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排序方式: 共有257条查询结果,搜索用时 15 毫秒
1.
Emily Olfson Catherine E. Cottrell Nicholas O. Davidson Christina A. Gurnett Jonathan W. Heusel Nathan O. Stitziel Li-Shiun Chen Sarah Hartz Rakesh Nagarajan Nancy L. Saccone Laura J. Bierut 《PloS one》2015,10(9)
The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations. 相似文献
2.
Human N-acetylgalactosamine-4-sulphate sulphatase. Purification, monoclonal antibody production and native and subunit Mr values. 总被引:5,自引:1,他引:4
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G J Gibson G T Saccone D A Brooks P R Clements J J Hopwood 《The Biochemical journal》1987,248(3):755-764
Initial purification of N-acetylgalactosamine-4-sulphate sulphatase from human liver homogenates containing approx. 1 mg of enzyme in 26 g of soluble proteins was achieved by a six-column chromatography procedure and yielded approx. 40 micrograms of a single major protein species. Enzyme thus prepared was used to produce N-acetylgalactosamine-4-sulphate sulphatase-specific monoclonal antibodies. The use of a monoclonal antibody linked to a solid support facilitated the purification of approx. 0.5 mg of N-acetylgalactosamine-4-sulphate sulphatase from a similar liver homogenate. Moreover the enzyme isolated contained a single protein species, shown by SDS/polyacrylamide-gel electrophoresis to have an Mr of 57,000, which dissociated into subunits of Mr 43,000 and 13,000 in the presence of reducing agents. Essentially identical enzyme preparations were isolated from homogenates of human kidney and lung and from concentrated human urine. The native protein Mr of enzyme from human liver and kidney was assessed by gel-permeation chromatography to be 43,000 on Ultrogel AcA and Bio-Gel P-150. The liver N-acetylgalactosamine-4-sulphate sulphatase was shown to have pH optima of approx. 4 and 5.5 with the oligosaccharide substrate (GalNAc4S-GlcA-GalitolNAc4S) and fluorogenic substrate (methylumbelliferyl sulphate) respectively. Km values of 60 microM and 4 mM and Vmax. values of 2 and 20 mumol/min per mg were determined with the oligosaccharide and fluorogenic substrates respectively. 相似文献
3.
In the past decade, the development of new DNA, RNA, and protein technologies has greatly incremented the knowledge about the organization and expression of mitochondrial DNA. The complete base sequence of mitochondrial DNA of several animals is known and many data are rapidly accumulating on the mitochondrial genomes of other systems. Here we discuss the results so far obtained that disclosed unexpected features of mitochondrial genetics. Furthermore, mitochondrial DNA has become established as a powerful tool for evolutionary studies in animals. Evidences are presented demonstrating that the evolution of mitochondrial DNA has proceeded in different ways in the various taxonomic groups. Data on heteroplasmic animals, which demonstrate the rapid evolution of mitochondrial DNA, are also presented. 相似文献
4.
Sequence-dependent DNA curvature: conformational signal present in the main regulatory region of the rat mitochondrial genome. 总被引:1,自引:0,他引:1
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Theoretical analysis and experimental approaches by gel electrophoresis in retarding conditions allowed us to identify the presence of an intrinsic bending in the D-loop containing region of the rat mitochondrial genome. The curvature was located in the right domain of the sequence analyzed, between the origin of replication of the heavy strand and its promoter. The preliminary evidence of a specific recognition of the bent DNA with mitochondrial matrix proteins suggests a probable role of this DNA conformation in the duplication and/or expression of the mammalian mitochondrial genome. 相似文献
5.
The origin of modern man is a highly debated issue that has recently been tackled by using mitochondrial DNA sequences. The limited genetic variability of human mtDNA has been explained in terms of a recent common genetic ancestry, thus implying that all modern-population mtDNAs originated from a single woman who lived in Africa less than 0.2 Mya. This divergence time is based on both the estimation of the rate of mtDNA change and its calibration date. Because different estimates of the rate of mtDNA evolution can completely change the scenario of the origin of modern man, we have reanalyzed the available mitochondrial sequence data by using an improved version of the statistical model, the "Markov clock," devised in our laboratory. Our analysis supports the African origin of modern man, but we found that the ancestral female from which all extant human mtDNAs originated lived in a time span of 0.3-0.8 Mya. Pushing back the date of the deepest root of the human implies that the earliest divergence would have been in the Homo erectus population. 相似文献
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In analyzing the silent nucleotide substitutions in some mammalian mitochondrial mRNA coding genes, we had found that the frequency of each of the four nucleotides in rat, mouse, and cow, but not in humans, is the same in the silent third codon position (Lanave C, Preparata G, Saccone C, Serio G (1984) J Mol Evol 20:86-93). Because our findings for these three species were compatible with a stationary Markov process for the evolution of nucleotide sequences, we applied such a model to calculate the effective evolutionary silent substitution rate (vs) and the divergence times among the species. In this paper we have analyzed the first and second codon positions in the same mammalian mitochondrial genes. We found that in the first and second codon positions the human mitochondrial genes satisfy the stationarity conditions. This has allowed us to use the stochastic model mentioned above to calculate the divergence times among mouse, rat, cow, and human. Furthermore, we have analyzed the silent substitution rate in one nuclear gene for these four mammals. We found that in this gene the effective silent substitution rate is about 3 times lower than in mitochondrial genes, and that humans are in this case stationary with respect to the other three mammals in the third codon position as well. Application of our Markov model to this latter gene yields divergence times consistent with our previous determinations. 相似文献
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10.
Summary A few years ago we presented a stationary Markov model of gene evolution according to which only homologous genes from not
too divergent species obeying the condition of being stationary may behave as reliable molecular clocks. A compartmentalized
model of the nuclear genome in which the genes are distributed in compartments, the isochores, defined by their G+C content
has been proposed recently. We have found that only homologous gene pairs that are stationary, and belong to the same isochore,
can be used consistently for the determination of phylogeny and base substitution rate. In particular, for the rodent-human
couple, only about half of the homologous gene pairs are stationary. Stationary genes evolve at the third silent codon position
with the same velocity independent of the genes and base composition. By contrast, nonstationary genes display apparent rate
values (pseudovelocities) that are significantly higher. Our results cast doubt upon recent claims of a large acceleration
in the rate of molecular evolution in rodents. 相似文献