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排序方式: 共有297条查询结果,搜索用时 15 毫秒
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Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations 总被引:2,自引:0,他引:2
O'Roak BJ Vives L Girirajan S Karakoc E Krumm N Coe BP Levy R Ko A Lee C Smith JD Turner EH Stanaway IB Vernot B Malig M Baker C Reilly B Akey JM Borenstein E Rieder MJ Nickerson DA Bernier R Shendure J Eichler EE 《Nature》2012,485(7397):246-250
It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics. 相似文献
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Stephens PJ Tarpey PS Davies H Van Loo P Greenman C Wedge DC Nik-Zainal S Martin S Varela I Bignell GR Yates LR Papaemmanuil E Beare D Butler A Cheverton A Gamble J Hinton J Jia M Jayakumar A Jones D Latimer C Lau KW McLaren S McBride DJ Menzies A Mudie L Raine K Rad R Chapman MS Teague J Easton D Langerød A;Oslo Breast Cancer Consortium 《Nature》2012,486(7403):400-404
All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease. 相似文献
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Patten IS Rana S Shahul S Rowe GC Jang C Liu L Hacker MR Rhee JS Mitchell J Mahmood F Hess P Farrell C Koulisis N Khankin EV Burke SD Tudorache I Bauersachs J del Monte F Hilfiker-Kleiner D Karumanchi SA Arany Z 《Nature》2012,485(7398):333-338
Peripartum cardiomyopathy (PPCM) is an often fatal disease that affects pregnant women who are near delivery, and it occurs more frequently in women with pre-eclampsia and/or multiple gestation. The aetiology of PPCM, and why it is associated with pre-eclampsia, remain unknown. Here we show that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble FLT1 (sFLT1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by subclinical cardiac dysfunction, the extent of which correlates with circulating levels of sFLT1. Exogenous sFLT1 alone caused diastolic dysfunction in wild-type mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFLT1. These data indicate that PPCM is mainly a vascular disease, caused by excess anti-angiogenic signalling in the peripartum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM. 相似文献
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Laura Greenwood Lucinda Lawson Eli Greenbaum Breda M. Zimkus 《Journal of Natural History》2020,54(1-4):63-85
ABSTRACT Using integrative approaches, a new large-bodied species of Phrynobatrachus is described from a series of 48 specimens from the montane forests of the West Usambara and North Pare Mountains of Tanzania. The most distinguishing morphological feature separating Phrynobatrachus ambanguluensis sp. nov from similar species is the markedly overhanging and pointed upper jaw and snout. Mitochondrial 16S rRNA indicates that the new species differs from all other species with published sequence data by a minimum distance of 4.75% and is sister to P. krefftii, with which it has been confused in the past. The new species is known from two forest reserves and is of high conservation concern given these areas are highly impacted by anthropogenic change. http://www.zoobank.org/urn:lsid:zoobank.org:pub:E0C82A87-47A5-426B-978D-96D27FA7A3B7 相似文献
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