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501.
502.
Rivière JB Mirzaa GM O'Roak BJ Beddaoui M Alcantara D Conway RL St-Onge J Schwartzentruber JA Gripp KW Nikkel SM Worthylake T Sullivan CT Ward TR Butler HE Kramer NA Albrecht B Armour CM Armstrong L Caluseriu O Cytrynbaum C Drolet BA Innes AM Lauzon JL Lin AE Mancini GM Meschino WS Reggin JD Saggar AK Lerman-Sagie T Uyanik G Weksberg R Zirn B Beaulieu CL;Finding of Rare Disease Genes 《Nature genetics》2012,44(8):934-940
Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism. 相似文献
503.
Barbieri CE Baca SC Lawrence MS Demichelis F Blattner M Theurillat JP White TA Stojanov P Van Allen E Stransky N Nickerson E Chae SS Boysen G Auclair D Onofrio RC Park K Kitabayashi N MacDonald TY Sheikh K Vuong T Guiducci C Cibulskis K Sivachenko A Carter SL Saksena G Voet D Hussain WM Ramos AH Winckler W Redman MC Ardlie K Tewari AK Mosquera JM Rupp N Wild PJ Moch H Morrissey C Nelson PS Kantoff PW Gabriel SB Golub TR Meyerson M Lander ES Getz G Rubin MA Garraway LA 《Nature genetics》2012,44(6):685-689
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Graubert TA Shen D Ding L Okeyo-Owuor T Lunn CL Shao J Krysiak K Harris CC Koboldt DC Larson DE McLellan MD Dooling DJ Abbott RM Fulton RS Schmidt H Kalicki-Veizer J O'Laughlin M Grillot M Baty J Heath S Frater JL Nasim T Link DC Tomasson MH Westervelt P DiPersio JF Mardis ER Ley TJ Wilson RK Walter MJ 《Nature genetics》2012,44(1):53-57
Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis. 相似文献
506.
Christopher Lawrence 《Annals of science》2013,70(4):455-471
Theories of familial, racial, and national degeneration in the late nineteenth and early twentieth centuries have been explored by historians in the context of social and moral pathology. At the same time nerve degeneration was studied in the post mortem room and in the laboratory but links to the broader ideology of degeneration have not been investigated by scholars. This paper joins these domains by examining the concept of Wallerian degeneration. It argues that various discourses—including those of the laboratory scientist, the clinician, and the social theorist—employed the term degeneration, and these discourses frequently overlapped demonstrating that degeneration was a ubiquitous fact of Victorian and Edwardian nature. 相似文献
507.
Haiman CA Chen GK Vachon CM Canzian F Dunning A Millikan RC Wang X Ademuyiwa F Ahmed S Ambrosone CB Baglietto L Balleine R Bandera EV Beckmann MW Berg CD Bernstein L Blomqvist C Blot WJ Brauch H Buring JE Carey LA Carpenter JE Chang-Claude J Chanock SJ Chasman DI Clarke CL Cox A Cross SS Deming SL Diasio RB Dimopoulos AM Driver WR Dünnebier T Durcan L Eccles D Edlund CK Ekici AB Fasching PA Feigelson HS Flesch-Janys D Fostira F Försti A Fountzilas G 《Nature genetics》2011,43(12):1210-1214
Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations. 相似文献
508.
509.
Lamandé SR Yuan Y Gresshoff IL Rowley L Belluoccio D Kaluarachchi K Little CB Botzenhart E Zerres K Amor DJ Cole WG Savarirayan R McIntyre P Bateman JF 《Nature genetics》2011,43(11):1142-1146
Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges. Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4. Functional testing of mutant TRPV4 in HEK-293 cells showed that the mutant proteins have poor cell-surface localization. Calcium influx in response to the synthetic TRPV4 agonists GSK1016790A and 4αPDD was significantly reduced, and mutant channels did not respond to hypotonic stress. Others have shown that gain-of-function TRPV4 mutations cause skeletal dysplasias and peripheral neuropathies. Our data indicate that TRPV4 mutations that reduce channel activity cause a third phenotype, inherited osteoarthropathy, and show the importance of TRPV4 activity in articular cartilage homeostasis. Our data raise the possibility that TRPV4 may also have a role in age- or injury-related osteoarthritis. 相似文献
510.
A framework for variation discovery and genotyping using next-generation DNA sequencing data 总被引:7,自引:0,他引:7
DePristo MA Banks E Poplin R Garimella KV Maguire JR Hartl C Philippakis AA del Angel G Rivas MA Hanna M McKenna A Fennell TJ Kernytsky AM Sivachenko AY Cibulskis K Gabriel SB Altshuler D Daly MJ 《Nature genetics》2011,43(5):491-498
Recent advances in sequencing technology make it possible to comprehensively catalog genetic variation in population samples, creating a foundation for understanding human disease, ancestry and evolution. The amounts of raw data produced are prodigious, and many computational steps are required to translate this output into high-quality variant calls. We present a unified analytic framework to discover and genotype variation among multiple samples simultaneously that achieves sensitive and specific results across five sequencing technologies and three distinct, canonical experimental designs. Our process includes (i) initial read mapping; (ii) local realignment around indels; (iii) base quality score recalibration; (iv) SNP discovery and genotyping to find all potential variants; and (v) machine learning to separate true segregating variation from machine artifacts common to next-generation sequencing technologies. We here discuss the application of these tools, instantiated in the Genome Analysis Toolkit, to deep whole-genome, whole-exome capture and multi-sample low-pass (~4×) 1000 Genomes Project datasets. 相似文献