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Journal of Immunology (Baltimore, Md. :... Feb 2018The MHC region encodes HLA genes and is the most complex region in the human genome. The extensively polymorphic nature of the HLA hinders accurate localization and...
The MHC region encodes HLA genes and is the most complex region in the human genome. The extensively polymorphic nature of the HLA hinders accurate localization and functional assessment of disease risk loci within this region. Using targeted capture sequencing and constructing individualized genomes for transcriptome alignment, we identified 908 novel transcripts within the human MHC region. These include 593 novel isoforms of known genes, 137 antisense strand RNAs, 119 novel long intergenic noncoding RNAs, and 5 transcripts of 3 novel putative protein-coding human endogenous retrovirus genes. We revealed allele-dependent expression imbalance involving 88% of all heterozygous transcribed single nucleotide polymorphisms throughout the MHC transcriptome. Among these variants, the genetic variant associated with Behçet's disease in the / region, which tags , is within novel long intergenic noncoding RNA transcripts that are exclusively expressed from the haplotype with the protective but not the disease risk allele. Further, the transcriptome within the MHC region can be defined by 14 distinct coexpression clusters, with evidence of coregulation by unique transcription factors in at least 9 of these clusters. Our data suggest a very complex regulatory map of the human MHC, and can help uncover functional consequences of disease risk loci in this region.
Topics: Allelic Imbalance; Humans; Major Histocompatibility Complex
PubMed: 29311362
DOI: 10.4049/jimmunol.1701061 -
Genome Research Aug 2000Most human cancers are characterized by genomic instability, the accumulation of multiple genetic alterations and allelic imbalance throughout the genome. Loss of... (Comparative Study)
Comparative Study
Most human cancers are characterized by genomic instability, the accumulation of multiple genetic alterations and allelic imbalance throughout the genome. Loss of heterozygosity (LOH) is a common form of allelic imbalance and the detection of LOH has been used to identify genomic regions that harbor tumor suppressor genes and to characterize tumor stages and progression. Here we describe the use of high-density oligonucleotide arrays for genome-wide scans for LOH and allelic imbalance in human tumors. The arrays contain redundant sets of probes for 600 genetic loci that are distributed across all human chromosomes. The arrays were used to detect allelic imbalance in two types of human tumors, and a subset of the results was confirmed using conventional gel-based methods. We also tested the ability to study heterogeneous cell populations and found that allelic imbalance can be detected in the presence of a substantial background of normal cells. The detection of LOH and other chromosomal changes using large numbers of single nucleotide polymorphism (SNP) markers should enable identification of patterns of allelic imbalance with potential prognostic and diagnostic utility.
Topics: Adenocarcinoma; Alleles; Child; DNA Mutational Analysis; Esophageal Neoplasms; Gene Amplification; Humans; Loss of Heterozygosity; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Prognosis; Reproducibility of Results
PubMed: 10958631
DOI: 10.1101/gr.10.8.1126 -
Cancer Discovery Apr 2012DNA repair competency is one determinant of sensitivity to certain chemotherapy drugs, such as cisplatin. Cancer cells with intact DNA repair can avoid the accumulation...
UNLABELLED
DNA repair competency is one determinant of sensitivity to certain chemotherapy drugs, such as cisplatin. Cancer cells with intact DNA repair can avoid the accumulation of genome damage during growth and also can repair platinum-induced DNA damage. We sought genomic signatures indicative of defective DNA repair in cell lines and tumors and correlated these signatures to platinum sensitivity. The number of subchromosomal regions with allelic imbalance extending to the telomere (N(tAI)) predicted cisplatin sensitivity in vitro and pathologic response to preoperative cisplatin treatment in patients with triple-negative breast cancer (TNBC). In serous ovarian cancer treated with platinum-based chemotherapy, higher levels of N(tAI) forecast a better initial response. We found an inverse relationship between BRCA1 expression and N(tAI) in sporadic TNBC and serous ovarian cancers without BRCA1 or BRCA2 mutation. Thus, accumulation of telomeric allelic imbalance is a marker of platinum sensitivity and suggests impaired DNA repair.
SIGNIFICANCE
Mutations in BRCA genes cause defects in DNA repair that predict sensitivity to DNA damaging agents, including platinum; however, some patients without BRCA mutations also benefit from these agents. NtAI, a genomic measure of unfaithfully repaired DNA, may identify cancer patients likely to benefit from treatments targeting defective DNA repair.
Topics: Allelic Imbalance; Antineoplastic Agents; Cell Line, Tumor; Chromosome Aberrations; Cisplatin; DNA Damage; DNA Repair; Drug Resistance, Neoplasm; Female; Genes, BRCA1; Humans; Models, Biological; Mutation; Ovarian Neoplasms; RNA, Messenger; Telomere
PubMed: 22576213
DOI: 10.1158/2159-8290.CD-11-0206 -
Medical Oncology (Northwood, London,... Jun 2013The aim of the study was to investigate the influence of allelic imbalance (AI) in several loci of tumor suppressor genes in 3p region on the non-small cell lung cancer...
The aim of the study was to investigate the influence of allelic imbalance (AI) in several loci of tumor suppressor genes in 3p region on the non-small cell lung cancer (NSCLC) development. We evaluated the frequency of loss of heterozygosity and/or microsatellite imbalance (LOH/MSI) and assessed their association with patients' characteristics (age, gender, tobacco addiction) and NSCLC classification according to TNM/AJCC staging. To analyze the potential role of AI involved in NSCLC pathogenesis, we allelotyped a group of 74 NSCLC patients using 7 microsatellite markers. The highest frequency of LOH/MSI, however, not statistically significant, was observed in RARβ and MLH1 (p = 0.104 and p = 0.216, respectively) loci. The association between high LOH/MSI frequency in 3p region with male gender (p = 0.041) as well as with age (especially >60 years) for RARβ and MLH1 genes (p = 0.0001 and p = 0.020, respectively) was documented. Statistically significant increased frequency of MLH1 allelic loss in squamous cell carcinoma (SCC) versus non-squamous cell carcinoma (non-SCC) was observed (p = 0.01). Significant increase in LOH/MSI frequency in 3p region (mainly in FHIT and MLH1 loci) in correlation with cigarette addiction in a lifetime (≥40 years and ≥40 Pack Years) was also documented (p < 0.05). The highest LOH/MSI was revealed in RARβ locus in IA tumors (p = 0.0001), while the similarly high allelic loss of MLH1 correlated with III A/B tumors (p = 0.0002), according to AJCC staging. The obtained results demonstrate that AI is influenced by tobacco smoking and seems to be vital in the molecular diagnosis of NSCLC, especially of SCC subtype.
Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Aged, 80 and over; Allelic Imbalance; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Female; Gene Frequency; Genetic Loci; Humans; Lung Neoplasms; Male; Middle Aged; MutL Protein Homolog 1; Nuclear Proteins; Receptors, Retinoic Acid
PubMed: 23504373
DOI: 10.1007/s12032-013-0532-9 -
Journal For Immunotherapy of Cancer Apr 2024The individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance...
BACKGROUND
The individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance of HLA-I loci in esophago-gastric adenocarcinoma (EGA) and determines the resulting repertoires of potentially immunogenic peptides.
METHODS
HLA genotypes and sequences of either (1) 10 relevant tumor-associated antigens (TAAs) or (2) patient-specific mutation-associated neoantigens (MANAs) were used to predict good-affinity binders using an in silico approach for MHC-binding (www.iedb.org). Imbalanced or lost expression of HLA-I-A/B/C alleles was analyzed by transcriptome sequencing. FluoroSpot assays and TCR sequencing were used to determine peptide-specific T-cell responses.
RESULTS
We show that germline homozygosity of HLA-I genes is significantly enriched in EGA patients (n=80) compared with an HLA-matched reference cohort (n=7605). Whereas the overall mutational burden is similar, the repertoire of potentially immunogenic peptides derived from TAAs and MANAs was lower in homozygous patients. Promiscuity of peptides binding to different HLA-I molecules was low for most TAAs and MANAs and in silico modeling of the homozygous to a heterozygous HLA genotype revealed normalized peptide repertoires. Transcriptome sequencing showed imbalanced expression of HLA-I alleles in 75% of heterozygous patients. Out of these, 33% showed complete loss of heterozygosity, whereas 66% had altered expression of only one or two HLA-I molecules. In a FluoroSpot assay, we determined that peptide-specific T-cell responses against NY-ESO-1 are derived from multiple peptides, which often exclusively bind only one HLA-I allele.
CONCLUSION
The high frequency of germline homozygosity in EGA patients suggests reduced cancer immunosurveillance leading to an increased cancer risk. Therapeutic targeting of allelic imbalance of HLA-I molecules should be considered in EGA.
Topics: Humans; Peptides; T-Lymphocytes; HLA Antigens; Antigens, Neoplasm; Allelic Imbalance; Adenocarcinoma; Germ Cells
PubMed: 38631707
DOI: 10.1136/jitc-2023-007268 -
Journal of Applied Genetics Feb 2019Analysis of allele-specific expression may help to elucidate the genetic architecture of complex traits including fat deposition in pigs. Here, we used pyrosequencing to...
Analysis of allele-specific expression of seven candidate genes involved in lipid metabolism in pig skeletal muscle and fat tissues reveals allelic imbalance of ACACA, LEP, SCD, and TNF.
Analysis of allele-specific expression may help to elucidate the genetic architecture of complex traits including fat deposition in pigs. Here, we used pyrosequencing to investigate the allele proportions of candidate genes (ACACA, ADIPOR1, FASN, LEP, ME1, SCD, and TNF) involved in regulation of lipid metabolism in two fat deposits (subcutaneous and visceral fat) and longissimus dorsi muscle of pigs representing Polish Large White, Polish Landrace, Duroc, and Pietrain breeds. We detected differential allelic expression of ACACA, LEP, SCD, and TNF in all tissues analyzed. To search for putative cis-regulatory elements involved in allele-specific expression, we quantified the methylation level within CpG islands located in 5'-flanking regions of ACACA and SCD. Comparison between samples showing markedly disproportionate allelic expression and control groups with similar levels of both alleles did not reveal significant differences. We also assessed the association of rs321308225 (c.*195C>A) an SNP located in the 3'UTR of ACACA with its allelic expression in Polish Landrace pigs, but it was not significant. We conclude that allelic imbalance occurs frequently in regard to genes involved in regulation of lipid deposition in pigs, and further studies are necessary to identify cis-regulatory elements affecting ACACA, LEP, SCD, and TNF expression in porcine fat tissues and skeletal muscle.
Topics: Acetyl-CoA Carboxylase; Adipose Tissue; Alleles; Allelic Imbalance; Animals; Genes; Leptin; Lipid Metabolism; Muscle, Skeletal; Polymorphism, Genetic; Stearoyl-CoA Desaturase; Swine; Tumor Necrosis Factor-alpha
PubMed: 30684136
DOI: 10.1007/s13353-019-00485-z -
Cell Apr 2002Cells often express only one gene from a set of two or more. African trypanosomes appear to accomplish this monoallelic expression by segregating the selected gene into... (Review)
Review
Cells often express only one gene from a set of two or more. African trypanosomes appear to accomplish this monoallelic expression by segregating the selected gene into a specific nuclear body. The possibility that such a structure might explain monoallelic expression in other multigene systems is discussed here.
Topics: Allelic Imbalance; Animals; Antigenic Variation; Cell Compartmentation; Cell Nucleus Structures; Gene Expression Regulation; Gene Silencing; Transcription, Genetic; Trypanosoma; Variant Surface Glycoproteins, Trypanosoma
PubMed: 11955440
DOI: 10.1016/s0092-8674(02)00711-0 -
Endocrine Oct 2013Parathyroid cancer is a rare, clinically aggressive cause of primary hyperparathyroidism, and whether these malignancies generally evolve from pre-existing benign...
Parathyroid cancer is a rare, clinically aggressive cause of primary hyperparathyroidism, and whether these malignancies generally evolve from pre-existing benign adenomas or arise de novo is unclear. Furthermore, while inactivation of the CDC73 (HRPT2) tumor suppressor gene, encoding parafibromin, is a major contributor, other genes essential to parathyroid carcinogenesis remain unknown. We sought to identify genomic regions potentially harboring such oncogenes or tumor suppressor genes, and to gain insight into the origins and molecular relationship of malignant versus benign parathyroid tumors. We performed genome-wide copy-number and loss of heterozygosity analysis using Affymetrix 50K SNP mapping arrays and/or comparative genomic hybridization on 16 primary parathyroid carcinomas, local recurrences or distant metastases, and matched normal controls, from 10 individuals. Recurrent regions of allelic loss were observed on chromosomes 1p, 3, and 13q suggesting that key parathyroid tumor suppressor genes are located in these chromosomal locations. Recurrent allelic gains were seen on chromosomes 1q and 16, suggesting the presence of parathyroid oncogenes on these chromosomes. Importantly, the most common alteration in benign parathyroid adenomas, loss of 11q, was not found as a recurrent change in the malignant parathyroid tissues. Molecular allelotyping using highly polymorphic microsatellite markers provided further confirmation that the prevalence of 11q loss is markedly and significantly lower in carcinomas as compared with adenomas. Our observations provide molecular support for the concept that sporadic parathyroid cancer usually arises de novo, rather than evolving from a pre-existing typical benign adenoma. Furthermore, these results help direct future investigation to ultimately determine which of the candidate genes in these chromosomal locations make significant contributions to the molecular pathogenesis of parathyroid cancer.
Topics: Adenoma; Adult; Aged; Allelic Imbalance; Carcinoma; Cohort Studies; Comparative Genomic Hybridization; DNA Copy Number Variations; Female; Humans; Hyperparathyroidism, Primary; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Parathyroid Neoplasms; Polymorphism, Single Nucleotide; Young Adult
PubMed: 23435613
DOI: 10.1007/s12020-013-9903-4 -
Cell Reports May 2023Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter...
Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2 mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2 mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2 mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration. Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2 mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2 brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2 mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.
Topics: Mice; Animals; Endothelial Cells; Haploinsufficiency; Organelle Biogenesis; Chromosome Deletion; Brain
PubMed: 37149866
DOI: 10.1016/j.celrep.2023.112485 -
BMC Genetics Apr 2016Multiple sclerosis is a chronic inflammatory, demyelinating disease of the central nervous system. Recent genome-wide studies have revealed more than 110 single...
BACKGROUND
Multiple sclerosis is a chronic inflammatory, demyelinating disease of the central nervous system. Recent genome-wide studies have revealed more than 110 single nucleotide polymorphisms as associated with susceptibility to multiple sclerosis, but their functional contribution to disease development is mostly unknown.
RESULTS
Consistent allelic imbalance was observed for rs907091 in IKZF3 and rs11609 in IQGAP1, which are in strong linkage disequilibrium with the multiple sclerosis associated single nucleotide polymorphisms rs12946510 and rs8042861, respectively. Using multiple sclerosis patients and healthy controls heterozygous for rs907091 and rs11609, we showed that the multiple sclerosis risk alleles at IKZF3 and IQGAP1 are expressed at higher levels as compared to the protective allele. Furthermore, individuals homozygous for the multiple sclerosis risk allele at IQGAP1 had a significantly higher total expression of IQGAP1 compared to individuals homozygous for the protective allele.
CONCLUSIONS
Our data indicate a possible regulatory role for the multiple sclerosis-associated IKZF3 and IQGAP1 variants. We suggest that such cis-acting mechanisms may contribute to the multiple sclerosis association of single nucleotide polymorphisms at IKZF3 and IQGAP1.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Allelic Imbalance; Case-Control Studies; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Genotyping Techniques; Humans; Ikaros Transcription Factor; Linkage Disequilibrium; Male; Middle Aged; Multiple Sclerosis; Polymorphism, Single Nucleotide; Sensitivity and Specificity; Young Adult; ras GTPase-Activating Proteins
PubMed: 27080863
DOI: 10.1186/s12863-016-0367-4