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Gifford, Casey A., Sanjeev S. Ranade, Ryan Samarakoon, Hazel T. Salunga, T. Yvanka de Soysa, Yu Huang, Ping Zhou et al. "Oligogenic inheritance of a human heart disease involving a genetic modifier". Science 364, n.º 6443 (30 de mayo de 2019): 865–70. http://dx.doi.org/10.1126/science.aat5056.
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Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the MKL2, MYH7, and NKX2-5 genes. The MYH7 and MKL2 variants were inherited from the affected, asymptomatic father and the rare NKX2-5 variant (minor allele frequency, 0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell–derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant’s contribution as a genetic modifier.
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Fan, Wenjun, Eetu Eklund, Rachel M. Sherman, Hester Liu, Stephanie Pitts, Brittany Ford, N. V. Rajeshkumar y Marikki Laiho. "Widespread genetic heterogeneity of human ribosomal RNA genes". RNA 28, n.º 4 (2 de febrero de 2022): 478–92. http://dx.doi.org/10.1261/rna.078925.121.
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Polymorphism drives survival under stress and provides adaptability. Genetic polymorphism of ribosomal RNA (rRNA) genes derives from internal repeat variation of this multicopy gene, and from interindividual variation. A considerable amount of rRNA sequence heterogeneity has been proposed but has been challenging to estimate given the scarcity of accurate reference sequences. We identified four rDNA copies on chromosome 21 (GRCh38) with 99% similarity to recently introduced reference sequence KY962518.1. We customized a GATK bioinformatics pipeline using the four rDNA loci, spanning a total 145 kb, for variant calling and used high-coverage whole-genome sequencing (WGS) data from the 1000 Genomes Project to analyze variants in 2504 individuals from 26 populations. We identified a total of 3791 variant positions. The variants positioned nonrandomly on the rRNA gene. Invariant regions included the promoter, early 5′ ETS, most of 18S, 5.8S, ITS1, and large areas of the intragenic spacer. A total of 470 variant positions were observed on 28S rRNA. The majority of the 28S rRNA variants were located on highly flexible human-expanded rRNA helical folds ES7L and ES27L, suggesting that these represent positions of diversity and are potentially under continuous evolution. Several variants were validated based on RNA-seq analyses. Population analyses showed remarkable ancestry-linked genetic variance and the presence of both high penetrance and frequent variants in the 5′ ETS, ITS2, and 28S regions segregating according to the continental populations. These findings provide a genetic view of rRNA gene array heterogeneity and raise the need to functionally assess how the 28S rRNA variants affect ribosome functions.
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Hutchinson, Anna, Jennifer Asimit y Chris Wallace. "Fine-mapping genetic associations". Human Molecular Genetics 29, R1 (3 de agosto de 2020): R81—R88. http://dx.doi.org/10.1093/hmg/ddaa148.
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Abstract Whilst thousands of genetic variants have been associated with human traits, identifying the subset of those variants that are causal requires a further ‘fine-mapping’ step. We review the basic fine-mapping approach, which is computationally fast and requires only summary data, but depends on an assumption of a single causal variant per associated region which is recognized as biologically unrealistic. We discuss different ways that the approach has been built upon to accommodate multiple causal variants in a region and to incorporate additional layers of functional annotation data. We further review methods for simultaneous fine-mapping of multiple datasets, either exploiting different linkage disequilibrium (LD) structures across ancestries or borrowing information between distinct but related traits. Finally, we look to the future and the opportunities that will be offered by increasingly accurate maps of causal variants for a multitude of human traits.
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Khanna, Tarun, Gordon Hanna, Michael J. E. Sternberg y Alessia David. "Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants". Human Genetics 140, n.º 5 (27 de enero de 2021): 805–12. http://dx.doi.org/10.1007/s00439-020-02246-z.
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AbstractThe interpretation of human genetic variation is one of the greatest challenges of modern genetics. New approaches are urgently needed to prioritize variants, especially those that are rare or lack a definitive clinical interpretation. We examined 10,136,597 human missense genetic variants from GnomAD, ClinVar and UniProt. We were able to perform large-scale atom-based mapping and phenotype interpretation of 3,960,015 of these variants onto 18,874 experimental and 84,818 in house predicted three-dimensional coordinates of the human proteome. We demonstrate that 14% of amino acid substitutions from the GnomAD database that could be structurally analysed are predicted to affect protein structure (n = 568,548, of which 566,439 rare or extremely rare) and may, therefore, have a yet unknown disease-causing effect. The same is true for 19.0% (n = 6266) of variants of unknown clinical significance or conflicting interpretation reported in the ClinVar database. The results of the structural analysis are available in the dedicated web catalogue Missense3D-DB (http://missense3d.bc.ic.ac.uk/). For each of the 4 M variants, the results of the structural analysis are presented in a friendly concise format that can be included in clinical genetic reports. A detailed report of the structural analysis is also available for the non-experts in structural biology. Population frequency and predictions from SIFT and PolyPhen are included for a more comprehensive variant interpretation. This is the first large-scale atom-based structural interpretation of human genetic variation and offers geneticists and the biomedical community a new approach to genetic variant interpretation.
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Keogh, Michael J., Wei Wei, Juvid Aryaman, Ian Wilson, Kevin Talbot, Martin R. Turner, Chris-Anne McKenzie et al. "Oligogenic genetic variation of neurodegenerative disease genes in 980 postmortem human brains". Journal of Neurology, Neurosurgery & Psychiatry 89, n.º 8 (13 de enero de 2018): 813–16. http://dx.doi.org/10.1136/jnnp-2017-317234.
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BackgroundSeveral studies suggest that multiple rare genetic variants in genes causing monogenic forms of neurodegenerative disorders interact synergistically to increase disease risk or reduce the age of onset, but these studies have not been validated in large sporadic case series.MethodsWe analysed 980 neuropathologically characterised human brains with Alzheimer’s disease (AD), Parkinson’s disease-dementia with Lewy bodies (PD-DLB), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and age-matched controls. Genetic variants were assessed using the American College of Medical Genetics criteria for pathogenicity. Individuals with two or more variants within a relevant disease gene panel were defined as ‘oligogenic’.ResultsThe majority of oligogenic variant combinations consisted of a highly penetrant allele or known risk factor in combination with another rare but likely benign allele. The presence of oligogenic variants did not influence the age of onset or disease severity. After controlling for the single known major risk allele, the frequency of oligogenic variants was no different between cases and controls.ConclusionsA priori, individuals with AD, PD-DLB and FTD-ALS are more likely to harbour a known genetic risk factor, and it is the burden of these variants in combination with rare benign alleles that is likely to be responsible for some oligogenic associations. Controlling for this bias is essential in studies investigating a potential role for oligogenic variation in neurodegenerative diseases.
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Kamat, Mihir A., James A. Blackshaw, Robin Young, Praveen Surendran, Stephen Burgess, John Danesh, Adam S. Butterworth y James R. Staley. "PhenoScanner V2: an expanded tool for searching human genotype–phenotype associations". Bioinformatics 35, n.º 22 (24 de junio de 2019): 4851–53. http://dx.doi.org/10.1093/bioinformatics/btz469.
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Abstract Summary PhenoScanner is a curated database of publicly available results from large-scale genetic association studies in humans. This online tool facilitates ‘phenome scans’, where genetic variants are cross-referenced for association with many phenotypes of different types. Here we present a major update of PhenoScanner (‘PhenoScanner V2’), including over 150 million genetic variants and more than 65 billion associations (compared to 350 million associations in PhenoScanner V1) with diseases and traits, gene expression, metabolite and protein levels, and epigenetic markers. The query options have been extended to include searches by genes, genomic regions and phenotypes, as well as for genetic variants. All variants are positionally annotated using the Variant Effect Predictor and the phenotypes are mapped to Experimental Factor Ontology terms. Linkage disequilibrium statistics from the 1000 Genomes project can be used to search for phenotype associations with proxy variants. Availability and implementation PhenoScanner V2 is available at www.phenoscanner.medschl.cam.ac.uk.
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Young, Barry P., Kathryn L. Post, Jesse T. Chao, Fabian Meili, Kurt Haas y Christopher Loewen. "Sentinel interaction mapping – a generic approach for the functional analysis of human disease gene variants using yeast". Disease Models & Mechanisms 13, n.º 7 (29 de mayo de 2020): dmm044560. http://dx.doi.org/10.1242/dmm.044560.
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ABSTRACTAdvances in sequencing technology have led to an explosion in the number of known genetic variants of human genes. A major challenge is to now determine which of these variants contribute to diseases as a result of their effect on gene function. Here, we describe a generic approach using the yeast Saccharomyces cerevisiae to quickly develop gene-specific in vivo assays that can be used to quantify the level of function of a genetic variant. Using synthetic dosage lethality screening, ‘sentinel’ yeast strains are identified that are sensitive to overexpression of a human disease gene. Variants of the gene can then be functionalized in a high-throughput fashion through simple growth assays using solid or liquid media. Sentinel interaction mapping (SIM) has the potential to create functional assays for the large majority of human disease genes that do not have a yeast orthologue. Using the tumour suppressor gene PTEN as an example, we show that SIM assays can provide a fast and economical means to screen a large number of genetic variants.
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Köksal, Zehra, Claus Børsting, Leonor Gusmão y Vania Pereira. "SNPtotree—Resolving the Phylogeny of SNPs on Non-Recombining DNA". Genes 14, n.º 10 (22 de septiembre de 2023): 1837. http://dx.doi.org/10.3390/genes14101837.
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Genetic variants on non-recombining DNA and the hierarchical order in which they accumulate are commonly of interest. This variant hierarchy can be established and combined with information on the population and geographic origin of the individuals carrying the variants to find population structures and infer migration patterns. Further, individuals can be assigned to the characterized populations, which is relevant in forensic genetics, genetic genealogy, and epidemiologic studies. However, there is currently no straightforward method to obtain such a variant hierarchy. Here, we introduce the software SNPtotree v1.0, which uniquely determines the hierarchical order of variants on non-recombining DNA without error-prone manual sorting. The algorithm uses pairwise variant comparisons to infer their relationships and integrates the combined information into a phylogenetic tree. Variants that have contradictory pairwise relationships or ambiguous positions in the tree are removed by the software. When benchmarked using two human Y-chromosomal massively parallel sequencing datasets, SNPtotree outperforms traditional methods in the accuracy of phylogenetic trees for sequencing data with high amounts of missing information. The phylogenetic trees of variants created using SNPtotree can be used to establish and maintain publicly available phylogeny databases to further explore genetic epidemiology and genealogy, as well as population and forensic genetics.
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Franti, Michael, Antoine Gessain, Pierre Darlu, Agnès Gautheret-Dejean, Haruhiko Kosuge, Philippe Mauclère, Jean-Thierry Aubin, Vladimir Gurtsevitch, Koichi Yamanishi y Henri Agut. "Genetic polymorphism of human herpesvirus-7 among human populations". Journal of General Virology 82, n.º 12 (1 de diciembre de 2001): 3045–50. http://dx.doi.org/10.1099/0022-1317-82-12-3045.
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The analysis of three human herpesvirus-7 (HHV-7) genes encoding phosphoprotein p100, glycoprotein B and major capsid protein respectively had previously shown the existence of distinct gene alleles, leading to the concept of HHV-7 variants. We have analysed the distribution of HHV-7 variants among 297 distinct subjects who belonged to different human populations from Africa, Asia, Europe and America. Two variants, designated Co1 and Co2, were found in 52% and 20% of studied subjects. Ten other variants, designated Co3–Co12, were less frequent and classified into two groups related to Co1 and Co2 respectively. While the former group was ubiquitous and the most frequent in Africa and Asia, the latter one was predominantly found in European and Mongol populations. Despite the high stability of the HHV-7 genome, a few nucleotide substitutions at precise positions define distinct variants which, to some extent, behave as markers of human populations.
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Spurdle, Amanda B., Stephanie Greville-Heygate, Antonis C. Antoniou, Melissa Brown, Leslie Burke, Miguel de la Hoya, Susan Domchek et al. "Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report". Journal of Medical Genetics 56, n.º 6 (8 de abril de 2019): 347–57. http://dx.doi.org/10.1136/jmedgenet-2018-105872.
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The vocabulary currently used to describe genetic variants and their consequences reflects many years of studying and discovering monogenic disease with high penetrance. With the recent rapid expansion of genetic testing brought about by wide availability of high-throughput massively parallel sequencing platforms, accurate variant interpretation has become a major issue. The vocabulary used to describe single genetic variants in silico, in vitro, in vivo and as a contributor to human disease uses terms in common, but the meaning is not necessarily shared across all these contexts. In the setting of cancer genetic tests, the added dimension of using data from genetic sequencing of tumour DNA to direct treatment is an additional source of confusion to those who are not experienced in cancer genetics. The language used to describe variants identified in cancer susceptibility genetic testing typically still reflects an outdated paradigm of Mendelian inheritance with dichotomous outcomes. Cancer is a common disease with complex genetic architecture; an improved lexicon is required to better communicate among scientists, clinicians and patients, the risks and implications of genetic variants detected. This review arises from a recognition of, and discussion about, inconsistencies in vocabulary usage by members of the ENIGMA international multidisciplinary consortium focused on variant classification in breast-ovarian cancer susceptibility genes. It sets out the vocabulary commonly used in genetic variant interpretation and reporting, and suggests a framework for a common vocabulary that may facilitate understanding and clarity in clinical reporting of germline genetic tests for cancer susceptibility.
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Nugraha, Bharmatisna Anggaharsya. "Review of Genetic Variants of Butyrylcholinesterase and Their Potential Impact on Human Health". Open Access Indonesian Journal of Medical Reviews 1, n.º 6 (15 de octubre de 2021): 135–40. http://dx.doi.org/10.37275/oaijmr.v1i6.56.
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Butyrylcholinesterase (BChE) is an enzyme found in plasma and many other parts of the body. It is enzyme that hydrolyses drugs containing ester bonds such as drugs acting at the neuromuscular junction (succinylcholine) and local anaesthetics (procaine). Examination of the gene for mutations or polymorphisms causing the observed biochemical phenotypes has isolated those responsible for all the most widely known variants. The molecular bases of several genetic variants of BChE have been reported, such as the Atypical variant, fluoride-resistant variant, silent variant, K variant, J variant and C5 variant. In general, BChE polymorphisms have been shown to produce enzymes with varying levels of catalytic activity. Genetic variants of human butyrylcholinesterase were one of the first examples in the new field of pharmacogenetics when it was recognized that abnormal response to the succinylcholine was due to a mutated enzyme with low binding affinity. Beside that, variant of BChE has potential impact for Alzheimer disease patology.
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Nugraha, Bharmatisna Anggaharsya. "Review of Genetic Variants of Butyrylcholinesterase and Their Potential Impact on Human Health". Natural Sciences Engineering and Technology Journal 1, n.º 1 (13 de agosto de 2021): 23–28. http://dx.doi.org/10.37275/nasetjournal.v1i1.5.
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Butyrylcholinesterase (BChE) is an enzyme found in plasma and many other parts of the body. It is enzyme that hydrolyses drugs containing ester bonds such as drugs acting at the neuromuscular junction (succinylcholine) and local anaesthetics (procaine). Examination of the gene for mutations or polymorphisms causing the observed biochemical phenotypes has isolated those responsible for all the most widely known variants. The molecular bases of several genetic variants of BChE have been reported, such as the Atypical variant, fluoride-resistant variant, silent variant, K variant, J variant and C5 variant. In general, BChE polymorphisms have been shown to produce enzymes with varying levels of catalytic activity. Genetic variants of human butyrylcholinesterase were one of the first examples in the new field of pharmacogenetics when it was recognized that abnormal response to the succinylcholine was due to a mutated enzyme with low binding affinity. Beside that, variant of BChE has potential impact for Alzheimer disease patology
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Nugraha, Bharmatisna Anggaharsya. "Review of Genetic Variants of Butyrylcholinesterase and Their Potential Impact on Human Health". Open Access Indonesian Journal of Medical Reviews 1, n.º 6 (31 de agosto de 2021): 135–45. http://dx.doi.org/10.37275/oaijmr.v1i6.575.
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Butyrylcholinesterase (BChE) is an enzyme found in plasma and many other parts of the body. It is enzyme that hydrolyses drugs containing ester bonds such as drugs acting at the neuromuscular junction (succinylcholine) and local anaesthetics (procaine). Examination of the gene for mutations or polymorphisms causing the observed biochemical phenotypes has isolated those responsible for all the most widely known variants. The molecular bases of several genetic variants of BChE have been reported, such as the Atypical variant, fluoride-resistant variant, silent variant, K variant, J variant and C5 variant. In general, BChE polymorphisms have been shown to produce enzymes with varying levels of catalytic activity. Genetic variants of human butyrylcholinesterase were one of the first examples in the new field of pharmacogenetics when it was recognized that abnormal response to the succinylcholine was due to a mutated enzyme with low binding affinity. Beside that, variant of BChE has potential impact for Alzheimer disease patology.
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Chen, Doudou, Tao Yang y Siquan Zhu. "Novel Likely Pathogenic Variants Identified by Panel-Based Exome Sequencing in Congenital Cataract Patients". Journal of Ophthalmology 2021 (17 de noviembre de 2021): 1–10. http://dx.doi.org/10.1155/2021/3847409.
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Purpose. To identify likely pathogenic variants in three families with congenital cataracts via panel-based exome sequencing. Methods. A panel containing 153 genes associated with congenital cataracts was designed. Genes were selected through reference to databases including the Human Gene Mutation Database (HGMD), Online Mendelian Inheritance in Man (OMIM), Genetic Home Reference, and the latest peer-reviewed publications on the genetics of hereditary cataracts. Panel-based exome sequencing was performed with the Illumina HiSeq X-Ten platform, and then the identified variants were confirmed with Sanger sequencing and evaluated according to the American College of Medical Genetics and Genomics (ACMG) criteria. Results. Three likely pathogenic variants were found. A novel CRYBB2: c.230G > T p.G77V variant was identified in family A, a novel CRYBB2: c.230G > A p.G77D variant was identified in family B, and a novel CRYGD: c.475delG p.A159Pfs∗9 variant was identified in family C. Conclusion. Panel-based exome sequencing revealed three likely pathogenic variants in three unrelated Chinese families with congenital cataracts. These data expand the genetic spectrum associated with congenital cataracts.
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Biondi, G., V. Calabró, S. Colonna-Romano, M. Giangregorio, P. Malaspina, R. Petrucci, C. Santolamazza, P. Santolamazza, E. Tramontano y G. Battistuzzi. "Common and rare genetic variants of human red blood cell enzymes in ltaly". Anthropologischer Anzeiger 47, n.º 2 (4 de julio de 1989): 155–74. http://dx.doi.org/10.1127/anthranz/47/1989/155.
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Abell, Nathan S., Marianne K. DeGorter, Michael J. Gloudemans, Emily Greenwald, Kevin S. Smith, Zihuai He y Stephen B. Montgomery. "Multiple causal variants underlie genetic associations in humans". Science 375, n.º 6586 (18 de marzo de 2022): 1247–54. http://dx.doi.org/10.1126/science.abj5117.
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Associations between genetic variation and traits are often in noncoding regions with strong linkage disequilibrium (LD), where a single causal variant is assumed to underlie the association. We applied a massively parallel reporter assay (MPRA) to functionally evaluate genetic variants in high, local LD for independent cis-expression quantitative trait loci (eQTL). We found that 17.7% of eQTLs exhibit more than one major allelic effect in tight LD. The detected regulatory variants were highly and specifically enriched for activating chromatin structures and allelic transcription factor binding. Integration of MPRA profiles with eQTL/complex trait colocalizations across 114 human traits and diseases identified causal variant sets demonstrating how genetic association signals can manifest through multiple, tightly linked causal variants.
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Villanea, Fernando A., Emilia Huerta-Sanchez y Keolu Fox. "ABO Genetic Variation in Neanderthals and Denisovans". Molecular Biology and Evolution 38, n.º 8 (23 de abril de 2021): 3373–82. http://dx.doi.org/10.1093/molbev/msab109.
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Abstract Variation at the ABO locus was one of the earliest sources of data in the study of human population identity and history, and to this day remains widely genotyped due to its importance in blood and tissue transfusions. Here, we look at ABO blood type variants in our archaic relatives: Neanderthals and Denisovans. Our goal is to understand the genetic landscape of the ABO gene in archaic humans, and how it relates to modern human ABO variation. We found two Neanderthal variants of the O allele in the Siberian Neanderthals (O1 and O2), one of these variants is shared with an European Neanderthal, who is a heterozygote for this O1 variant and a rare cis-AB variant. The Denisovan individual is heterozygous for two variants of the O1 allele, functionally similar to variants found widely in modern humans. Perhaps more surprisingly, the O2 allele variant found in Siberian Neanderthals can be found at low frequencies in modern Europeans and Southeast Asians, and the O1 allele variant found in Siberian and European Neanderthal is also found at very low frequency in modern East Asians. Our genetic distance analyses suggest both alleles survive in modern humans due to inbreeding with Neanderthals. We find that the sequence backgrounds of the surviving Neanderthal-like O alleles in modern humans retain a higher sequence divergence than other surviving Neanderthal genome fragments, supporting a view of balancing selection operating in the Neanderthal ABO alleles by retaining highly diverse haplotypes compared with portions of the genome evolving neutrally.
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Dace, Phoebe y Gregory M. Findlay. "Reducing uncertainty in genetic testing with Saturation Genome Editing". Medizinische Genetik 34, n.º 4 (29 de noviembre de 2022): 297–304. http://dx.doi.org/10.1515/medgen-2022-2159.
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Abstract Accurate interpretation of human genetic data is critical for optimizing outcomes in the era of genomic medicine. Powerful methods for testing genetic variants for functional effects are allowing researchers to characterize thousands of variants across disease genes. Here, we review experimental tools enabling highly scalable assays of variants, focusing specifically on Saturation Genome Editing (SGE). We discuss examples of how this technique is being implemented for variant testing at scale and describe how SGE data for BRCA1 have been clinically validated and used to aid variant interpretation. The initial success at predicting variant pathogenicity with SGE has spurred efforts to expand this and related techniques to many more genes.
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Sun, Benjamin B., Mitja I. Kurki, Christopher N. Foley, Asma Mechakra, Chia-Yen Chen, Eric Marshall, Jemma B. Wilk et al. "Genetic associations of protein-coding variants in human disease". Nature 603, n.º 7899 (23 de febrero de 2022): 95–102. http://dx.doi.org/10.1038/s41586-022-04394-w.
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AbstractGenome-wide association studies (GWAS) have identified thousands of genetic variants linked to the risk of human disease. However, GWAS have so far remained largely underpowered in relation to identifying associations in the rare and low-frequency allelic spectrum and have lacked the resolution to trace causal mechanisms to underlying genes1. Here we combined whole-exome sequencing in 392,814 UK Biobank participants with imputed genotypes from 260,405 FinnGen participants (653,219 total individuals) to conduct association meta-analyses for 744 disease endpoints across the protein-coding allelic frequency spectrum, bridging the gap between common and rare variant studies. We identified 975 associations, with more than one-third being previously unreported. We demonstrate population-level relevance for mutations previously ascribed to causing single-gene disorders, map GWAS associations to likely causal genes, explain disease mechanisms, and systematically relate disease associations to levels of 117 biomarkers and clinical-stage drug targets. Combining sequencing and genotyping in two population biobanks enabled us to benefit from increased power to detect and explain disease associations, validate findings through replication and propose medical actionability for rare genetic variants. Our study provides a compendium of protein-coding variant associations for future insights into disease biology and drug discovery.
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Jew, Brandon y Jae Hoon Sul. "Variant calling and quality control of large-scale human genome sequencing data". Emerging Topics in Life Sciences 3, n.º 4 (29 de julio de 2019): 399–409. http://dx.doi.org/10.1042/etls20190007.
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Abstract Next-generation sequencing has allowed genetic studies to collect genome sequencing data from a large number of individuals. However, raw sequencing data are not usually interpretable due to fragmentation of the genome and technical biases; therefore, analysis of these data requires many computational approaches. First, for each sequenced individual, sequencing data are aligned and further processed to account for technical biases. Then, variant calling is performed to obtain information on the positions of genetic variants and their corresponding genotypes. Quality control (QC) is applied to identify individuals and genetic variants with sequencing errors. These procedures are necessary to generate accurate variant calls from sequencing data, and many computational approaches have been developed for these tasks. This review will focus on current widely used approaches for variant calling and QC.
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Ramaswamy, Sathishkumar, Ruchi Jain, Maha El Naofal, Nour Halabi, Sawsan Yaslam, Alan Taylor y Ahmad Abou Tayoun. "Middle Eastern Genetic Variation Improves Clinical Annotation of the Human Genome". Journal of Personalized Medicine 12, n.º 3 (9 de marzo de 2022): 423. http://dx.doi.org/10.3390/jpm12030423.
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Genetic variation in populations of Middle Eastern origin remains highly underrepresented in most comprehensive genomic databases. This underrepresentation hampers the functional annotation of the human genome and challenges accurate clinical variant interpretation. To highlight the importance of capturing genetic variation in the Middle East, we aggregated whole exome and genome sequencing data from 2116 individuals in the Middle East and established the Middle East Variation (MEV) database. Of the high-impact coding (missense and loss of function) variants in this database, 53% were absent from the most comprehensive Genome Aggregation Database (gnomAD), thus representing a unique Middle Eastern variation dataset which might directly impact clinical variant interpretation. We highlight 39 variants with minor allele frequency >1% in the MEV database that were previously reported as rare disease variants in ClinVar and the Human Gene Mutation Database (HGMD). Furthermore, the MEV database consisted of 281 putative homozygous loss of function (LoF) variants, or complete knockouts, of which 31.7% (89/281) were absent from gnomAD. This set represents either complete knockouts of 83 unique genes in reportedly healthy individuals, with implications regarding disease penetrance and expressivity, or might affect dispensable exons, thus refining the clinical annotation of those regions. Intriguingly, 24 of those genes have several clinically significant variants reported in ClinVar and/or HGMD. Our study shows that genetic variation in the Middle East improves functional annotation and clinical interpretation of the genome and emphasizes the need for expanding sequencing studies in the Middle East and other underrepresented populations.
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Ma’ruf, Muhammad, Justitia Cahyani Fadli, Muhammad Reza Mahendra, Lalu Muhammad Irham, Nanik Sulistyani, Wirawan Adikusuma, Rockie Chong y Abdi Wira Septama. "A bioinformatic approach to identify pathogenic variants for Stevens-Johnson syndrome". Genomics & Informatics 21, n.º 2 (30 de junio de 2023): e26. http://dx.doi.org/10.5808/gi.23010.
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Stevens-Johnson syndrome (SJS) produces a severe hypersensitivity reaction caused by Herpes simplex virus or mycoplasma infection, vaccination, systemic disease, or other agents. Several studies have investigated the genetic susceptibility involved in SJS. To provide further genetic insights into the pathogenesis of SJS, this study prioritized high-impact, SJS-associated pathogenic variants through integrating bioinformatic and population genetic data. First, we identified SJS-associated single nucleotide polymorphisms from the genome-wide association studies catalog, followed by genome annotation with HaploReg and variant validation with Ensembl. Subsequently, expression quantitative trait locus (eQTL) from GTEx identified human genetic variants with differential gene expression across human tissues. Our results indicate that two variants, namely rs2074494 and rs5010528, which are encoded by the HLA-C (human leukocyte antigen C) gene, were found to be differentially expressed in skin. The allele frequencies for rs2074494 and rs5010528 also appear to significantly differ across continents. We highlight the utility of these population-specific HLA-C genetic variants for genetic association studies, and aid in early prognosis and disease treatment of SJS.
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Smith, Benjamin M., Hussein Traboulsi, John H. M. Austin, Ani Manichaikul, Eric A. Hoffman, Eugene R. Bleecker, Wellington V. Cardoso et al. "Human airway branch variation and chronic obstructive pulmonary disease". Proceedings of the National Academy of Sciences 115, n.º 5 (16 de enero de 2018): E974—E981. http://dx.doi.org/10.1073/pnas.1715564115.
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Susceptibility to chronic obstructive pulmonary disease (COPD) beyond cigarette smoking is incompletely understood, although several genetic variants associated with COPD are known to regulate airway branch development. We demonstrate that in vivo central airway branch variants are present in 26.5% of the general population, are unchanged over 10 y, and exhibit strong familial aggregation. The most common airway branch variant is associated with COPD in two cohorts (n = 5,054), with greater central airway bifurcation density, and with emphysema throughout the lung. The second most common airway branch variant is associated with COPD among smokers, with narrower airway lumens in all lobes, and with genetic polymorphisms within the FGF10 gene. We conclude that central airway branch variation, readily detected by computed tomography, is a biomarker of widely altered lung structure with a genetic basis and represents a COPD susceptibility factor.
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Ray, Evan C., Jingxin Chen, Tanika N. Kelly, Jiang He, L. Lee Hamm, Dongfeng Gu, Lawrence C. Shimmin et al. "Human epithelial Na+ channel missense variants identified in the GenSalt study alter channel activity". American Journal of Physiology-Renal Physiology 311, n.º 5 (1 de noviembre de 2016): F908—F914. http://dx.doi.org/10.1152/ajprenal.00426.2016.
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Mutations in genes encoding subunits of the epithelial Na+ channel (ENaC) can cause early onset familial hypertension, demonstrating the importance of this channel in modulating blood pressure. It remains unclear whether other genetic variants resulting in subtler alterations of channel function result in hypertension or altered sensitivity of blood pressure to dietary salt. This study sought to identify functional human ENaC variants to examine how these variants alter channel activity and to explore whether these variants are associated with altered sensitivity of blood pressure to dietary salt. Six-hundred participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study with salt-sensitive or salt-resistant blood pressure underwent sequencing of the genes encoding ENaC subunits. Functional effects of identified variants were examined in a Xenopus oocyte expression system. Variants that increased channel activity included three in the gene encoding the α-subunit (αS115N, αR476W, and αV481M), one in the β-subunit (βS635N), and one in the γ-subunit (γL438Q). One α-subunit variant (αA334T) and one γ-subunit variant (βD31N) decreased channel activity. Several α-subunit extracellular domain variants altered channel inhibition by extracellular Na+ (Na+ self-inhibition). One variant (αA334T) decreased and one (αV481M) increased cell surface expression. Association between these variants and salt sensitivity did not reach statistical significance. This study identifies novel functional human ENaC variants and demonstrates that some variants alter channel cell surface expression and/or Na+ self-inhibition.
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Erdman, Andrew R., Lara M. Mangravite, Thomas J. Urban, Leah L. Lagpacan, Richard A. Castro, Melanie de la Cruz, Wendy Chan et al. "The human organic anion transporter 3 (OAT3; SLC22A8): genetic variation and functional genomics". American Journal of Physiology-Renal Physiology 290, n.º 4 (abril de 2006): F905—F912. http://dx.doi.org/10.1152/ajprenal.00272.2005.
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The human organic anion transporter, OAT3 ( SLC22A8), plays a critical role in renal drug elimination, by mediating the entry of a wide variety of organic anions, including a number of commonly used pharmaceuticals, into the renal proximal tubular cells. To understand the nature and extent of genetic variation in OAT3, and to determine whether such variation affects its function, we identified OAT3 variants in a large, ethnically diverse sample population and studied their transport activities in cellular assays. We identified a total of 10 distinct coding-region variants, which altered the encoded amino acid sequence, in DNA samples from 270 individuals (80 African-Americans, 80 European-Americans, 60 Asian-Americans, and 50 Mexican-Americans). The overall prevalence of these OAT3 variants was relatively low among the screened population, with only three variants having allele frequencies of >1% in a particular ethnic group. Clones of each variant were created by site-directed mutagenesis, expressed in HEK-293 cells, and tested for function using the model substrates, estrone sulfate (ES) and cimetidine (CIM). The results revealed a high degree of functional heterogeneity among OAT3 variants, with three variants (p. Arg149Ser, p. Gln239Stop, and p. Ile260Arg) that resulted in complete loss of function, and several others with significantly reduced function. One of the more common variants (p. Ile305Phe), found in 3.5% of Asian-Americans, appeared to have altered substrate specificity. This variant exhibited a reduced ability to transport ES, but a preserved ability to transport CIM. These data suggest that genetic variation in OAT3 may contribute to variation in the disposition of drugs.
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Domené, Sabina, Paula A. Scaglia, Mariana L. Gutiérrez y Horacio M. Domené. "Applying Bioinformatic Platforms, In Vitro, and In Vivo Functional Assays in the Characterization of Genetic Variants in the GH/IGF Pathway Affecting Growth and Development". Cells 10, n.º 8 (12 de agosto de 2021): 2063. http://dx.doi.org/10.3390/cells10082063.
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Heritability accounts for over 80% of adult human height, indicating that genetic variability is the main determinant of stature. The rapid technological development of Next-Generation Sequencing (NGS), particularly Whole Exome Sequencing (WES), has resulted in the characterization of several genetic conditions affecting growth and development. The greatest challenge of NGS remains the high number of candidate variants identified. In silico bioinformatic tools represent the first approach for classifying these variants. However, solving the complicated problem of variant interpretation requires the use of experimental approaches such as in vitro and, when needed, in vivo functional assays. In this review, we will discuss a rational approach to apply to the gene variants identified in children with growth and developmental defects including: (i) bioinformatic tools; (ii) in silico modeling tools; (iii) in vitro functional assays; and (iv) the development of in vivo models. While bioinformatic tools are useful for a preliminary selection of potentially pathogenic variants, in vitro—and sometimes also in vivo—functional assays are further required to unequivocally determine the pathogenicity of a novel genetic variant. This long, time-consuming, and expensive process is the only scientifically proven method to determine causality between a genetic variant and a human genetic disease.
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Solano, A. R., M. Garrido, P. G. Mele, E. J. Podestá y J. K. V. Reichardt. "THE HUMAN VARIOME PROJECT COUNTRY NODE OF ARGENTINA IN THE FIRST TWO YEARS OF ACTIVITY: PAST, PRESENT AND FUTURE". Journal of Basic and Applied Genetics 30, n.º 2 (28 de diciembre de 2019): 41–46. http://dx.doi.org/10.35407/bag.2019.xxx.02.04.
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The Human Variome Project (HVP) is an international effort aiming systematically to collect and share information on all human genetic variants. It has been working for years in collaboration with local scientific societies by establishing systems to collect every genetic variant reported in a country and to store these variants within a database repository: LOVD (Argentinian chapter: ar.lovd.org). Formally established in 2017 in the Argentinian Node, up to June 2019 we collected more than 25,000 genetic variants deposited by 17 different laboratories. Nowadays the HVP country nodes represent more than 30 countries. In Latin America there are four country nodes: Argentina, Brazil, Mexico and Venezuela; the first two interacted recently launching the LatinGen database. In the present work we want to share our experience in applying the HVP project focusing on its organization, rules and nomenclature to reach the goal of sharing genetic variants and depositing them in the Leiden Open Variation Database. Contributing laboratories are seeking to share variant data to gain access all over the country. It is one of our goals to stimulate the highest quality by organizing courses, applying current nomenclature rules, sponsoring lectures in national congresses, distributing newsletter to serve the Argentinian genomics community and to stimulate the interaction among Latin America countries. Key words: Data sharing, Argentinian chapter of LOVD, Human Variome Project (HVP)-Argentina
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Shima, James E., Takafumi Komori, Travis R. Taylor, Doug Stryke, Michiko Kawamoto, Susan J. Johns, Elaine J. Carlson, Thomas E. Ferrin y Kathleen M. Giacomini. "Genetic variants of human organic anion transporter 4 demonstrate altered transport of endogenous substrates". American Journal of Physiology-Renal Physiology 299, n.º 4 (octubre de 2010): F767—F775. http://dx.doi.org/10.1152/ajprenal.00312.2010.
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Apical reabsorption from the urine has been shown to be important for such processes as the maintenance of critical metabolites in the blood and the excretion of nephrotoxic compounds. The solute carrier (SLC) transporter OAT4 ( SLC22A11) is expressed on the apical membrane of renal proximal tubule cells and is known to mediate the transport of a variety of xenobiotic and endogenous organic anions. Functional characterization of genetic variants of apical transporters thought to mediate reabsorption, such as OAT4, may provide insight into the genetic factors influencing the complex pathways involved in drug elimination and metabolite reclamation occurring in the kidney. Naturally occurring genetic variants of OAT4 were identified in public databases and by resequencing DNA samples from 272 individuals comprising 4 distinct ethnic groups. Nine total nonsynonymous variants were identified and functionally assessed using uptake of three radiolabeled substrates. A nonsense variant, R48Stop, and three other variants (R121C, V155G, and V155M) were found at frequencies of at least 2% in an ethnic group specific fashion. The L29P, R48Stop, and H469R variants displayed a complete loss of function, and kinetic analysis identified a reduced Vmax in the common nonsynonymous variants. Plasma membrane levels of OAT4 protein were absent or reduced in the nonfunctional variants, providing a mechanistic reason for the observed loss of function. Characterization of the genetic variants of reabsorptive transporters such as OAT4 is an important step in understanding variability in tubular reabsorption with important implications in innate homeostatic processes and drug disposition.
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Le, Vinh. "A computational framework to analyze human genomes". Journal of Computer Science and Cybernetics 35, n.º 2 (3 de junio de 2019): 105–18. http://dx.doi.org/10.15625/1813-9663/35/2/13827.
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The advent of genomic technologies has led to the current genomic era. Large-scale human genome projects have resulted in a huge amount of genomic data. Analyzing human genomes is a challenging task including a number of key steps from short read alignment, variant calling, and variant annotating. In this paper, the state-of-the-art computational methods and databases for each step will be analyzed to suggest a practical and efficient guideline for whole human genome analyses. This paper also discusses frameworks to combine variants from various genome analysis pipelines to obtain reliable variants. Finally, we will address advantages as well as discordances of widely-used variant annotation methods to evaluate the clinical significance of variants. The review will empower bioinformaticians to efficiently perform human genome analyses, and more importantly, help genetic consultants understand and properly interpret mutations for clinical purposes.
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Alex O. Sierra-Rosales, Katya I. Rosales-Rosales, Jesús F. Salas-Montes, Oziel A. Vidales-Simental y Brissia Lazalde. "Genetic variants and influence in cognitive diseases". GSC Advanced Research and Reviews 21, n.º 3 (30 de diciembre de 2024): 062–68. https://doi.org/10.30574/gscarr.2024.21.3.0456.
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The relationship between genetic variation and cognitive ability has become a central focus in modern genetics and neuroscience. Cognitive functions are complex traits influenced by both genetic and environmental factors. Over the past decades, advances in genomic technologies, such as genome-wide association studies (GWAS), have revealed a multitude of genetic variants associated with cognitive performance. One of the most studied types of genetic variation are single nucleotide polymorphisms (SNPs), which represent the most common form of variation in the human genome. Evidence indicates that copy number variations (CNVs) play an important role along with the SNPs.
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Valentini, Samuel, Francesco Gandolfi, Mattia Carolo, Davide Dalfovo, Lara Pozza y Alessandro Romanel. "Polympact: exploring functional relations among common human genetic variants". Nucleic Acids Research 50, n.º 3 (21 de enero de 2022): 1335–50. http://dx.doi.org/10.1093/nar/gkac024.
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Abstract In the last years, many studies were able to identify associations between common genetic variants and complex diseases. However, the mechanistic biological links explaining these associations are still mostly unknown. Common variants are usually associated with a relatively small effect size, suggesting that interactions among multiple variants might be a major genetic component of complex diseases. Hence, elucidating the presence of functional relations among variants may be fundamental to identify putative variants’ interactions. To this aim, we developed Polympact, a web-based resource that allows to explore functional relations among human common variants by exploiting variants’ functional element landscape, their impact on transcription factor binding motifs, and their effect on transcript levels of protein-coding genes. Polympact characterizes over 18 million common variants and allows to explore putative relations by combining clustering analysis and innovative similarity and interaction network models. The properties of the network models were studied and the utility of Polympact was demonstrated by analysing the rich sets of Breast Cancer and Alzheimer's GWAS variants. We identified relations among multiple variants, suggesting putative interactions. Polympact is freely available at bcglab.cibio.unitn.it/polympact.
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Pir, Mustafa S., Halil I. Bilgin, Ahmet Sayici, Fatih Coşkun, Furkan M. Torun, Pei Zhao, Yahong Kang, Sebiha Cevik y Oktay I. Kaplan. "ConVarT: a search engine for matching human genetic variants with variants from non-human species". Nucleic Acids Research 50, n.º D1 (28 de octubre de 2021): D1172—D1178. http://dx.doi.org/10.1093/nar/gkab939.
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Abstract The availability of genetic variants, together with phenotypic annotations from model organisms, facilitates comparing these variants with equivalent variants in humans. However, existing databases and search tools do not make it easy to scan for equivalent variants, namely ‘matching variants’ (MatchVars) between humans and other organisms. Therefore, we developed an integrated search engine called ConVarT (http://www.convart.org/) for matching variants between humans, mice, and Caenorhabditis elegans. ConVarT incorporates annotations (including phenotypic and pathogenic) into variants, and these previously unexploited phenotypic MatchVars from mice and C. elegans can give clues about the functional consequence of human genetic variants. Our analysis shows that many phenotypic variants in different genes from mice and C. elegans, so far, have no counterparts in humans, and thus, can be useful resources when evaluating a relationship between a new human mutation and a disease.
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Toncheva, Draga, Sena Karachanak-Yankova, Maria Marinova, Plamenka Borovska y Dimitar Serbezov. "Susceptibility to Neurodegenerative Disorders: Insights from Paleogenomic Data". Human Biology 93, n.º 4 (septiembre de 2021): 289–97. http://dx.doi.org/10.1353/hub.2021.a917652.
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abstract: Ancient human genome data accumulated in recent years can be employed to establish the spatiotemporal trajectories of genetic variants associated with human diseases. Such knowledge might illuminate if and how past adaptations impact contemporary human health and medicine. Scarcely any studies have yet attempted to evaluate genetic susceptibility to neurodegenerative disorders in ancient human communities. Using publicly available ancient human genome-wide data, this study evaluated the molecular predisposition to neurodegenerative disorders in ancient human communities. Ancient genome-wide data was screened for the presence of variants unequivocally associated with neuro-degenerative disorders in modern populations, identifying two rare variants in the LRRK2 gene associated with Mendelian Parkinson’s disease, a pathogenic variant in the CRH gene associated with an uncommon form of epilepsy, and a rare variant in the TREM2 gene that is a possible risk modifier associated with Alzheimer’s disease. Their historical and geographic prevalence was also assessed, indicating differing spatiotemporal frequency dynamics for these clinically significant variants. Neurodegenerative disorders often have poorly understood pathogenesis that might be elucidated by studying the interaction of past genetic variability with ecological and evolutionary factors such as adverse environmental conditions, specific selective pressures, periods of population isolation, and admixture processes. Data on molecular predisposition to neurodegenerative disorders in ancient genomes is instructive to modern medical diagnostic and therapeutic practices.
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Burke, Megan F., Michael Morley, Yifan Yang, Theodore Drivas, Mingyao Li, Mingyao Ritchie y Thomas Cappola. "93137 Interrogating cardio-protective MTSS1 variants in human populations". Journal of Clinical and Translational Science 5, s1 (marzo de 2021): 124–25. http://dx.doi.org/10.1017/cts.2021.718.
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ABSTRACT IMPACT: It is our hope that a better understanding of the relationship between genetic variants that influence heart failure precursor traits will not only inform clinical care, but enable better assessment of inherited risk and will identify new biological targets for drug development. OBJECTIVES/GOALS: In this project, using a large-scale human genomic dataset with extensive phenotype data available, we intend to interrogate the known MTSS1 variants that have been associated with heart failure (HF) in previous GWAS studies in order to understand the directionality and mechanisms of their effects. METHODS/STUDY POPULATION: Data was obtained from the UK Biobank, a large prospective cohort of ˜500,000 patients across the United Kingdom with extensive phenotype data, including ˜50,000 patients with cardiac MRI and ˜200,000 with whole exome sequencing. We test for associations between genetic variants at the MTSS1 locus and HF precursor traits using logistic regression or linear regression, adjusting for age, gender, and principal components (PCs) of ancestry. For rare variant analyses we ‘bin’ rare variants (MAF < 0.01) using the software tool BioBin to aggregate low frequency genetic variants into single genetic units. RESULTS/ANTICIPATED RESULTS: Preliminary data have shown that variants in the known MTSS1 enhancer region which reduce MTSS1 expression are associated with smaller, more contractile hearts. We anticipate that common variants known to reduce enhancer activity will attenuate heart failure precursor traits, will be associated with a reduced risk clinical heart failure, and will favorably impact clinical outcomes once HF is established. We also anticipate that rare exonic variants predicted to impair MTSS1 function will attenuate heart failure precursor traits. DISCUSSION/SIGNIFICANCE OF FINDINGS: Through this work, we intend to take advantage of multiple novel approaches to better understand a complex disease process, identify a new potential therapeutic target (namely one that targets cardiac function), and to determine which patient subgroups will benefit from this our therapeutic interventions and why.
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Spedicati, Beatrice, Massimiliano Cocca, Roberto Palmisano, Flavio Faletra, Caterina Barbieri, Margherita Francescatto, Massimo Mezzavilla et al. "Natural human knockouts and Mendelian disorders: deep phenotyping in Italian isolates". European Journal of Human Genetics 29, n.º 8 (16 de marzo de 2021): 1272–81. http://dx.doi.org/10.1038/s41431-021-00850-9.
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AbstractWhole genome sequencing (WGS) allows the identification of human knockouts (HKOs), individuals in whom loss of function (LoF) variants disrupt both alleles of a given gene. HKOs are a valuable model for understanding the consequences of genes function loss. Naturally occurring biallelic LoF variants tend to be significantly enriched in “genetic isolates,” making these populations specifically suited for HKO studies. In this work, a meticulous WGS data analysis combined with an in-depth phenotypic assessment of 947 individuals from three Italian genetic isolates led to the identification of ten biallelic LoF variants in ten OMIM genes associated with known autosomal recessive diseases. Notably, only a minority of the identified HKOs (C7, F12, and GPR68 genes) displayed the expected phenotype. For most of the genes, instead, (ACADSB, FANCL, GRK1, LGI4, MPO, PGAM2, and RP1L1), the carriers showed none or few of the signs and symptoms typically associated with the related diseases. Of particular interest is a case presenting with a FANCL biallelic LoF variant and a positive diepoxybutane test but lacking a full Fanconi anemia phenotypic spectrum. Identifying KO subjects displaying expected phenotypes suggests that the lack of correct genetic diagnoses may lead to inappropriate and delayed treatment. In contrast, the presence of HKOs with phenotypes deviating from the expected patterns underlines how LoF variants may be responsible for broader phenotypic spectra. Overall, these results highlight the importance of in-depth phenotypical characterization to understand the role of LoF variants and the advantage of studying these variants in genetic isolates.
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Vabret, Astrid, Julia Dina, Thomas Mourez, Stéphanie Gouarin, Joëlle Petitjean, Sylvie van der Werf y François Freymuth. "Inter- and intra-variant genetic heterogeneity of human coronavirus OC43 strains in France". Journal of General Virology 87, n.º 11 (1 de noviembre de 2006): 3349–53. http://dx.doi.org/10.1099/vir.0.82065-0.
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Human coronavirus OC43 (HCoV-OC43) causes acute, self-limited respiratory infections. A close relationship between bovine coronaviruses (BCoVs) and HCoV-OC43 has recently been demonstrated. This study includes seven clinical, non-cell culture-adapted, contemporary HCoV-OC43 strains detected in France in 2003. By using RT-PCR and clonal sequencing of the S1 gene of HCoV-OC43, the inter-variant heterogeneity of the HCoV-OC43 circulating strains was studied and the intra-variant diversity was assessed by investigation of a quasispecies cloud. This paper brings to the forefront a high genetic diversity of circulating HCoV-OC43 variants. Genetically different groups are defined among the variants described in this study. One of these variants holds characteristics of an outlier and presents a deletion of 12 nt, also found in BCoV strains. Moreover, the presence of HCoV-OC43 as a quasispecies cloud in vivo during an acute respiratory-tract illness was discovered. It has also been revealed that quasispecies-cloud sizes are similar for the two viral populations tested.
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Jassim, Tabarak Sabah y Rusul Waleed Ali. "Review Article: Genetic Polymorphism Studies and Insurgence of Human Genetic Diseases". Journal for Research in Applied Sciences and Biotechnology 1, n.º 5 (2 de enero de 2023): 161–78. http://dx.doi.org/10.55544/jrasb.1.5.17.
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Single nucleotides polymorphism is the biological variant that affects people the most frequently (SNPs). Due of the link to hereditary illnesses, Polymorphisms are significant for hereditary investigations. Throughout this article, researchers examined a specific subset of SNPs that alter the sequencing of the related enzyme. Researchers created a brand-new technique that, beginning with sequencing data, can determine if a novel phenotypic resulting from an SNP is connected to a genetic abnormality. The greatest prevalent sort of genomic variability throughout the human genome is represented by solitary nucleotides polymorphism (SNPs). Understanding whether human genetic variants are associated with Chromosomal and complicated disorders is probably among a more essential objectives of SNP research. Non coding SNPs (NSSNPs), which cause solitary point mutations in molecules, are the subject of intense attention.
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Mombo, Landry Erik, Cyrille Bisseye, Patrick Mickala, Simon Ossari y Maria Makuwa. "Genotyping of CCR5 Gene, CCR2b and SDF1 Variants Related to HIV-1 Infection in Gabonese Subjects". Intervirology 58, n.º 1 (2015): 22–26. http://dx.doi.org/10.1159/000369016.
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Objective: Given the magnitude of the HIV epidemic infection, many viral and human factors were analyzed, and the most decisive was the variant CCR5-Δ32. The presence of a low HIV prevalence (1.8%) in Gabon in the 1990s, compared to neighboring countries, represents a paradox that led us to search for viral and human genetic variants in this country. In this study, only variants of coreceptors and chemokines were investigated. Methods: Variants of the coding region of the CCR5 gene were analyzed by denaturing gradient gel electrophoresis, and then variants of SDF1 and CCR2b were determined by polymerase chain reaction-restriction fragment length polymorphism. Results: Four rare variants of the CCR5 coreceptor were found, while CCR5-Δ32 and CCR5m303 variants were not found. No association with CCR2b-V64I (17%) and SDF1-3′A (2%) variants was determined in relation to HIV-1 infection in Gabonese patients. Conclusion: The paradox of HIV seroprevalence in Gabon, which ended in the 2000s, was not caused by human genetic variants but rather by environmental factors.
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Rada-Iglesias, Alvaro. "Genetic variation within transcriptional regulatory elements and its implications for human disease". Biological Chemistry 395, n.º 12 (1 de diciembre de 2014): 1453–60. http://dx.doi.org/10.1515/hsz-2014-0109.
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Abstract Common human pathologies have a complicated etiology involving both genetic and environmental risk factors. Moreover, the genetic basis of these disorders is also complex, with multiple and weak genetic variants contributing to disease susceptibility. In addition, most of these risk genetic variants occur outside genes, within the vast non-coding human genomic space. In this review I first illustrate how large-scale genomic studies aimed at mapping cis-regulatory elements in the human genome are facilitating the identification of disease-causative non-coding genetic variation. I then discuss some of the challenges that remain to be solved before the pathological consequences of non-coding genetic variation can be fully appreciated. Ultimately, revealing the genetics of human complex disease can be a critical step towards more personalized and effective diagnosis and treatments.
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Chatterjee, Prabrisha y Sanat Chatterjee. "SIGNIFICANCE OF GENETIC CASEIN POLYMORPHISM IN ANIMAL HUSBANDRY". International Journal of Engineering Applied Sciences and Technology 8, n.º 4 (1 de agosto de 2023): 177–82. http://dx.doi.org/10.33564/ijeast.2023.v08i04.024.
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: Milk proteins are a rich source of peptides which are bioactive. Beta-casomorphin-7 ( BCM-7) is produced by successive proteolytic ingestion of beta- casein variants A1 and B, while not observed in A2 variant. The large amount of proteins in bovine’s milk are caseins, which consist of four categories ( αs1, αs2, β, and κ) encrypted by corresponding genes ( CSN1S1, CSN1S2, CSN2, and CSN3, respectively). Ingestion of A1 beta-casein showed the way for the emergence of beta-casomorphin-7 (BCM-7), a peptide that has been proposed to be a major cause of various human hazards.The relative profuseness of proline, methionine, and α-lactose were the highest in A2 variant of β-casein, while glycine, citric acid, choline, and cAMP (cyclic Adenosine Monophosphate) exhibited the highest abundance in A1 variant. These results thus come up with novel insights into the effect of casein variants, further expediting research into the biogenesis of milk ingredients and the prospective physiological activity of milk correlated with variants of β-casein.
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Adamson, Kathryn Isabel, Eamonn Sheridan y Andrew James Grierson. "Use of zebrafish models to investigate rare human disease". Journal of Medical Genetics 55, n.º 10 (31 de julio de 2018): 641–49. http://dx.doi.org/10.1136/jmedgenet-2018-105358.
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Rare diseases are collectively common and often extremely debilitating. Following the emergence of next-generation sequencing (NGS) technologies, the variants underpinning rare genetic disorders are being unearthed at an accelerating rate. However, many rare conditions lack effective treatments due to their poorly understood pathophysiology. There is therefore a growing demand for the development of novel experimental models of rare genetic diseases, so that potentially causative variants can be validated, pathogenic mechanisms can be investigated and therapeutic targets can be identified. Animal models of rare diseases need to be genetically and physiologically similar to humans, and well-suited to large-scale experimental manipulation, considering the vast number of novel variants that are being identified through NGS. The zebrafish has emerged as a popular model system for investigating these variants, combining conserved vertebrate characteristics with a capacity for large-scale phenotypic and therapeutic screening. In this review, we aim to highlight the unique advantages of the zebrafish over other in vivo model systems for the large-scale study of rare genetic variants. We will also consider the generation of zebrafish disease models from a practical standpoint, by discussing how genome editing technologies, particularly the recently developed clustered regularly interspaced repeat (CRISPR)/CRISPR-associated protein 9 system, can be used to model rare pathogenic variants in zebrafish. Finally, we will review examples in the literature where zebrafish models have played a pivotal role in confirming variant causality and revealing the underlying mechanisms of rare diseases, often with wider implications for our understanding of human biology.
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Shin, Sunyoung, Rebecca Hudson, Christopher Harrison, Mark Craven y Sündüz Keleş. "atSNP Search: a web resource for statistically evaluating influence of human genetic variation on transcription factor binding". Bioinformatics 35, n.º 15 (10 de diciembre de 2018): 2657–59. http://dx.doi.org/10.1093/bioinformatics/bty1010.
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AbstractSummaryUnderstanding the regulatory roles of non-coding genetic variants has become a central goal for interpreting results of genome-wide association studies. The regulatory significance of the variants may be interrogated by assessing their influence on transcription factor binding. We have developed atSNP Search, a comprehensive web database for evaluating motif matches to the human genome with both reference and variant alleles and assessing the overall significance of the variant alterations on the motif matches. Convenient search features, comprehensive search outputs and a useful help menu are key components of atSNP Search. atSNP Search enables convenient interpretation of regulatory variants by statistical significance testing and composite logo plots, which are graphical representations of motif matches with the reference and variant alleles. Existing motif-based regulatory variant discovery tools only consider a limited pool of variants due to storage or other limitations. In contrast, atSNP Search users can test more than 37 billion variant-motif pairs with marginal significance in motif matches or match alteration. Computational evidence from atSNP Search, when combined with experimental validation, may help with the discovery of underlying disease mechanisms.Availability and implementationatSNP Search is freely available at http://atsnp.biostat.wisc.edu.Supplementary informationSupplementary data are available at Bioinformatics online.
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Chen, Che-Hong, Benjamin R. Kraemer, Lucia Lee y Daria Mochly-Rosen. "Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)". Biomolecules 11, n.º 10 (29 de septiembre de 2021): 1423. http://dx.doi.org/10.3390/biom11101423.
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Human aldehyde dehydrogenase (ALDH) is a multigene family with 19 functional members encoding a class of diverse but important enzymes for detoxification or biotransformation of different endogenous and exogenous aldehyde substrates. Genetic mutations in the ALDH genes can cause the accumulation of toxic aldehydes and abnormal carbonyl metabolism and serious human pathologies. However, the physiological functions and substrate specificity of many ALDH genes are still unknown. Although many genetic variants of the ALDH gene family exist in human populations, their phenotype or clinical consequences have not been determined. Using the most comprehensive global human Genome Aggregation Database, gnomAD, we annotated here 1350 common variants in the 19 ALDH genes. These 1350 common variants represent all known genetic polymorphisms with a variant allele frequency of ≥0.1% (or an expected occurrence of ≥1 carrier per 500 individuals) in any of the seven major ethnic groups recorded by gnomAD. We detailed 13 types of DNA sequence variants, their genomic positions, SNP ID numbers, and allele frequencies among the seven major ethnic groups worldwide for each of the 19 ALDH genes. For the 313 missense variants identified in the gnomAD, we used two software algorithms, Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant From Tolerant (SIFT), to predict the consequences of the variants on the structure and function of the enzyme. Finally, gene constraint analysis was used to predict how well genetic mutations were tolerated by selection forces for each of the ALDH genes in humans. Based on the ratio of observed and expected variant numbers in gnomAD, the three ALDH1A gene members, ALDH1A1, ALDH1A2, and ALDH1A3, appeared to have the lowest tolerance for loss-of-function mutations as compared to the other ALDH genes (# observed/# expected ratio 0.15–0.26). These analyses suggest that the ALDH1A1, ALDH1A2, and ALDH1A3 enzymes may serve a more essential function as compared with the other ALDH enzymes; functional loss mutations are much less common in healthy human populations than expected. This informatic analysis may assist the research community in determining the physiological function of ALDH isozymes and associate common variants with clinical phenotypes.
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Ferraro, Nicole M., Benjamin J. Strober, Jonah Einson, Nathan S. Abell, Francois Aguet, Alvaro N. Barbeira, Margot Brandt et al. "Transcriptomic signatures across human tissues identify functional rare genetic variation". Science 369, n.º 6509 (10 de septiembre de 2020): eaaz5900. http://dx.doi.org/10.1126/science.aaz5900.
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Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs. We developed Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function, validated these predictions in additional cohorts and through experimental assays, and used them to assess RVs in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. Our results link thousands of RVs to diverse molecular effects and provide evidence to associate RVs affecting the transcriptome with human traits.
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Pan, Qi, Yue-Juan Liu, Xue-Feng Bai, Xiao-Le Han, Yong Jiang, Bo Ai, Shan-Shan Shi et al. "VARAdb: a comprehensive variation annotation database for human". Nucleic Acids Research 49, n.º D1 (23 de octubre de 2020): D1431—D1444. http://dx.doi.org/10.1093/nar/gkaa922.
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Abstract With the study of human diseases and biological processes increasing, a large number of non-coding variants have been identified and facilitated. The rapid accumulation of genetic and epigenomic information has resulted in an urgent need to collect and process data to explore the regulation of non-coding variants. Here, we developed a comprehensive variation annotation database for human (VARAdb, http://www.licpathway.net/VARAdb/), which specifically considers non-coding variants. VARAdb provides annotation information for 577,283,813 variations and novel variants, prioritizes variations based on scores using nine annotation categories, and supports pathway downstream analysis. Importantly, VARAdb integrates a large amount of genetic and epigenomic data into five annotation sections, which include ‘Variation information’, ‘Regulatory information’, ‘Related genes’, ‘Chromatin accessibility’ and ‘Chromatin interaction’. The detailed annotation information consists of motif changes, risk SNPs, LD SNPs, eQTLs, clinical variant-drug-gene pairs, sequence conservation, somatic mutations, enhancers, super enhancers, promoters, transcription factors, chromatin states, histone modifications, chromatin accessibility regions and chromatin interactions. This database is a user-friendly interface to query, browse and visualize variations and related annotation information. VARAdb is a useful resource for selecting potential functional variations and interpreting their effects on human diseases and biological processes.
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Luo, Jiaqi, Tianliangwen Zhou, Xiaobin You, Yi Zi, Xiaoting Li, Yangming Wu, Zhaoji Lan et al. "Assessing concordance among human, in silico predictions and functional assays on genetic variant classification". Bioinformatics 35, n.º 24 (29 de mayo de 2019): 5163–70. http://dx.doi.org/10.1093/bioinformatics/btz442.
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Abstract Motivation A variety of in silico tools have been developed and frequently used to aid high-throughput rapid variant classification, but their performances vary, and their ability to classify variants of uncertain significance were not systemically assessed previously due to lack of validation data. This has been changed recently by advances of functional assays, where functional impact of genetic changes can be measured in single-nucleotide resolution using saturation genome editing (SGE) assay. Results We demonstrated the neural network model AIVAR (Artificial Intelligent VARiant classifier) was highly comparable to human experts on multiple verified datasets. Although highly accurate on known variants, AIVAR together with CADD and PhyloP showed non-significant concordance with SGE function scores. Moreover, our results indicated that neural network model trained from functional assay data may not produce accurate prediction on known variants. Availability and implementation All source code of AIVAR is deposited and freely available at https://github.com/TopGene/AIvar. Supplementary information Supplementary data are available at Bioinformatics online.
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Liu, Chaochun, William A. Rennie, C. Steven Carmack, Shaveta Kanoria, Jijun Cheng, Jun Lu y Ye Ding. "Effects of genetic variations on microRNA: target interactions". Nucleic Acids Research 42, n.º 15 (31 de julio de 2014): 9543–52. http://dx.doi.org/10.1093/nar/gku675.
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Abstract Genetic variations within microRNA (miRNA) binding sites can affect miRNA-mediated gene regulation, which may lead to phenotypes and diseases. We perform a transcriptome-scale analysis of genetic variants and miRNA:target interactions identified by CLASH. This analysis reveals that rare variants tend to reside in CDSs, whereas common variants tend to reside in the 3′ UTRs. miRNA binding sites are more likely to reside within those targets in the transcriptome with lower variant densities, especially target regions in which nucleotides have low mutation frequencies. Furthermore, an overwhelming majority of genetic variants within or near miRNA binding sites can alter not only the potential of miRNA:target hybridization but also the structural accessibility of the binding sites and flanking regions. These suggest an interpretation for certain associations between genetic variants and diseases, i.e. modulation of miRNA-mediated gene regulation by common or rare variants within or near miRNA binding sites, likely through target structure alterations. Our data will be valuable for discovering new associations among miRNAs, genetic variations and human diseases.
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Boonin, Patcharin, Sommon Klumsathian, Nareenart Iemwimangsa, Insee Sensorn, Angkana Charoenyingwatana, Wasun Chantratita y Takol Chareonsirisuthigul. "Detection of Genetic Variants in Thai Population by Trio-Based Whole-Genome Sequencing Study". Biology 14, n.º 3 (17 de marzo de 2025): 301. https://doi.org/10.3390/biology14030301.
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This trio-based whole-genome sequencing (WGS) study enhances the accuracy of variant detection by leveraging parental genotypes, which facilitates the identification of de novo mutations and population-specific variants. Nonetheless, the comprehensive genetic variation data of the Thai population remain limited, posing challenges to advancing personalized medicine and population-based screening strategies. We establish the genetic variation information of a healthy Thai population by analyzing the sequences of 40 trios, yielding 120 whole genomes (excluding offspring). The resulting dataset encompasses 20.2 million variants, including 1.1 million novel and 19.1 million known variants. Within this dataset, we identify 169 pathogenic variants, of which 56 are classified as rare and 87 are absent from the ClinVar database as of version 2023. These pathogenic variants, particularly the rare and de novo mutations, will likely be of significant interest for genetic association studies. Notably, one pathogenic variant linked to a de novo mutation is found in the SF3B2 gene, which is associated with craniofacial microsomia. With its innovative methodology and comprehensive dataset, our trio-based whole-genome sequencing study provides an invaluable representation of the genetic variations in the Thai population. These data provide a critical foundation for further analyses of the pathogenic variants related to human disease phenotypes in genetic association studies.
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Zhang, Dan-Dan, Xiao-Yu He, Liu Yang, Bang-Sheng Wu, Yan Fu, Wei-Shi Liu, Yu Guo et al. "Exome sequencing identifies novel genetic variants associated with varicose veins". PLOS Genetics 20, n.º 7 (9 de julio de 2024): e1011339. http://dx.doi.org/10.1371/journal.pgen.1011339.
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Background Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood. Methods We conducted an exome-wide association study of VV using whole-exome sequencing data from the UK Biobank, and focused on common and rare variants using single-variant association analysis and gene-level collapsing analysis. Findings A total of 13,823,269 autosomal genetic variants were obtained after quality control. We identified 36 VV-related independent common variants mapping to 34 genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations between genes and VV were replicated in FinnGen. PIEZO1 was the closest gene associated with VV (P = 5.05 × 10−31), and it was found to reach exome-wide significance in both single-variant and collapsing analyses. Two novel rare variant genes (ECE1 and METTL21A) associated with VV were identified, of which METTL21A was associated only with females. The pleiotropic effects of VV-related genes suggested that body size, inflammation, and pulmonary function are strongly associated with the development of VV. Conclusions Our findings highlight the importance of causal genes for VV and provide new directions for treatment.
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Virgili, Fabio. "Genetic variants as modulators of human (patho) physiology". Free Radical Biology and Medicine 177 (diciembre de 2021): S53. http://dx.doi.org/10.1016/j.freeradbiomed.2021.08.029.
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