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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.
To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤ 5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.
Copyright © 2013 Elsevier Inc. All rights reserved.
We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.
DNA methylation mediates imprinted gene expression by passing an epigenomic state across generations and differentially marking specific regulatory regions on maternal and paternal alleles. Imprinting has been tied to the evolution of the placenta in mammals and defects of imprinting have been associated with human diseases. Although recent advances in genome sequencing have revolutionized the study of DNA methylation, existing methylome data remain largely untapped in the study of imprinting. We present a statistical model to describe allele-specific methylation (ASM) in data from high-throughput short-read bisulfite sequencing. Simulation results indicate technical specifications of existing methylome data, such as read length and coverage, are sufficient for full-genome ASM profiling based on our model. We used our model to analyze methylomes for a diverse set of human cell types, including cultured and uncultured differentiated cells, embryonic stem cells and induced pluripotent stem cells. Regions of ASM identified most consistently across methylomes are tightly connected with known imprinted genes and precisely delineate the boundaries of several known imprinting control regions. Predicted regions of ASM common to multiple cell types frequently mark noncoding RNA promoters and represent promising starting points for targeted validation. More generally, our model provides the analytical complement to cutting-edge experimental technologies for surveying ASM in specific cell types and across species.
We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.
Copyright © 2011 Elsevier Inc. All rights reserved.
Using a genome-wide gene expression data set generated from Affymetrix GeneChip Human Exon 1.0ST array, we comprehensively surveyed the role of 322 X chromosome gene expression traits on cellular sensitivity to cisplatin and carboplatin. We identified 31 and 17 X chromosome genes whose expression levels are significantly correlated (after multiple testing correction) with sensitivity to carboplatin and cisplatin, respectively, in the combined HapMap CEU (Utah residents with ancestry from northern and western Europe) and YRI (Yoruba in Ibahan, Nigeria) populations (false discovery rate, FDR < 0.05). Of those, 14 overlap for both cisplatin and carboplatin. Using an independent gene expression quantification method, the Illumina Sentrix Human-6 Expression BeadChip, measured on the same HapMap cell lines, we found that 4 and 2 of these genes are significantly associated with carboplatin and cisplatin sensitivity, respectively, in both analyses. Two genes, CTPS2 and DLG3, were identified by both genome-wide gene expression analyses as correlated with cellular sensitivity to both platinating agents. The expression of DLG3 gene was also found to correlate with cellular sensitivity to platinating agents in NCI-60 cancer cell lines. In addition, we evaluated whether the expression of X chromosome genes contributed to the observed differences in sensitivity to the platinums between CEU and YRI-derived cell lines. Of the 34 distinct genes significantly correlated with either carboplatin or cisplatin sensitivity, 14 are differentially expressed (defined as P < 0.05) between CEU and YRI. Thus, sex chromosome genes play a role in cellular sensitivity to platinating agents and differences in the expression level of these genes are an important source of variation that should be included in comprehensive pharmacogenomic studies.
BACKGROUND - Some familial amyloidotic polyneuropathy (FAP) patients show the post-transplant progression of the clinical symptoms. Although the presence of recipient-derived cells in transplanted livers has been reported, no studies investigating the functional significance of this post-transplant chimerism in transplanted FAP patients were performed. The aims of this study were to evaluate amyloidogenic transthyretin (ATTR) production of recipient-derived cells and the relationship between the protein from recipient-derived cells and the progression of FAP symptoms after liver transplantation (LT).
METHODS - Seven FAP ATTR Val30Met patients who underwent LT were included in this study. In one male patient with sex-mismatched donor, fluorescence in situ hybridization (FISH) method was performed on a liver biopsy sample using DNA probes for visualizing X and Y chromosomes to detect the recipient-derived cells. In three patients including the FISH-analysed patient, ATTR mRNA expression in transplanted livers was evaluated by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method and realtime quantitative reverse transcription-PCR. In five of the seven patients, ATTR in serum protein expression was measured by mass spectrometry.
RESULTS - One FAP patient has 3.1% recipient-derived cells in the transplanted liver. The ATTR mRNA was not expressed in any of the three transplanted livers. The ATTR was not detected in any sera of the sampled patients.
CONCLUSION - Although the FAP patient had recipient-derived cells in the transplanted liver, the recipient-derived cells did not contribute to the production of ATTR in our specific case. The effect of recipient-derived cells on the post-transplant progression of FAP symptoms may be negligible.
A novel COL4A5 mutation causes rapid progression to end-stage renal disease in males, despite the absence of clinical and biopsy findings associated with Alport syndrome. Affected males have proteinuria, variable hematuria, and an early progression to end-stage renal disease. Renal biopsy findings include global and segmental glomerulosclerosis, mesangial hypercellularity and basement membrane immune complex deposition. Exon sequencing of the COL4A5 locus identified a thymine to guanine transversion at nucleotide 665, resulting in a phenylalanine to cysteine missense mutation at codon 222. The phenylalanine at position 222 is absolutely conserved among vertebrates. This mutation was confirmed in 4 affected males and 4 female obligate carriers, but was absent in 6 asymptomatic male family members and 198 unrelated individuals. Immunostaining for α5(IV) collagen in renal biopsies from affected males was normal. This mutation, in a non-collagenous interruption associated with severe renal disease, provides evidence for the importance of this structural motif and suggests the range of phenotypes associated with COL4A5 mutations is more diverse than previously realized. Hence, COL4A5 mutation analysis should be considered when glomerulonephritis presents in an X-linked inheritance pattern, even with a presentation distinct from Alport syndrome.
The genetic variants underlying the strong heritable component of prostate cancer remain largely unknown. Genome-wide association studies of prostate cancer have yielded several variants that have significantly replicated across studies, predominantly in cases unselected for family history of prostate cancer. Additional candidate gene variants have also been proposed, many evaluated within familial prostate cancer study populations. Such variants hold great potential value for risk stratification, particularly for early-onset or aggressive prostate cancer, given the comorbidities associated with current therapies. Here, we investigate a Caucasian study population of 523 independent familial prostate cancer cases and 523 age-matched controls without a personal or family history of prostate cancer. We replicate identified associations at genome-wide association study loci 8q24, 11q13, and 2p15 (P = 2.9 x 10(-4) to P = 4.7 x 10(-5)), showing study population power. We also find evidence to support reported associations at candidate genes RNASEL, EZH2, and NKX3-1 (P = 0.031 to P = 0.0085). We further explore a set of candidate genes related to RNASEL and to its role in retroviral restriction, identifying nominal associations at XPR1 and RBM9. The effects at 8q24 seem more pronounced for those diagnosed at an early age, whereas at 2p15 and RNASEL the effects were more pronounced at a later age. However, these trends did not reach statistical significance. The effects at 2p15 were statistically significantly more pronounced for those diagnosed with aggressive disease.
We conducted an association study to identify risk variants for familial prostate cancer within the HPCX locus at Xq27 among Americans of Northern European descent. We investigated a total of 507 familial prostate cancer probands and 507 age-matched controls without a personal or family history of prostate cancer. The study population was subdivided into a set of training subjects to explore genetic variation of the locus potentially impacting risk of prostate cancer, and an independent set of test subjects to confirm the association and to assign significance, addressing multiple comparisons. We identified a 22.9 kb haplotype nominally associated with prostate cancer among training subjects (292 cases, 292 controls; chi(2) = 5.08, P = 0.020), that was confirmed among test subjects (215 cases, 215 controls; chi(2) = 3.73, P = 0.040). The haplotype predisposed to prostate cancer with an odds ratio of 3.41 (95% CI 1.04-11.17, P = 0.034) among test subjects. The haplotype extending from rs5907859 to rs1493189 is concordant with a prior study of the region within the Finnish founder population, and warrants further independent investigation.