Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes
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PROVIDER: EGAS00001004235 | EGA |
REPOSITORIES: EGA
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Project description:We have combined high-quality genome sequencing and RNA-sequencing data within a 17-individual, three generation family. Using these data, we have contrasted cis-acting expression, allele-specific expression and splicing quantitative trait loci (collectively termed eQTLs) within the family to eQTLs discovered within a cell-type and ethnicity-matched population sample. We identified that eQTL that exhibit larger effects in the family compared to the population are enriched for rare regulatory and splicing variants and were more likely to influence essential genes. In addition, we identify several large effect-size eQTLs within the family for genes involved in complex disease. Through analysis of eQTLs in a large family we also report the utility of non-coding genome annotation to predicting the effect of rare non-coding variants. We find that a combination of distance to the transcription start site, evolutionary constraint and epigenetic annotation is considerably more informative for predicting the consequence of rare non-coding variants than for common variants. In summary, through transcriptome analyses within a large family we are able to identify the contribution of rare non-coding variants to expression phenotypes and further demonstrate the predictive potential of diverse non-coding genome annotation for interpretation of the impact of rare non-coding variants. RNA-Sequencing of CEPH/UTAH family 1463
2014-09-01 | E-GEOD-56961 | biostudies-arrayexpress
Project description:We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with de novo variants in the AFF3 degron , a sequence involved in its binding to ubiquitin ligase. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects. In line with this hypothesis, we describe an individual presenting a KINSSHIP-like phenotype carrying a partial duplication of AFF3. Further screening of intellectual disability cohorts revealed nine individuals with heterozygous and three with homozygous loss-of-function (LoF) variants, as well as two probands with compound LoF/missense and six with biallelic missense mutations in AFF3, who displayed a milder syndrome. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA confirming their association with the ablation of aff3. Conversely, the missense isoforms did not complement demonstrating the deleteriousness of the variants identified in affected individuals. To assess the different effect of these variants, we profiled the transcriptome of fibroblasts of affected individuals and isogenic cells harboring DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. While the same pathways are affected, only one-third of the differentially expressed genes are common to both homozygote datasets, indicating that AFF3 LoF and DN mutations largely modulate transcriptomes differently. In particular, the apical junction and DNA repair pathways displayed opposite modulation. Our results and the high pleiotropy shown by this locus in GWASes suggest that even slight changes in the AFF3 function might be deleterious.
2024-02-14 | GSE241621 | GEO
Project description:We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with de novo variants in the AFF3 degron , a sequence involved in its binding to ubiquitin ligase. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects. In line with this hypothesis, we describe an individual presenting a KINSSHIP-like phenotype carrying a partial duplication of AFF3. Further screening of intellectual disability cohorts revealed nine individuals with heterozygous and three with homozygous loss-of-function (LoF) variants, as well as two probands with compound LoF/missense and six with biallelic missense mutations in AFF3, who displayed a milder syndrome. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA confirming their association with the ablation of aff3. Conversely, the missense isoforms did not complement demonstrating the deleteriousness of the variants identified in affected individuals. To assess the different effect of these variants, we profiled the transcriptome of fibroblasts of affected individuals and isogenic cells harboring DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. While the same pathways are affected, only one-third of the differentially expressed genes are common to both homozygote datasets, indicating that AFF3 LoF and DN mutations largely modulate transcriptomes differently. In particular, the apical junction and DNA repair pathways displayed opposite modulation. Our results and the high pleiotropy shown by this locus in GWASes suggest that even slight changes in the AFF3 function might be deleterious.
2024-02-14 | GSE246554 | GEO
Project description:We have combined high-quality genome sequencing and RNA-sequencing data within a 17-individual, three generation family. Using these data, we have contrasted cis-acting expression, allele-specific expression and splicing quantitative trait loci (collectively termed eQTLs) within the family to eQTLs discovered within a cell-type and ethnicity-matched population sample. We identified that eQTL that exhibit larger effects in the family compared to the population are enriched for rare regulatory and splicing variants and were more likely to influence essential genes. In addition, we identify several large effect-size eQTLs within the family for genes involved in complex disease. Through analysis of eQTLs in a large family we also report the utility of non-coding genome annotation to predicting the effect of rare non-coding variants. We find that a combination of distance to the transcription start site, evolutionary constraint and epigenetic annotation is considerably more informative for predicting the consequence of rare non-coding variants than for common variants. In summary, through transcriptome analyses within a large family we are able to identify the contribution of rare non-coding variants to expression phenotypes and further demonstrate the predictive potential of diverse non-coding genome annotation for interpretation of the impact of rare non-coding variants.
2014-09-01 | GSE56961 | GEO
Project description:Exome sequencing studies have identified multiple genes harboring de novo loss-of-function (LoF) variants in individuals with autism spectrum disorders (ASD), including TBR1, a master regulator of cortical development. We performed ChIP-seq for TBR1 during mouse cortical neurogenesis and show that TBR1-bound regions are enriched adjacent to ASD genes. ASD genes were also enriched among genes that are differentially expressed in Tbr1 knockouts, which together with the ChIP-seq data, suggests direct transcriptional regulation. Of the 9 ASD genes examined, 7 were misexpressed in the cortices of Tbr1 knockout mice, including 6 with increased expression in the deep cortical layers. ASD genes with adjacent cortical TBR1 ChIP-seq peaks also showed unusually low levels of LoF mutations in a reference human population and among Icelanders. We then leveraged TBR1 binding to identify an appealing subset of candidate ASD genes. Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development.
2016-06-17 | GSE71384 | GEO
Project description:NAA15 is a component of the NatA complex that acetylates amino terminal (Nt) protein residues and influences protein synthesis. We identified multiple damaging NAA15 variants in congenital heart disease patients, including four loss-of-function (LoF) variants, one missense (R276W) de novo variant and 15 rare inherited missense variants. To understand the effects of these variants on NatA complex activity, we introduced heterozygous LoF, compound heterozygous and missense residues iPS cells using CRISPR/Cas9. Haploinsufficient NAA15 iPS cells differentiate into cardiomyocytes, unlike NAA15-null iPS cells, presumably due to alterations in the amount and composition of the NatA complex. Mass spectrometry (MS)-based N-terminomics analyses showed that nearly 80% of iPS cell proteins displayed partial or complete Nt-acetylation. Between null and haploinsufficient NAA15 cells, 32 and 9 NatA-specific targeted proteins differed in their Nt-acetylation degree, respectively. In addition, the steady-state protein levels of more than 560 proteins were altered in mutant compared to wild type cells. While most NatA-specific Nt-acetylated proteins were fully acetylated, ~19 proteins were partially acetylated. NAA15-haploinsufficiency abrogated Nt-acetylation of 4 of these proteins but did not affect the acetylation of the other 15 proteins. Similar patterns of acetylation loss in few proteins were observed in both NAA15 haploinsufficient and NAA15 R276W iPS cells. These studies define human proteins that appear to require the full NAA15 complex for normal acetylation and imply that deficiencies in one or more of these NAA15 target proteins contribute to normal cardiac development. The current dataset contains all shotgun proteomics data related to this study.
2021-07-07 | PXD017672 | Pride
Project description:NAA15 is a component of the NatA complex that acetylates amino terminal (Nt) protein residues and influences protein synthesis. We identified multiple damaging NAA15 variants in congenital heart disease patients, including four loss-of-function (LoF) variants, one missense (R276W) de novo variant and 15 rare inherited missense variants. To understand the effects of these variants on NatA complex activity, we introduced heterozygous LoF, compound heterozygous and missense residues iPS cells using CRISPR/Cas9. Haploinsufficient NAA15 iPS cells differentiate into cardiomyocytes, unlike NAA15-null iPS cells, presumably due to alterations in the amount and composition of the NatA complex. Mass spectrometry (MS)-based N-terminomics analyses showed that nearly 80% of iPS cell proteins displayed partial or complete Nt-acetylation. Between null and haploinsufficient NAA15 cells, 32 and 9 NatA-specific targeted proteins differed in their Nt-acetylation degree, respectively. In addition, the steady-state protein levels of more than 560 proteins were altered in mutant compared to wild type cells. While most NatA-specific Nt-acetylated proteins were fully acetylated, ~19 proteins were partially acetylated. NAA15-haploinsufficiency abrogated Nt-acetylation of 4 of these proteins but did not affect the acetylation of the other 15 proteins. Similar patterns of acetylation loss in few proteins were observed in both NAA15 haploinsufficient and NAA15 R276W iPS cells. These studies define human proteins that appear to require the full NAA15 complex for normal acetylation and imply that deficiencies in one or more of these NAA15 target proteins contribute to normal cardiac development. The current dataset contains all N-terminomics data related to this study.
2021-08-30 | PXD018013 | Pride
Project description:The transcriptomes of three immortalized ovarian surface epithelial cell lines (iOSE, PMID: 17266044) and primary OSE cells (Innoprot, Derio, Spain) and four immortalized fallopian tube secretory epithelial (iFTE) cell lines (PMID: 21502498, 22936217) were compared. RNA-sequencing was done from rRNA depleted total RNA (Ribo-Zero rRNA Removal Kit) to approx. 20 million 50 bp paired end reads per sample. A discriminative gene expression signature comprised of 211 genes was developed and used to classify isolated and EpCAM enriched primary ovarian cancer cells (PMID: 25991672). Impact of this signature on overall survival was assessed from several publicly available ovarian cancer gene expression data sets. Background: High grade serous ovarian cancer (HGSOC) is characterized by extensive local, i.e. peritoneal, tumor spread, manifested in two different clinical presentations, miliary (many millet sized peritoneal implants) and non-miliary (few large exophytically growing peritoneal nodes), and an overall unfavorable outcome. HGSOC is thought to arise from fallopian tube secretory epithelial cells, via so called serous tubal intraepithelial carcinomas (STICs) but an ovarian origin was never ruled out for at least some cases. Comparative transcriptome analyses of isolated tumor cells from fresh HGSOC tissues and (immortalized) ovarian surface epithelial and fallopian tube secretory epithelial cell lines revealed a close relation between putative origin and tumor spread characteristic, i.e. miliary from tubes and non-miliary from ovaries.
2016-12-15 | E-MTAB-5240 | biostudies-arrayexpress
Project description:Understanding the function of rare non-coding genetic variants represents a significant challenge. Here, we developed MapUTR, a screen to identify rare 3’ UTR variants affecting mRNA abundance post-transcriptionally. Among 17,301 rare variants, an average of 24.5% were functional, with 70% in cancer-related genes, many in critical cancer pathways. This observation motivated a further interrogation of 11,929 cancer somatic mutations, uncovering 3,928 (33%) functional mutations in well-established cancer driver genes, such as CDKN2A. Functional MapUTR variants were enriched in miRNA targets and protein-RNA interaction sites. Based on MapUTR, we define a new metric, untranslated tumor mutation burden (uTMB), reflecting the amount of somatic functional MapUTR variants of a tumor. We showed the potential of uTMB in predicting patient survival. Through prime editing, we characterized three variants in cancer-relevant genes (MFN2, FOSL2, and IRAK1), illustrating their cancer-driving potential. Our study elucidates the function of thousands of non-coding variants, nominates non-coding cancer driver mutations, and demonstrates their potential contributions to cancer.
2024-02-06 | GSE232570 | GEO
Project description:Understanding the function of rare non-coding genetic variants represents a significant challenge. Here, we developed MapUTR, a screen to identify rare 3’ UTR variants affecting mRNA abundance post-transcriptionally. Among 17,301 rare variants, an average of 24.5% were functional, with 70% in cancer-related genes, many in critical cancer pathways. This observation motivated a further interrogation of 11,929 cancer somatic mutations, uncovering 3,928 (33%) functional mutations in well-established cancer driver genes, such as CDKN2A. Functional MapUTR variants were enriched in miRNA targets and protein-RNA interaction sites. Based on MapUTR, we define a new metric, untranslated tumor mutation burden (uTMB), reflecting the amount of somatic functional MapUTR variants of a tumor. We showed the potential of uTMB in predicting patient survival. Through prime editing, we characterized three variants in cancer-relevant genes (MFN2, FOSL2, and IRAK1), illustrating their cancer-driving potential. Our study elucidates the function of thousands of non-coding variants, nominates non-coding cancer driver mutations, and demonstrates their potential contributions to cancer.
2024-02-06 | GSE232572 | GEO