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В обзоре рассматриваются основные достижения в области общей и молекулярной генетики сна, главным образом медленноволновой ...
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В обзоре рассматриваются основные достижения в области общей и молекулярной генетики сна, главным образом медленноволновой (обычной) его фазы, в том числе раскрытие природы таких наследственных нарушений, как фатальная семейная инсомния, цирка-дианные расстройства сна и болезнь Крейтцфельда-Якоба, обнаружение генетических маркеров ЭЭГ сна и т. п.
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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 accelerat...
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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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The importance of understanding the population genetics and evolution of microbial pathogens is increasing as a result of the spread and re-emergence of many infectious diseases and their impact for public health. In the last few ...
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The importance of understanding the population genetics and evolution of microbial pathogens is increasing as a result of the spread and re-emergence of many infectious diseases and their impact for public health. In the last few years, the development of high throughput multi-gene sequence methodologies has opened new opportunities for studying pathogen populations, providing reliable and robust means for both epidemiological and evolutionary investigations. For instance, for many pathogens, multilocus sequence typing has become the "gold standard" in molecular epidemiology, allowing strain identification and discovery. However, there is a huge gap between typing a clinical collection of isolates and making inferences about their evolutionary history and population genetics. Critical issues for studying microbial pathogens such as an adequate sampling design and the appropriate selection of the genetic technique are also required, and will rely on the scale of study and the characteristics of the biological system (e.g., multi- vs. single-host pathogens and vector vs. food or air-borne pathogens). My aim here is to discuss some of these issues in more detail and illustrate how these aspects are often overlooked and easily neglected in the field. Finally, given the rapid accumulation of complete genome sequences and the increasing effort on microbiology research, it is clear that now more than ever integrative approaches bringing together epidemiology and evolutionary biology are needed for understanding the diversity of microbial pathogens.
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Dosage compensation in Drosophila melanogaster involves the selective targeting of the male X chromosome by the dosage compensation complex (DCC) and the coordinate, similar to 2-fold activation of most genes. The principles that ...
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Dosage compensation in Drosophila melanogaster involves the selective targeting of the male X chromosome by the dosage compensation complex (DCC) and the coordinate, similar to 2-fold activation of most genes. The principles that allow the DCC to distinguish the X chromosome from the autosomes are not understood. Targeting presumably involves DNA sequence elements whose combination or enrichment mark the X chromosome. DNA sequences that characterize 'chromosomal entry sites' or 'high-affinity sites' may serve such a function. However, to date no DNA binding domain that could interpret sequence information has been identified within the subunits of the DCC. Early genetic studies suggested that MSL1 and MSL2 serve to recognize high-affinity sites (HAS) in vivo, but a direct interaction of these DCC subunits with DNA has not been studied. We now show that recombinant MSL2, through its CXC domain, directly binds DNA with low nanomolar affinity. The DNA binding of MSL2 or of an MSL2-MSL1 complex does not discriminate between different sequences in vitro, but in a reporter gene assay in vivo, suggesting the existence of an unknown selectivity cofactor. Reporter gene assays and localization of GFP-fusion proteins confirm the important contribution of the CXC domain for DCC targeting in vivo.
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In tetraploid sour cherry (Prunus cerasus L.), the accumulation of nonfunctional S-haplotypes with disrupted pistil-component (stylar-S) and/or pollen-component (pollen-S) function leads to a genotype-dependent loss of gametophyti...
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In tetraploid sour cherry (Prunus cerasus L.), the accumulation of nonfunctional S-haplotypes with disrupted pistil-component (stylar-S) and/or pollen-component (pollen-S) function leads to a genotype-dependent loss of gametophytic self-incompatibility (GSI). Tetraploid Chinese cherry (Prunus pseudocerasus L.) exhibits self-compatibility. In this study, we characterized four S-haplotype-specific F-box protein genes (SFBs) from pollen cDNA of Chinese cherry cv. 'Taixiaohongying' with the S-genotype S (1) S (2) S (3) S (4) . Of the four SFBs, three showed typical characteristics of SFBs from other Prunus species and functioned as SFB genes; these were termed SFB (a) (GQ395341), SFB (b) (GQ395340), and SFB (c) (EU267943), respectively. The fourth SFB, termed SFB (d) (GQ395339), has a 100-bp deletion that resulted in the transcript for SFB (d) lacking the F-box domain. SFB (d) lost the pollen-S specific function and functioned as the SFB gene mutant. The results of reverse transcription-PCR analysis indicated that the four SFB genes were transcribed at approximately the same intensity.
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Hearing loss is one of the most prevalent disabilities worldwide, and has a significant impact on quality of life. The adult-onset type of the condition is highly heritable but the genetic causes are largely unknown, which is in c...
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Hearing loss is one of the most prevalent disabilities worldwide, and has a significant impact on quality of life. The adult-onset type of the condition is highly heritable but the genetic causes are largely unknown, which is in contrast to childhood-onset hearing loss.Family and cohort studies included exome sequencing and characterisation of the hearing phenotype. Ex vivo protein expression addressed the functional effect of a DNA variant.An in-frame deletion of 12 nucleotides in Collectively, the presented data demonstrate that an inherited form of adult-onset hearing loss is relatively common, with potentially thousands of individuals at risk in the Netherlands and beyond, which makes it an attractive target for developing a (genetic) therapy.
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Introduction Hereditary haemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder caused by mutations in the genes ENG, ACVRL1, and SMAD4. Yet the genetic cause remains unknown for some families even after exhausti...
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Introduction Hereditary haemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder caused by mutations in the genes ENG, ACVRL1, and SMAD4. Yet the genetic cause remains unknown for some families even after exhaustive exome analysis. We hypothesised that non-coding regions of the known HHT genes may harbour variants that disrupt splicing in these cases. Methods DNA from 35 individuals with clinical findings of HHT and 2 healthy controls from 13 families underwent whole genome sequencing. Additionally, 87 unrelated cases suspected to have HHT were evaluated using a custom designed next-generation sequencing panel to capture the coding and non-coding regions of ENG, ACVRL1 and SMAD4. Individuals from both groups had tested negative previously for a mutation in the coding region of known HHT genes. Samples were sequenced on a HiSeq2500 instrument and data were analysed to identify novel and rare variants. Results Eight cases had a novel non-coding ACVRL1 variant that disrupted splicing. One family had an ACVRL1intron 9:chromosome 3 translocation, the first reported case of a translocation causing HHT. The other seven cases had a variant located within a similar to 300 bp CT-rich 'hotspot' region of ACVRL1intron 9 that disrupted splicing. Conclusions Despite the difficulty of interpreting deep intronic variants, our study highlights the importance of non-coding regions in the disease mechanism of HHT, particularly the CT-rich hotspot region of ACVRL1intron 9. The addition of this region to HHT molecular diagnostic testing algorithms will improve clinical sensitivity.
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While not being considered a common cancer, since 1975 oesophageal adenocarcinoma (OAC) has had the fastest-rising incidence of any malignancy in Caucasian Western populations. In the absence of major improvements in treatment sin...
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While not being considered a common cancer, since 1975 oesophageal adenocarcinoma (OAC) has had the fastest-rising incidence of any malignancy in Caucasian Western populations. In the absence of major improvements in treatment since this rise began, the number of deaths has also increased rapidly. In contrast, there have been significant advances in basic science in this period. One such advance is the discovery of DNA copy number aberrations (CNAs), and their potential role in carcinogenesis. The study of CNAs offers the potential to answer fundamental clinical questions in OAC, which in turn may lead to improved diagnosis, staging and treatment. This review outlines current clinical dilemmas in OAC, discusses the role that CNAs have been shown to play to date and highlights potential future applications.
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While not being considered a common cancer, since 1975 oesophageal adenocarcinoma (OAC) has had the fastest-rising incidence of any malignancy in Caucasian Western populations. In the absence of major improvements in treatment sin...
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While not being considered a common cancer, since 1975 oesophageal adenocarcinoma (OAC) has had the fastest-rising incidence of any malignancy in Caucasian Western populations. In the absence of major improvements in treatment since this rise began, the number of deaths has also increased rapidly. In contrast, there have been significant advances in basic science in this period. One such advance is the discovery of DNA copy number aberrations (CNAs), and their potential role in carcinogenesis. The study of CNAs offers the potential to answer fundamental clinical questions in OAC, which in turn may lead to improved diagnosis, staging and treatment. This review outlines current clinical dilemmas in OAC, discusses the role that CNAs have been shown to play to date and highlights potential future applications.
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