Diabetes, a chronic condition characterized by an inability to maintain normal glucose levels significantly accounts for enhancing the cost of healthcare expenditure. Managing diabetes using a ...standard medication protocol more often leads to progressive failure in effectively treating the associated complications. The recent trends involve understanding of diabetes's genetic architecture and its consequences have provided the background for application of precision medicine for customizing protocols for preventing and managing the diabetes therapy. Further, utilizing the electronic health data and genetic information for assisting care and planning therapeutic protocol for monogenic form of diabetes is well-executed example of genomic medicine. The present write-up emphasized recent advances about the causes and effects of diabetes genetics. This also drive to the need for the further investigation for ensuring the appropriate knowledge to enable patients and healthcare providers to make informed decisions for obtaining the best possible outcome.
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Kaspar Hauser’s parentage has been the subject of research and debate for nearly 200 years. As for his possible aristocratic descent through the House of Baden, there is suspicion that he was swapped ...as a baby, kidnapped, and kept in isolation to bring a collateral lineage to the throne. In the last 28 years, various genetic analyses have been carried out to investigate this possible aristocratic origin. Previous results using less sensitive Sanger and electrophoresis-based methods were contradictory, and moreover, the authenticity of some samples was disputed, thus leaving the question open. Our analyses using modern capture- and whole genome-based massively parallel sequencing techniques reveal that the mitochondrial DNA haplotypes in different samples attributed to Kaspar Hauser were identical, demonstrating authenticity for the first time, and clearly different from the mitochondrial lineage of the House of Baden, which rules out a maternal relationship and thus the widely believed “Prince theory”.
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•Independent genetic mtDNA analyses in three laboratories gave identical results•Hair and blood samples attributed to Kaspar Hauser yielded the same mtDNA•Kaspar Hauser’s mtDNA is unambiguously different from the “Baden lineage”
Techniques in genetics; Molecular genetics; History
Abdominal and thoracic aortic aneurysms (AAAs, TAAs) remain a major cause of deaths worldwide, in part due to the lack of reliable prognostic markers or early warning signs. Sox6 has been found to ...regulate renin controlling blood pressure. We hypothesized that Sox6 may serve as an important regulator of the mechanisms contributing to hypertension-induced aortic aneurysms. Phenotype and laboratory-wide association scans in a clinical cohort found that SOX6 gene expression is associated with aortic aneurysm in subjects of European ancestry. Sox6 and tumor necrosis factor alpha (TNF-α) expression were upregulated in aortic tissues from patients affected by either AAA or TAA. In Sox6 knockout mice with angiotensin-II-induced AAA, we found that Sox6 plays critical role in the development and progression of AAA. Our data support a regulatory role of SOX6 in the development of hypertension-induced AAA, suggesting that Sox6 may be a therapeutic target for the treatment of aortic aneurysms.
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•Transcription factor SOX6 is associated with abdominal and thoracic aortic aneurysm•LabWAS provides clinical measurements associated with aortic aneurysm diagnosis•Knocking out Sox6 attenuated hypertension-induced abdominal aortic aneurysm
Medical science; Cardiovascular medicine; Molecular Genetics
Decades of research show that genes play an vital role in the etiology of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders. Family, twin, and adoption studies ...show that ADHD runs in families. ADHD's high heritability of 74% motivated the search for ADHD susceptibility genes. Genetic linkage studies show that the effects of DNA risk variants on ADHD must, individually, be very small. Genome-wide association studies (GWAS) have implicated several genetic loci at the genome-wide level of statistical significance. These studies also show that about a third of ADHD's heritability is due to a polygenic component comprising many common variants each having small effects. From studies of copy number variants we have also learned that the rare insertions or deletions account for part of ADHD's heritability. These findings have implicated new biological pathways that may eventually have implications for treatment development.
See Charidimou (doi:
10.1093/aww253
) for a scientific commentary on this article
.
Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations is a newly recognised and often ...misdiagnosed neurovascular syndrome caused by mutations in
TREX1
. Stam
et al
. provide the first comprehensive clinical, pathological and radiological characterization of RVCL-S, and highlight cerebral mass lesions, impaired liver and kidney function, and premature death.
See Charidimou (doi:
10.1093/aww253
) for a scientific commentary on this article
.
Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations is a newly recognised and often misdiagnosed neurovascular syndrome caused by mutations in
TREX1
. Stam
et al
. provide the first comprehensive clinical, pathological and radiological characterization of RVCL-S, and highlight cerebral mass lesions, impaired liver and kidney function, and premature death.
See Charidimou (doi:
10.1093/aww253
) for a scientific commentary on this article
.
Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in
TREX1
, which was termed ‘retinal vasculopathy with cerebral leukodystrophy’. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different
TREX1
mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhancement in 97% of them; (ii) rim-enhancing mass lesions in 84%; and (iii) calcifications in the white matter in 52%. Ninety per cent had clinical manifestations of brain disease, including focal neurological deficits (68%), migraine (59%), cognitive impairment (56%), psychiatric disturbances (42%), and seizures (17%). One mutation carrier had enhancing brain lesions and neurological features but unknown retinopathy status. Additional systemic features included liver disease (78%), anaemia (74%), nephropathy (61%), hypertension (60%), mild Raynaud’s phenomenon (40%), and gastro-intestinal bleeding (27%). Mean (± standard deviation) age at diagnosis was 42.9 ± 8.3 years and at death 53.1 ± 9.6 years. Pathological examination revealed systemic vasculopathy with luminal narrowing and multi-laminated basement membranes. The 13 mutation carriers without retinopathy or brain lesions were on average 8 years younger (mean age: 35.1 ± 10.6 years). Of them, 54% had mild Raynaud’s phenomenon, 42% had migraine, and 23% had psychiatric disturbances. Retinal vasculopathy with cerebral leukodystrophy is an autosomal dominant systemic small-vessel disease due to specific
TREX1
mutations and clinically primarily characterized by (i) visual impairment from vascular retinopathy; and (ii) neurological decline and premature death due to progressive enhancing cerebral white matter lesions. Impaired liver and kidney function, anaemia sometimes associated with gastrointestinal bleeding, hypertension, migraine, and Raynaud’s phenomenon appear to be part of the clinical spectrum as well. Penetrance seems high. Because of the pathogenetic basis and the emerging clinical picture with systemic manifestations and conspicuous absence of leukodystrophy, we renamed the disease ‘retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations’. We propose diagnostic criteria to facilitate clinical recognition and future studies.
Reproducibility in research can be compromised by both biological and technical variation, but most of the focus is on removing the latter. Here we investigate the effects of biological variation in ...HeLa cell lines using a systems-wide approach. We determine the degree of molecular and phenotypic variability across 14 stock HeLa samples from 13 international laboratories. We cultured cells in uniform conditions and profiled genome-wide copy numbers, mRNAs, proteins and protein turnover rates in each cell line. We discovered substantial heterogeneity between HeLa variants, especially between lines of the CCL2 and Kyoto varieties, and observed progressive divergence within a specific cell line over 50 successive passages. Genomic variability has a complex, nonlinear effect on transcriptome, proteome and protein turnover profiles, and proteotype patterns explain the varying phenotypic response of different cell lines to Salmonella infection. These findings have implications for the interpretation and reproducibility of research results obtained from human cultured cells.
Genomes assembled de novo from short reads are highly fragmented relative to the finished chromosomes of Homo sapiens and key model organisms generated by the Human Genome Project. To address this ...problem, we need scalable, cost-effective methods to obtain assemblies with chromosome-scale contiguity. Here we show that genome-wide chromatin interaction data sets, such as those generated by Hi-C, are a rich source of long-range information for assigning, ordering and orienting genomic sequences to chromosomes, including across centromeres. To exploit this finding, we developed an algorithm that uses Hi-C data for ultra-long-range scaffolding of de novo genome assemblies. We demonstrate the approach by combining shotgun fragment and short jump mate-pair sequences with Hi-C data to generate chromosome-scale de novo assemblies of the human, mouse and Drosophila genomes, achieving--for the human genome--98% accuracy in assigning scaffolds to chromosome groups and 99% accuracy in ordering and orienting scaffolds within chromosome groups. Hi-C data can also be used to validate chromosomal translocations in cancer genomes.
Ribonucleoside monophosphates (rNMPs) are abundantly found within genomic DNA of cells. The embedded rNMPs alter DNA properties and impact genome stability. Mutations in ribonuclease (RNase) H2, a ...key enzyme for rNMP removal, are associated with the Aicardi-Goutières syndrome (AGS), a severe neurological disorder. Here, we engineered orthologs of the human RNASEH2A-G37S and RNASEH2C-R69W AGS mutations in yeast Saccharomyces cerevisiae: rnh201-G42S and rnh203-K46W. Using the ribose-seq technique and the Ribose-Map bioinformatics toolkit, we unveiled rNMP abundance, composition, hotspots, and sequence context in these AGS-ortholog mutants. We found a high rNMP presence in the nuclear genome of rnh201-G42S-mutant cells, and an elevated rCMP content in both mutants, reflecting preferential cleavage of RNase H2 at rGMP. We discovered unique rNMP patterns in each mutant, showing differential activity of the AGS mutants on the leading or lagging replication strands. This study guides future research on rNMP characteristics in human genomes with AGS mutations.
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•Yeast AGS-mutant rnh201-G42S shows lower ribonucleotide activity•Yeast AGS-mutant rnh203-K46W has altered specificity on ribonucleotides•rC rises in AGS yeast mutant nuclear and mitochondrial DNA•In the G42S ortholog, rNMPs are preceded by dA; in R69W, rNMPs are preceded by dC
Nucleic acids; Genomics; Molecular genetics; Model organism
In recent years, major breakthroughs in RNA-modification-mediated regulation of gene expression have been made, leading to the emerging field of epitranscriptomics.Our understanding of the ...distribution, regulation and function of these dynamic RNA modifications is based on sequencing technologies. In this Review, we focus on the major mRNA modifications in the transcriptome of eukaryotic cells: N6-methyladenosine, N6, 2'-O-dimethyladenosine, 5-methylcytidine, 5-hydroxylmethylcytidine, inosine, pseudouridine and N
-methyladenosine. We discuss the sequencing technologies used to profile these epitranscriptomic marks, including scale, resolution, quantitative feature, pre-enrichment capability and the corresponding bioinformatics tools. We also discuss the challenges of epitranscriptome profiling and highlight the prospect of future detection tools. We aim to guide the choice of different detection methods and inspire new ideas in RNA biology.
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