HGG Advances最新文献

{"title":"Letter to the editor.","authors":"Cary O Harding, Michael Martinez","doi":"10.1016/j.xhgg.2024.100308","DOIUrl":"10.1016/j.xhgg.2024.100308","url":null,"abstract":"","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11192771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A power-based sliding window approach to evaluate the clinical impact of rare genetic variants in the nucleotide sequence or the spatial position of the folded protein.","authors":"Elizabeth T Cirulli, Kelly M Schiabor Barrett, Alexandre Bolze, Daniel P Judge, Pamala A Pawloski, Joseph J Grzymski, William Lee, Nicole L Washington","doi":"10.1016/j.xhgg.2024.100284","DOIUrl":"10.1016/j.xhgg.2024.100284","url":null,"abstract":"<p><p>Systematic determination of novel variant pathogenicity remains a major challenge, even when there is an established association between a gene and phenotype. Here we present Power Window (PW), a sliding window technique that identifies the impactful regions of a gene using population-scale clinico-genomic datasets. By sizing analysis windows on the number of variant carriers, rather than the number of variants or nucleotides, statistical power is held constant, enabling the localization of clinical phenotypes and removal of unassociated gene regions. The windows can be built by sliding across either the nucleotide sequence of the gene (through 1D space) or the positions of the amino acids in the folded protein (through 3D space). Using a training set of 350k exomes from the UK Biobank (UKB), we developed PW models for well-established gene-disease associations and tested their accuracy in two independent cohorts (117k UKB exomes and 65k exomes sequenced at Helix in the Healthy Nevada Project, myGenetics, or In Our DNA SC studies). The significant models retained a median of 49% of the qualifying variant carriers in each gene (range 2%-98%), with quantitative traits showing a median effect size improvement of 66% compared with aggregating variants across the entire gene, and binary traits' odds ratios improving by a median of 2.2-fold. PW showcases that electronic health record-based statistical analyses can accurately distinguish between novel coding variants in established genes that will have high phenotypic penetrance and those that will not, unlocking new potential for human genomics research, drug development, variant interpretation, and precision medicine.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11004801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140176784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Massively parallel reporter assay confirms regulatory potential of hQTLs and reveals important variants in lupus and other autoimmune diseases.","authors":"Yao Fu, Jennifer A Kelly, Jaanam Gopalakrishnan, Richard C Pelikan, Kandice L Tessneer, Satish Pasula, Kiely Grundahl, David A Murphy, Patrick M Gaffney","doi":"10.1016/j.xhgg.2024.100279","DOIUrl":"10.1016/j.xhgg.2024.100279","url":null,"abstract":"<p><p>We designed a massively parallel reporter assay (MPRA) in an Epstein-Barr virus transformed B cell line to directly characterize the potential for histone post-translational modifications, i.e., histone quantitative trait loci (hQTLs), expression QTLs (eQTLs), and variants on systemic lupus erythematosus (SLE) and autoimmune (AI) disease risk haplotypes to modulate regulatory activity in an allele-dependent manner. Our study demonstrates that hQTLs, as a group, are more likely to modulate regulatory activity in an MPRA compared with other variant classes tested, including a set of eQTLs previously shown to interact with hQTLs and tested AI risk variants. In addition, we nominate 17 variants (including 11 previously unreported) as putative causal variants for SLE and another 14 for various other AI diseases, prioritizing these variants for future functional studies in primary and immortalized B cells. Thus, we uncover important insights into the mechanistic relationships among genotype, epigenetics, and gene expression in SLE and AI disease phenotypes.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10943488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139933217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver regulatory mechanisms of noncoding variants at lipid and metabolic trait loci.","authors":"Gautam K Pandey, Swarooparani Vadlamudi, Kevin W Currin, Anne H Moxley, Jayna C Nicholas, Jessica C McAfee, K Alaine Broadaway, Karen L Mohlke","doi":"10.1016/j.xhgg.2024.100275","DOIUrl":"10.1016/j.xhgg.2024.100275","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) have identified hundreds of risk loci for liver disease and lipid-related metabolic traits, although identifying their target genes and molecular mechanisms remains challenging. We predicted target genes at GWAS signals by integrating them with molecular quantitative trait loci for liver gene expression (eQTL) and liver chromatin accessibility QTL (caQTL). We predicted specific regulatory caQTL variants at four GWAS signals located near EFHD1, LITAF, ZNF329, and GPR180. Using transcriptional reporter assays, we determined that caQTL variants rs13395911, rs11644920, rs34003091, and rs9556404 exhibit allelic differences in regulatory activity. We also performed a protein binding assay for rs13395911 and found that FOXA2 differentially interacts with the alleles of rs13395911. For variants rs13395911 and rs11644920 in putative enhancer regulatory elements, we used CRISPRi to demonstrate that repression of the enhancers altered the expression of the predicted target and/or nearby genes. Repression of the element at rs13395911 reduced the expression of EFHD1, and repression of the element at rs11644920 reduced the expression of LITAF, SNN, and TXNDC11. Finally, we showed that EFHD1 is a metabolically active gene in HepG2 cells. Together, these results provide key steps to connect genetic variants with cellular mechanisms and help elucidate the causes of liver disease.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10881423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139651843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical, immunohistochemical, and genetic characterization of splice-altering biallelic DES variants: Therapeutic implications.","authors":"Janelle Geist Hauserman, Chamindra G Laverty, Sandra Donkervoort, Ying Hu, Sarah Silverstein, Sarah B Neuhaus, Dimah Saade, Gabrielle Vaughn, Denise Malicki, Rupleen Kaur, Yuesheng Li, Yan Luo, Poching Liu, Patrick Burr, A Reghan Foley, Payam Mohassel, Carsten G Bönnemann","doi":"10.1016/j.xhgg.2024.100274","DOIUrl":"10.1016/j.xhgg.2024.100274","url":null,"abstract":"<p><p>Pathogenic variants in the DES gene clinically manifest as progressive skeletal muscle weakness, cardiomyopathy with associated severe arrhythmias, and respiratory insufficiency, and are collectively known as desminopathies. While most DES pathogenic variants act via a dominant mechanism, recessively acting variants have also been reported. Currently, there are no effective therapeutic interventions for desminopathies of any type. Here, we report an affected individual with rapidly progressive dilated cardiomyopathy, requiring heart transplantation at age 13 years, in the setting of childhood-onset skeletal muscle weakness. We identified biallelic DES variants (c.640-13 T>A and c.1288+1 G>A) and show aberrant DES gene splicing in the affected individual's muscle. Through the generation of an inducible lentiviral system, we transdifferentiated fibroblast cultures derived from the affected individual into myoblasts and validated this system using RNA sequencing. We tested rationally designed, custom antisense oligonucleotides to screen for splice correction in these transdifferentiated cells and a functional minigene splicing assay. However, rather than correctly redirecting splicing, we found them to induce undesired exon skipping. Our results indicate that, while an individual precision-based molecular therapeutic approach to splice-altering pathogenic variants is promising, careful preclinical testing is imperative for each novel variant to test the feasibility of this type of approach for translation.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10876619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139742237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guidance on use of race, ethnicity, and geographic origin as proxies for genetic ancestry groups in biomedical publications.","authors":"W Gregory Feero, Robert D Steiner, Anne Slavotinek, Tiago Faial, Michael J Bamshad, Jehannine Austin, Bruce R Korf, Annette Flanagin, Kirsten Bibbins-Domingo","doi":"10.1016/j.xhgg.2024.100282","DOIUrl":"10.1016/j.xhgg.2024.100282","url":null,"abstract":"","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11019354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140120983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features.","authors":"Morad Ansari, Kamli N W Faour, Akiko Shimamura, Graeme Grimes, Emeline M Kao, Erica R Denhoff, Ana Blatnik, Daniel Ben-Isvy, Lily Wang, Benjamin M Helm, Helen Firth, Amy M Breman, Emilia K Bijlsma, Aiko Iwata-Otsubo, Thomy J L de Ravel, Vincent Fusaro, Alan Fryer, Keith Nykamp, Lara G Stühn, Tobias B Haack, G Christoph Korenke, Panayiotis Constantinou, Kinga M Bujakowska, Karen J Low, Emily Place, Jennifer Humberson, Melanie P Napier, Jessica Hoffman, Jane Juusola, Matthew A Deardorff, Wanqing Shao, Shira Rockowitz, Ian Krantz, Maninder Kaur, Sarah Raible, Victoria Dortenzio, Sabine Kliesch, Moriel Singer-Berk, Emily Groopman, Stephanie DiTroia, Sonia Ballal, Siddharth Srivastava, Kathrin Rothfelder, Saskia Biskup, Jessica Rzasa, Jennifer Kerkhof, Haley McConkey, Bekim Sadikovic, Sarah Hilton, Siddharth Banka, Frank Tüttelmann, Donald F Conrad, Anne O'Donnell-Luria, Michael E Talkowski, David R FitzPatrick, Philip M Boone","doi":"10.1016/j.xhgg.2024.100273","DOIUrl":"10.1016/j.xhgg.2024.100273","url":null,"abstract":"<p><p>Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated with SMC3 loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants in SMC3, and analyzed population databases to characterize mutational intolerance in this gene. Here, we show that SMC3 behaves as an archetypal haploinsufficient gene: it is highly constrained against pLoF variants, strongly depleted for missense variants, and pLoF variants are associated with a range of developmental phenotypes. Among 14 individuals with SMC3 pLoF variants, phenotypes were variable but coalesced on low growth parameters, developmental delay/intellectual disability, and dysmorphism, reminiscent of atypical CdLS. Comparisons to individuals with SMC3 missense/in-frame indel variants demonstrated an overall milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, and some had alternative symptomatologies with rational biological links to SMC3. Analyses of tumor and model system transcriptomic data and epigenetic data in a subset of cases suggest that SMC3 pLoF variants reduce SMC3 expression but do not strongly support clustering with functional genomic signatures of typical CdLS. Our finding of substantial population-scale LoF intolerance in concert with variable growth and developmental features in subjects with SMC3 pLoF variants expands the scope of cohesinopathies, informs on their allelic architecture, and suggests the existence of additional clearly LoF-constrained genes whose disease links will be confirmed only by multilayered genomic data paired with careful phenotyping.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10876629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139651833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Olfactory receptor genes and chromosome 11 structural aberrations: Players or spectators?","authors":"Serena Redaelli, Francesca Romana Grati, Viviana Tritto, Giuliana Giannuzzi, Maria Paola Recalcati, Elena Sala, Nicoletta Villa, Francesca Crosti, Gaia Roversi, Francesca Malvestiti, Valentina Zanatta, Elena Repetti, Ornella Rodeschini, Chiara Valtorta, Ilaria Catusi, Lorenza Romitti, Emanuela Martinoli, Donatella Conconi, Leda Dalprà, Marialuisa Lavitrano, Paola Riva, Angela Bentivegna","doi":"10.1016/j.xhgg.2023.100261","DOIUrl":"10.1016/j.xhgg.2023.100261","url":null,"abstract":"<p><p>The largest multi-gene family in metazoans is the family of olfactory receptor (OR) genes. Human ORs are organized in clusters over most chromosomes and seem to include >0.1% the human genome. Because 369 out of 856 OR genes are mapped on chromosome 11 (HSA11), we sought to determine whether they mediate structural rearrangements involving this chromosome. To this aim, we analyzed 220 specimens collected during diagnostic procedures involving structural rearrangements of chromosome 11. A total of 222 chromosomal abnormalities were included, consisting of inversions, deletions, translocations, duplications, and one insertion, detected by conventional chromosome analysis and/or fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (array-CGH). We verified by bioinformatics and statistical approaches the occurrence of breakpoints in cytobands with or without OR genes. We found that OR genes are not involved in chromosome 11 reciprocal translocations, suggesting that different DNA motifs and mechanisms based on homology or non-homology recombination can cause chromosome 11 structural alterations. We also considered the proximity between the chromosomal territories of chromosome 11 and its partner chromosomes involved in the translocations by using the deposited Hi-C data concerning the possible occurrence of chromosome interactions. Interestingly, most of the breakpoints are located in regions highly involved in chromosome interactions. Further studies should be carried out to confirm the potential role of chromosome territories' proximity in promoting genome structural variation, so fundamental in our understanding of the molecular basis of medical genetics and evolutionary genetics.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10820794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139075234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantifying negative selection on synonymous variants.","authors":"Mikhail Gudkov, Loïc Thibaut, Eleni Giannoulatou","doi":"10.1016/j.xhgg.2024.100262","DOIUrl":"10.1016/j.xhgg.2024.100262","url":null,"abstract":"<p><p>Widespread adoption of DNA sequencing has resulted in large numbers of genetic variants, whose contribution to disease is not easily determined. Although many types of variation are known to disrupt cellular processes in predictable ways, for some categories of variants, the effects may not be directly detectable. A particular example is synonymous variants, that is, those single-nucleotide variants that create a codon substitution, such that the produced amino acid sequence is unaffected. Contrary to the original theory suggesting that synonymous variants are benign, there is a growing volume of research showing that, despite their \"silent\" mechanism of action, some synonymous variation may be deleterious. Here, we studied the extent of the negative selective pressure acting on different classes of synonymous variants by analyzing the relative enrichment of synonymous singleton variants in the human exomes provided by gnomAD. Using a modification of the mutability-adjusted proportion of singletons (MAPS) metric as a measure of purifying selection, we found that some classes of synonymous variants are subject to stronger negative selection than others. For instance, variants that reduce codon optimality undergo stronger selection than optimality-increasing variants. Besides, selection affects synonymous variants implicated in splice-site-loss or splice-site-gain events. To understand what drives this negative selection, we tested a number of predictors in the aim to explain the variability in the selection scores. Our findings provide insights into the effects of synonymous variants at the population level, highlighting the specifics of the role that these variants play in health and disease.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10835449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139404654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell analysis identified POSTN⁺ cells associated with the aggressive phenotype and risk of esophageal squamous cell carcinoma.","authors":"Yuqian Tan, Lina Song, Jialing Ma, Miaoxin Pan, Siyuan Niu, Xinying Yue, Yueping Li, Linglong Gu, Shasha Liu, Jiang Chang","doi":"10.1016/j.xhgg.2024.100278","DOIUrl":"10.1016/j.xhgg.2024.100278","url":null,"abstract":"<p><p>Tumors are intricate and heterogeneous systems characterized by mosaic cancer cell populations with diverse expression profiles. Leveraging single-cell technologies, we employed the Scissor algorithm to delineate an epithelial subpopulation associated with the aggressive phenotype in esophageal squamous cell carcinoma (ESCC). This identified subpopulation exhibited elevated expression of genes involved in critical pathways, such as epithelial-mesenchymal transition and PI3K-Akt. Key signature genes within this subpopulation, namely CAV1, COL3A1, COL6A1, POSTN, and TAGLN, demonstrated significant upregulation concomitant with both tumorigenesis and tumor progression across independent single-cell datasets. Furthermore, we selected 1,450 expression quantitative trait loci of the top 62 signature genes of this cell subpopulation to investigate their potential in predicting ESCC risk. The results showed that the POSTN loci were predominantly associated with ESCC susceptibility. Through functional annotation and replication analyses, we identified that the rs1028728 in the POSTN promoter was significantly associated with increased ESCC risk in 7,049 ESCC cases and 8,063 controls (odds ratio = 1.29, 95% confidence interval: 1.18-1.42, p = 4.03 × 10^-8). Subsequent biochemical experiments showed that the rs1028728[T] allele enhanced POSTN expression by affecting the binding of PRRX1 in the POSTN promoter. In summary, our meticulous single-cell analysis delineates an invasive epithelial subpopulation in ESCC, with POSTN emerging as an important marker for the aggressive phenotype. These findings offer more insights into potential strategies for the prevention and intervention of ESCC, enriching our understanding of this complex cancer landscape.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10924139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139900533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}