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Human Genetics

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https://www.readbyqxmd.com/read/28434044/faulty-rna-splicing-consequences-and-therapeutic-opportunities-in-brain-and-muscle-disorders
#1
REVIEW
Vittoria Pagliarini, Piergiorgio La Rosa, Claudio Sette
Alternative splicing is a powerful mechanism that largely expands the coding potential of eukaryotic genomes. Indeed, its complex and flexible regulation is exploited by cells to adapt to various environmental conditions, through production of protein variants displaying different functions. Such flexibility, however, is accompanied by high risk of errors, and dysregulation of splicing is now recognized as an important factor in human diseases. Notably, the RNA-based nature of splicing, which involves high specificity through base pair recognition, offers a remarkable therapeutic opportunity by allowing design of tools with elevated target selectivity...
April 22, 2017: Human Genetics
https://www.readbyqxmd.com/read/28429085/the-role-of-rna-alternative-splicing-in-regulating-cancer-metabolism
#2
REVIEW
Itamar Kozlovski, Zahava Siegfried, Adi Amar-Schwartz, Rotem Karni
Tumor cells alter their metabolism by a wide array of mechanisms to promote growth and proliferation. Dysregulated expression and/or somatic mutations of key components of the glycolytic pathway/TCA cycle as well as other metabolic pathways allow tumor cells to improve their ability to survive harsh conditions such as hypoxia and the presence of reactive oxygen species, as well as the ability to obtain nutrients to increase lipids, protein, and nucleic acids biogenesis. Approximately 95% of the human protein encoding genes undergo alternative splicing (AS), a regulated process of gene expression that greatly diversifies the proteome by creating multiple proteins from a single gene...
April 20, 2017: Human Genetics
https://www.readbyqxmd.com/read/28424864/loss-of-chromosome-y-loy-in-blood-cells-is-associated-with-increased-risk-for-disease-and-mortality-in-aging-men
#3
REVIEW
Lars A Forsberg
Recent discoveries have shown that harboring cells without the Y chromosome in the peripheral blood is associated with increased risk for all-cause mortality and disease such as different forms of cancer, Alzheimer's disease, as well as other conditions in aging men. In the entire world, the life expectancy of men is shorter compared to women, a sex difference that has been known for centuries, but the underlying mechanism(s) are not well understood. As a male-specific genetic risk factor, an increased risk for pathology and mortality associated with mosaic loss of chromosome Y (LOY) in blood cells could help to explain that men on average live shorter lives compared to women...
April 19, 2017: Human Genetics
https://www.readbyqxmd.com/read/28405812/estimating-the-prevalence-of-functional-exonic-splice-regulatory-information
#4
REVIEW
Rosina Savisaar, Laurence D Hurst
In addition to coding information, human exons contain sequences necessary for correct splicing. These elements are known to be under purifying selection and their disruption can cause disease. However, the density of functional exonic splicing information remains profoundly uncertain. Several groups have experimentally investigated how mutations at different exonic positions affect splicing. They have found splice information to be distributed widely in exons, with one estimate putting the proportion of splicing-relevant nucleotides at >90%...
April 12, 2017: Human Genetics
https://www.readbyqxmd.com/read/28393272/heterozygous-hnrnpu-variants-cause-early-onset-epilepsy-and-severe-intellectual-disability
#5
Nuria C Bramswig, Hermann-Josef Lüdecke, Fadi F Hamdan, Janine Altmüller, Filippo Beleggia, Nursel H Elcioglu, Catharine Freyer, Erica H Gerkes, Yasemin Kendir Demirkol, Kelly G Knupp, Alma Kuechler, Yun Li, Daniel H Lowenstein, Jacques L Michaud, Kristen Park, Alexander P A Stegmann, Hermine E Veenstra-Knol, Thomas Wieland, Bernd Wollnik, Hartmut Engels, Tim M Strom, Tjitske Kleefstra, Dagmar Wieczorek
Pathogenic variants in genes encoding subunits of the spliceosome are the cause of several human diseases, such as neurodegenerative diseases. The RNA splicing process is facilitated by the spliceosome, a large RNA-protein complex consisting of small nuclear ribonucleoproteins (snRNPs), and many other proteins, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). The HNRNPU gene (OMIM *602869) encodes the heterogeneous nuclear ribonucleoprotein U, which plays a crucial role in mammalian development. HNRNPU is expressed in the fetal brain and adult heart, kidney, liver, brain, and cerebellum...
April 9, 2017: Human Genetics
https://www.readbyqxmd.com/read/28393271/analysis-of-implantation-and-ongoing-pregnancy-rates-following-the-transfer-of-mosaic-diploid-aneuploid-blastocysts
#6
Elpida Fragouli, Samer Alfarawati, Katharina Spath, Dhruti Babariya, Nicoletta Tarozzi, Andrea Borini, Dagan Wells
Preimplantation genetic testing for aneuploidy (PGT-A) is widely used in IVF and aims to improve outcomes by avoiding aneuploid embryo transfers. Chromosomal mosaicism is extremely common in early development and could affect the efficacy of PGT-A by causing incorrect embryo classification. Recent innovations have allowed accurate mosaicism detection in trophectoderm samples taken from blastocysts. However, there is little data concerning the impact of mosaicism on viability, and the optimal clinical pathway for such embryos is unclear...
April 9, 2017: Human Genetics
https://www.readbyqxmd.com/read/28391526/trans-ethnic-fine-mapping-of-genetic-loci-for-body-mass-index-in-the-diverse-ancestral-populations-of-the-population-architecture-using-genomics-and-epidemiology-page-study-reveals-evidence-for-multiple-signals-at-established-loci
#7
Lindsay Fernández-Rhodes, Jian Gong, Jeffrey Haessler, Nora Franceschini, Mariaelisa Graff, Katherine K Nishimura, Yujie Wang, Heather M Highland, Sachiko Yoneyama, William S Bush, Robert Goodloe, Marylyn D Ritchie, Dana Crawford, Myron Gross, Myriam Fornage, Petra Buzkova, Ran Tao, Carmen Isasi, Larissa Avilés-Santa, Martha Daviglus, Rachel H Mackey, Denise Houston, C Charles Gu, Georg Ehret, Khanh-Dung H Nguyen, Cora E Lewis, Mark Leppert, Marguerite R Irvin, Unhee Lim, Christopher A Haiman, Loic Le Marchand, Fredrick Schumacher, Lynne Wilkens, Yingchang Lu, Erwin P Bottinger, Ruth J L Loos, Wayne H-H Sheu, Xiuqing Guo, Wen-Jane Lee, Yang Hai, Yi-Jen Hung, Devin Absher, I-Chien Wu, Kent D Taylor, I-Te Lee, Yeheng Liu, Tzung-Dau Wang, Thomas Quertermous, Jyh-Ming J Juang, Jerome I Rotter, Themistocles Assimes, Chao A Hsiung, Yii-Der Ida Chen, Ross Prentice, Lewis H Kuller, JoAnn E Manson, Charles Kooperberg, Paul Smokowski, Whitney R Robinson, Penny Gordon-Larsen, Rongling Li, Lucia Hindorff, Steven Buyske, Tara C Matise, Ulrike Peters, Kari E North
Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study...
April 8, 2017: Human Genetics
https://www.readbyqxmd.com/read/28391525/regsnps-splicing-a-tool-for-prioritizing-synonymous-single-nucleotide-substitution
#8
Xinjun Zhang, Meng Li, Hai Lin, Xi Rao, Weixing Feng, Yuedong Yang, Matthew Mort, David N Cooper, Yue Wang, Yadong Wang, Clark Wells, Yaoqi Zhou, Yunlong Liu
While synonymous single-nucleotide variants (sSNVs) have largely been unstudied, since they do not alter protein sequence, mounting evidence suggests that they may affect RNA conformation, splicing, and the stability of nascent-mRNAs to promote various diseases. Accurately prioritizing deleterious sSNVs from a pool of neutral ones can significantly improve our ability of selecting functional genetic variants identified from various genome-sequencing projects, and, therefore, advance our understanding of disease etiology...
April 8, 2017: Human Genetics
https://www.readbyqxmd.com/read/28391524/intron-retention-as-a-component-of-regulated-gene-expression-programs
#9
REVIEW
Aishwarya G Jacob, Christopher W J Smith
Intron retention has long been an exemplar of regulated splicing with case studies of individual events serving as models that provided key mechanistic insights into the process of splicing control. In organisms such as plants and budding yeast, intron retention is well understood as a major mechanism of gene expression regulation. In contrast, in mammalian systems, the extent and functional significance of intron retention have, until recently, remained greatly underappreciated. Technical challenges to the global detection and quantitation of transcripts with retained introns have often led to intron retention being overlooked or dismissed as "noise"...
April 8, 2017: Human Genetics
https://www.readbyqxmd.com/read/28386624/mutated-pet117-causes-complex-iv-deficiency-and-is-associated-with-neurodevelopmental-regression-and-medulla-oblongata-lesions
#10
G H Renkema, G Visser, F Baertling, L T Wintjes, V M Wolters, J van Montfrans, G A P de Kort, P G J Nikkels, P M van Hasselt, S N van der Crabben, R J T Rodenburg
The genetic basis of the many progressive, multi systemic, mitochondrial diseases that cause a lack of cellular ATP production is heterogeneous, with defects found both in the mitochondrial genome as well as in the nuclear genome. Many different mutations have been found in the genes encoding subunits of the enzyme complexes of the oxidative phosphorylation system. In addition, mutations in genes encoding proteins involved in the assembly of these complexes are known to cause mitochondrial disorders. Here we describe two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging, and an isolated complex IV deficiency and reduced levels of individual complex IV subunits...
April 6, 2017: Human Genetics
https://www.readbyqxmd.com/read/28382513/rna-splicing-and-splicing-regulator-changes-in-prostate-cancer-pathology
#11
REVIEW
Jennifer Munkley, Karen Livermore, Prabhakar Rajan, David J Elliott
Changes in mRNA splice patterns have been associated with key pathological mechanisms in prostate cancer progression. The androgen receptor (abbreviated AR) transcription factor is a major driver of prostate cancer pathology and activated by androgen steroid hormones. Selection of alternative promoters by the activated AR can critically alter gene function by switching mRNA isoform production, including creating a pro-oncogenic isoform of the normally tumour suppressor gene TSC2. A number of androgen-regulated genes generate alternatively spliced mRNA isoforms, including a prostate-specific splice isoform of ST6GALNAC1 mRNA...
April 5, 2017: Human Genetics
https://www.readbyqxmd.com/read/28378101/human-y-chromosome-copy-number-variation-in-the-next-generation-sequencing-era-and-beyond
#12
REVIEW
Andrea Massaia, Yali Xue
The human Y chromosome provides a fertile ground for structural rearrangements owing to its haploidy and high content of repeated sequences. The methodologies used for copy number variation (CNV) studies have developed over the years. Low-throughput techniques based on direct observation of rearrangements were developed early on, and are still used, often to complement array-based or sequencing approaches which have limited power in regions with high repeat content and specifically in the presence of long, identical repeats, such as those found in human sex chromosomes...
April 4, 2017: Human Genetics
https://www.readbyqxmd.com/read/28374192/sequential-recruitment-of-study-participants-may-inflate-genetic-heritability-estimates
#13
Damia Noce, Martin Gögele, Christine Schwienbacher, Giulia Caprioli, Alessandro De Grandi, Luisa Foco, Stefan Platzgummer, Peter P Pramstaller, Cristian Pattaro
After the success of genome-wide association studies to uncover complex trait loci, attempts to explain the remaining genetic heritability (h (2)) are mainly focused on unraveling rare variant associations and gene-gene or gene-environment interactions. Little attention is paid to the possibility that h (2) estimates are inflated as a consequence of the epidemiological study design. We studied the time series of 54 biochemical traits in 4373 individuals from the Cooperative Health Research In South Tyrol (CHRIS) study, a pedigree-based study enrolling ten participants/day over several years, with close relatives preferentially invited within the same day...
April 3, 2017: Human Genetics
https://www.readbyqxmd.com/read/28374191/alternative-splicing-the-pledge-the-turn-and-the-prestige-the-key-role-of-alternative-splicing-in-human-biological-systems
#14
REVIEW
L M Gallego-Paez, M C Bordone, A C Leote, N Saraiva-Agostinho, M Ascensão-Ferreira, N L Barbosa-Morais
Alternative pre-mRNA splicing is a tightly controlled process conducted by the spliceosome, with the assistance of several regulators, resulting in the expression of different transcript isoforms from the same gene and increasing both transcriptome and proteome complexity. The differences between alternative isoforms may be subtle but enough to change the function or localization of the translated proteins. A fine control of the isoform balance is, therefore, needed throughout developmental stages and adult tissues or physiological conditions and it does not come as a surprise that several diseases are caused by its deregulation...
April 3, 2017: Human Genetics
https://www.readbyqxmd.com/read/28374190/a-genome-wide-study-of-hardy-weinberg-equilibrium-with-next-generation-sequence-data
#15
Jan Graffelman, Deepti Jain, Bruce Weir
Statistical tests for Hardy-Weinberg equilibrium have been an important tool for detecting genotyping errors in the past, and remain important in the quality control of next generation sequence data. In this paper, we analyze complete chromosomes of the 1000 genomes project by using exact test procedures for autosomal and X-chromosomal variants. We find that the rate of disequilibrium largely exceeds what might be expected by chance alone for all chromosomes. Observed disequilibrium is, in about 60% of the cases, due to heterozygote excess...
April 3, 2017: Human Genetics
https://www.readbyqxmd.com/read/28364159/modulation-of-aberrant-splicing-in-human-rna-diseases-by-chemical-compounds
#16
REVIEW
Naoyuki Kataoka
Pre-mRNA splicing is an essential step for gene expression in higher eukaryotes. Alternative splicing contributes to diversity of the expressed proteins from the limited number of genes. Disruption of splicing regulation often results in hereditary and sporadic diseases called as 'RNA diseases'. Modulation of splicing by small chemical compounds and nucleic acids has been tried to target aberrant splicing in those diseases. Several RNA diseases and splicing-target therapeutic approaches will be briefly introduced in this review...
March 31, 2017: Human Genetics
https://www.readbyqxmd.com/read/28352986/genetic-associations-with-lipoprotein-subfraction-measures-differ-by-ethnicity-in-the-multi-ethnic-study-of-atherosclerosis-mesa
#17
Zhe Wang, Ani Manichukal, David C Goff, Samia Mora, Jose M Ordovas, Nicholas M Pajewski, Wendy S Post, Jerome I Rotter, Michele M Sale, Stephanie A Santorico, David Siscovick, Michael Y Tsai, Donna K Arnett, Stephen Rich, Alexis C Frazier-Wood
A recent genome-wide association study associated 62 single nucleotide polymorphisms (SNPs) from 43 genomic loci, with fasting lipoprotein subfractions in European-Americans (EAs) at genome-wide levels of significance across three independent samples. Whether these associations are consistent across ethnicities with a non-European ancestry is unknown. We analyzed 15 lipoprotein subfraction measures, on 1677 African-Americans (AAs), 1450 Hispanic-Americans (HAs), and 775 Chinese-Americans (CHN) participating in the multi-ethnic study of atherosclerosis (MESA)...
March 28, 2017: Human Genetics
https://www.readbyqxmd.com/read/28349240/the-human-gene-mutation-database-towards-a-comprehensive-repository-of-inherited-mutation-data-for-medical-research-genetic-diagnosis-and-next-generation-sequencing-studies
#18
REVIEW
Peter D Stenson, Matthew Mort, Edward V Ball, Katy Evans, Matthew Hayden, Sally Heywood, Michelle Hussain, Andrew D Phillips, David N Cooper
The Human Gene Mutation Database (HGMD(®)) constitutes a comprehensive collection of published germline mutations in nuclear genes that underlie, or are closely associated with human inherited disease. At the time of writing (March 2017), the database contained in excess of 203,000 different gene lesions identified in over 8000 genes manually curated from over 2600 journals. With new mutation entries currently accumulating at a rate exceeding 17,000 per annum, HGMD represents de facto the central unified gene/disease-oriented repository of heritable mutations causing human genetic disease used worldwide by researchers, clinicians, diagnostic laboratories and genetic counsellors, and is an essential tool for the annotation of next-generation sequencing data...
March 27, 2017: Human Genetics
https://www.readbyqxmd.com/read/28349239/detecting-past-male-mediated-expansions-using-the-y-chromosome
#19
REVIEW
Chiara Batini, Mark A Jobling
Males and females display biological differences that lead to a higher variance of offspring number in males, and this is frequently exacerbated in human societies by mating practices, and possibly by past socio-cultural circumstances. This implies that the genetic record might contain the imprint of past male-mediated expansions, which can be investigated by analysing the male-specific region of the Y chromosome (MSY). Here, we review studies that have used MSY data to infer such expansions. Sets of short-tandem repeats define haplotypes of very low average frequencies, but in a few cases, high-frequency haplotypes are observed, forming the core of descent clusters...
March 27, 2017: Human Genetics
https://www.readbyqxmd.com/read/28337550/common-genetic-etiology-between-multiple-sclerosis-like-single-gene-disorders-and-familial-multiple-sclerosis
#20
Anthony L Traboulsee, A Dessa Sadovnick, Mary Encarnacion, Cecily Q Bernales, Irene M Yee, Maria G Criscuoli, Carles Vilariño-Güell
Several single-gene disorders with clinical and radiological characteristics similar to those observed in multiple sclerosis (MS) patients have been described. To evaluate whether this phenotypic overlap can be ascribed to a common genetic etiology, 28 genes known to present pathogenic mutations for 24 of these disorders were sequenced in 270 MS patients. All identified variants were genotyped in 2131 MS cases and 830 healthy controls, and those exclusively observed in patients were assessed for segregation within families...
March 23, 2017: Human Genetics
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