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41.
De novo mutations revealed by whole-exome sequencing are strongly associated with autism 总被引:1,自引:0,他引:1
Sanders SJ Murtha MT Gupta AR Murdoch JD Raubeson MJ Willsey AJ Ercan-Sencicek AG DiLullo NM Parikshak NN Stein JL Walker MF Ober GT Teran NA Song Y El-Fishawy P Murtha RC Choi M Overton JD Bjornson RD Carriero NJ Meyer KA Bilguvar K Mane SM Sestan N Lifton RP Günel M Roeder K Geschwind DH Devlin B State MW 《Nature》2012,485(7397):237-241
Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance. 相似文献
42.
PR Steinmetz JE Kraus C Larroux JU Hammel A Amon-Hassenzahl E Houliston G Wörheide M Nickel BM Degnan U Technau 《Nature》2012,487(7406):231-234
Striated muscles are present in bilaterian animals (for example, vertebrates, insects and annelids) and some non-bilaterian eumetazoans (that is, cnidarians and ctenophores). The considerable ultrastructural similarity of striated muscles between these animal groups is thought to reflect a common evolutionary origin. Here we show that a muscle protein core set, including a type II myosin heavy chain (MyHC) motor protein characteristic of striated muscles in vertebrates, was already present in unicellular organisms before the origin of multicellular animals. Furthermore, 'striated muscle' and 'non-muscle' myhc orthologues are expressed differentially in two sponges, compatible with a functional diversification before the origin of true muscles and the subsequent use of striated muscle MyHC in fast-contracting smooth and striated muscle. Cnidarians and ctenophores possess striated muscle myhc orthologues but lack crucial components of bilaterian striated muscles, such as genes that code for titin and the troponin complex, suggesting the convergent evolution of striated muscles. Consistently, jellyfish orthologues of a shared set of bilaterian Z-disc proteins are not associated with striated muscles, but are instead expressed elsewhere or ubiquitously. The independent evolution of eumetazoan striated muscles through the addition of new proteins to a pre-existing, ancestral contractile apparatus may serve as a model for the evolution of complex animal cell types. 相似文献
43.
Becker D Selbach M Rollenhagen C Ballmaier M Meyer TF Mann M Bumann D 《Nature》2006,440(7082):303-307
New antibiotics are urgently needed to control infectious diseases. Metabolic enzymes could represent attractive targets for such antibiotics, but in vivo target validation is largely lacking. Here we have obtained in vivo information about over 700 Salmonella enterica enzymes from network analysis of mutant phenotypes, genome comparisons and Salmonella proteomes from infected mice. Over 400 of these enzymes are non-essential for Salmonella virulence, reflecting extensive metabolic redundancies and access to surprisingly diverse host nutrients. The essential enzymes identified were almost exclusively associated with a small subgroup of pathways, enabling us to perform a nearly exhaustive screen. Sixty-four enzymes identified as essential in Salmonella are conserved in other important human pathogens, but almost all belong to metabolic pathways that are inhibited by current antibiotics or that have previously been considered for antimicrobial development. Our comprehensive in vivo analysis thus suggests a shortage of new metabolic targets for broad-spectrum antibiotics, and draws attention to some previously known but unexploited targets. 相似文献
44.
Summary The suprachiasmatic nucleus, a hypothalamic center important in mediation of circadian and estrous cycles, is shown in adult rats to have seasonal changes in its uptake capacity in vitro for3H-serotonin.Supported in part by grants from the National Institute of Mental Health (MH-25091), the National Institute of Health (HD-10263, HD-03352, 5-T01-HD00104-10), USPHS, and the Ford Foundation (grant No. 630-0505 B, C). 相似文献
45.
46.
The forefront of research into the complexes of uranium reveals chemical transformations that challenge and expand our view of this unique element. Certain ligands form multiple bonds to uranium, and small, inert molecules such as nitrogen and carbon dioxide become reactive when in complex with the metal. Such complexes provide clues to the catalytic future of uranium, in which the applications of the element extend far beyond the nuclear industry. Most excitingly, the ability of uranium to use its outermost f electrons for binding ligands might enable the element to catalyse reactions that are impossible with conventional, transition-metal catalysts. 相似文献
47.
Summary It is found that chondroitinsulfuric acid is composed of unbranched chain-molecules containing rests of glucuronic acid and N-acetyl-galactosamine-6-sulfate combined in one of the following manners (a) or (b):
相似文献
48.
It has long been known that messenger RNAs (mRNAs) of ciliates and in particular of Paramecium are not translated well in heterologous in vitro translation systems. Recently, we have demonstrated for Paramecium primaurelia that this phenomenon results from the presence of well-defined blocking sites in the coding sequences of almost all mRNAs, and that these sites are an intrinsic feature of the primary as opposed to the secondary structure of the mRNAs. Here we show that both the gene and the mRNA for the G surface antigen of P. primaurelia contain numerous TAA and TAG codons scattered throughout their coding sequences. We propose that these codons do not represent termination codons in P. primaurelia but instead code for glutamic acid or glutamine and that the in vitro translation of Paramecium mRNAs is blocked by their presence. 相似文献
49.
Conclusions Optimization of the parameters of sample preparation, sample application, probe concentration and also membrane suitability have a considerable influence on the specificity of 3-end labelled oligonucleotides. 相似文献
50.