic cells at different stages. We found that a family of X-linked miRNAs named spermatogenesis-related miRNAs (spermiRs) is predominantly expressed in the early meiotic phases and has a conserved testis-specific high expression pattern in different mammals. We identified one spermiR homolog in opossum; this homolog might originate from THER1, a retrotransposon that is active in marsupials but extinct in current placental mammals. SpermiRs have expanded rapidly with mammalian evolution and are diverged into two clades, spermiR-L and spermiR-R, which are likely to have been generated at least in part by tandem duplication mediated by flanking retrotransposable elements. Notably, despite having undergone highly frequent lineage-specific duplication events, the sequences encoding all spermiR family members are strictly located between two protein-coding genes, Slitrk2 and Fmr1. Moreover, spermiR-Ls and spermiR-Rs have evolved different expression patterns during spermatogenesis in different mammals. Intriguingly, the seed sequences of spermiRs, which are critical for the recognition of target genes, are highly divergent within and among mammals, whereas spermiR target genes largely overlap. When miR-741, the most highly expressed spermiR, is knocked out in cultured mouse spermatogonial stem cells (SSCs), another spermiR, miR-465a-5p, is dramatically upregulated and becomes the most abundant miRNA. Notably, miR-741-/- SSCs grow normally, and the genome-wide expression levels of mRNAs remain unchanged. All these observations indicate functional compensation between spermiR family members and strong coevolution between spermiRs and their targets.


Assuntos
Evolução Molecular , Genes Ligados ao Cromossomo X , Mamíferos/genética , MicroRNAs/genética , Espermatozoides/metabolismo , Animais , Sequência de Bases , Proteína do X Frágil de Retardo Mental/genética , Masculino , Mamíferos/metabolismo , Proteínas de Membrana/genética , Camundongos , Família Multigênica , Proteínas do Tecido Nervoso/genética , Testículo/metabolismo
15.
Nat Genet ; 51(2): 285-295, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643252

RESUMO

During X-chromosome inactivation (XCI), one of the two X-inactivation centers (Xics) upregulates the noncoding RNA Xist to initiate chromosomal silencing in cis. How one Xic is chosen to upregulate Xist remains unclear. Models proposed include localization of one Xic at the nuclear envelope or transient homologous Xic pairing followed by asymmetric transcription factor distribution at Xist's antisense Xite/Tsix locus. Here, we use a TetO/TetR system that can inducibly relocate one or both Xics to the nuclear lamina in differentiating mouse embryonic stem cells. We find that neither nuclear lamina localization nor reduction of Xic homologous pairing influences monoallelic Xist upregulation or choice-making. We also show that transient pairing is associated with biallelic expression, not only at Xist/Tsix but also at other X-linked loci that can escape XCI. Finally, we show that Xic pairing occurs in wavelike patterns, coinciding with genome dynamics and the onset of global regulatory programs during early differentiation.


Assuntos
Núcleo Celular/genética , Inativação do Cromossomo X/genética , Cromossomo X/genética , Animais , Diferenciação Celular/genética , Linhagem Celular , Células-Tronco Embrionárias/fisiologia , Feminino , Regulação da Expressão Gênica/genética , Genes Ligados ao Cromossomo X/genética , Camundongos , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Regulação para Cima/genética
16.
BMC Bioinformatics ; 20(1): 11, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30616589

RESUMO

BACKGROUND: Skewed X chromosome inactivation (XCI), which is a non-random process, is frequently observed in both healthy and affected females. Furthermore, skewed XCI has been reported to be related to many X-linked diseases. However, no statistical method is available in the literature to measure the degree of the skewness of XCI for case-control design. Therefore, it is necessary to develop methods for such a task. RESULTS: In this article, we first proposed a statistical measure for the degree of XCI skewing by using a case-control design, which is a ratio of two logistic regression coefficients after a simple reparameterization. Based on the point estimate of the ratio, we further developed three types of confidence intervals (the likelihood ratio, Fieller's and delta methods) to evaluate its variation. Simulation results demonstrated that the likelihood ratio method and the Fieller's method have more accurate coverage probability and more balanced tail errors than the delta method. We also applied these proposed methods to analyze the Graves' disease data for their practical use and found that rs3827440 probably undergoes a skewed XCI pattern with 68.7% of cells in heterozygous females having the risk allele T active, while the other 31.3% of cells keeping the normal allele C active. CONCLUSIONS: For practical application, we suggest using the Fieller's method in large samples due to the non-iterative computation procedure and using the LR method otherwise for its robustness despite its slightly heavy computational burden.


Assuntos
Cromossomos Humanos X/genética , Genes Ligados ao Cromossomo X , Heterozigoto , Modelos Estatísticos , Inativação do Cromossomo X , Alelos , Estudos de Casos e Controles , Feminino , Humanos
17.
BMC Genomics ; 20(1): 42, 2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642250

RESUMO

BACKGROUND: During the evolution of mammalian sex chromosomes, the degeneration of Y-linked homologs has led to a dosage imbalance between X-linked and autosomal genes. The evolutionary resolution to such dosage imbalance, as hypothesized by Susumu Ohno fifty years ago, should be doubling the expression of X-linked genes. Recent studies have nevertheless shown that the X to autosome expression ratio equals ~ 1 in haploid human parthenogenetic embryonic stem (pES) cells and ~ 0.5 in diploid pES cells, suggesting no doubled expression for X-linked genes and refuting Ohno's hypothesis. RESULTS: Here, by reanalyzing an RNA-seq-based single-cell transcriptome dataset of human embryos, we found that from the 8-cell stage until the time-point just prior to implantation, the expression levels of X-linked genes are not two-fold upregulated in male cells and gradually decrease from two-fold in female cells. Additional analyses of gene expression noise further suggest that the dosage sensitivity of X-linked genes is weaker than that of autosomal genes in differentiated female cells, which contradicts a key assumption in Ohno's hypothesis, that most X-linked genes are dosage sensitive. Moreover, the dosage-sensitive housekeeping genes are preferentially located on autosomes, implying selection against X-linkage for dosage-sensitive genes. CONCLUSIONS: We observed dosage imbalance between X-linked and autosomal genes, as well as relatively high expression noise from X-linked genes. These results collectively suggest that X-linked genes are less dosage sensitive than autosomal genes, putting one primary assumption of Ohno's hypothesis in question.


Assuntos
Compensação de Dosagem (Genética) , Genes Ligados ao Cromossomo X , Animais , Cromossomos Humanos X , Cromossomos Humanos Y , Bases de Dados de Ácidos Nucleicos , Embrião de Mamíferos/citologia , Evolução Molecular , Feminino , Dosagem de Genes , Humanos , Masculino
18.
Acta Biochim Biophys Sin (Shanghai) ; 51(2): 178-184, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576400

RESUMO

Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous eye movement disorder which seriously reduces childhood visual acuity. X-linked inheritance is the most common pattern, and mutations in FERM domain-containing protein 7 (FRMD7) are the major cause. Here, we recruited a four-generation Chinese family with X-linked ICN for the causative mutational screening of FRMD7. A novel missense variant, c.805 A > C, was identified in the proband. The mutation was confirmed in all the affected individuals but was not detected in unaffected family members or 100 unrelated Chinese male controls. The mutation causes a substitution of lysine to glutamine at position 269 (p.Lys269Gln, K269Q). The FRMD7 mutant inhibits the formation and extension of neurites. Moreover, the mutation disrupts FRMD7 interaction with calcium/calmodulin-dependent serine protein kinase and neurite formation. Together, our data expand the mutation spectrum of FRMD7 causing ICN and provide an insight into the pathogenesis of nystagmus.


Assuntos
Proteínas do Citoesqueleto/genética , Genes Ligados ao Cromossomo X/genética , Predisposição Genética para Doença/genética , Proteínas de Membrana/genética , Mutação de Sentido Incorreto , Nistagmo Congênito/genética , Adulto , Idoso , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Saúde da Família , Feminino , Humanos , Masculino , Linhagem , Homologia de Sequência de Aminoácidos
19.
Clin Dysmorphol ; 28(1): 1-6, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30179896

RESUMO

UBE2A-related X-linked intellectual disability is characterized by a distinctive facial phenotype (dense eyebrows and eyelashes, synophrys, hypertelorism, upslanted palpebral fissures, wide mouth, and thin lips), generalized hirsutism, hypoplastic genitalia, short stature, hypotonia, seizures, and severe intellectual disability. Five affected males in two families are described here and compared with the previously reported 17 males in eight families. The new cases are notable for the absence of nail dystrophy, previously considered a defining manifestation, and for the presence of hypogammaglobulinemia and adult-onset ataxia.


Assuntos
Genes Ligados ao Cromossomo X , Deficiência Intelectual/genética , Enzimas de Conjugação de Ubiquitina/genética , Adulto , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Masculino , Mutação/genética , Linhagem , Gravidez , Adulto Jovem
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