共查询到20条相似文献，搜索用时 15 毫秒
1.
Background
Discovering causal genetic variants from large genetic association studies poses many difficult challenges. Assessing which genetic markers are involved in determining trait status is a computationally demanding task, especially in the presence of gene-gene interactions.Results
A non-parametric Bayesian approach in the form of a Bayesian neural network is proposed for use in analyzing genetic association studies. Demonstrations on synthetic and real data reveal they are able to efficiently and accurately determine which variants are involved in determining case-control status. By using graphics processing units (GPUs) the time needed to build these models is decreased by several orders of magnitude. In comparison with commonly used approaches for detecting interactions, Bayesian neural networks perform very well across a broad spectrum of possible genetic relationships.Conclusions
The proposed framework is shown to be a powerful method for detecting causal SNPs while being computationally efficient enough to handle large datasets.Electronic supplementary material
The online version of this article (doi:10.1186/s12859-014-0368-0) contains supplementary material, which is available to authorized users. 相似文献2.
Background
The power of the genome wide association studies starts to go down when the minor allele frequency (MAF) is below 0.05. Here, we proposed the use of Cohen’s h in detecting disease associated rare variants. The variance stabilizing effect based on the arcsine square root transformation of MAFs to generate Cohen’s h contributed to the statistical power for rare variants analysis. We re-analyzed published datasets, one microarray and one sequencing based, and used simulation to compare the performance of Cohen’s h with the risk difference (RD) and odds ratio (OR).Results
The analysis showed that the type 1 error rate of Cohen’s h was as expected and Cohen’s h and RD were both less biased and had higher power than OR. The advantage of Cohen’s h was more obvious when MAF was less than 0.01.Conclusions
Cohen’s h can increase the power to find genetic association of rare variants and diseases, especially when MAF is less than 0.01.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-875) contains supplementary material, which is available to authorized users. 相似文献3.
Diego Forni Uberto Pozzoli Rachele Cagliani Claudia Tresoldi Giorgia Menozzi Stefania Riva Franca R Guerini Giacomo P Comi Elisabetta Bolognesi Nereo Bresolin Mario Clerici Manuela Sironi 《Genome biology》2014,15(10)
Background
The temporal coordination of biological processes into daily cycles is a common feature of most living organisms. In humans, disruption of circadian rhythms is commonly observed in psychiatric diseases, including schizophrenia, bipolar disorder, depression and autism. Light therapy is the most effective treatment for seasonal affective disorder and circadian-related treatments sustain antidepressant response in bipolar disorder patients. Day/night cycles represent a major circadian synchronizing signal and vary widely with latitude.Results
We apply a geographically explicit model to show that out-of-Africa migration, which led humans to occupy a wide latitudinal area, affected the evolutionary history of circadian regulatory genes. The SNPs we identify using this model display consistent signals of natural selection using tests based on population genetic differentiation and haplotype homozygosity. Signals of natural selection driven by annual photoperiod variation are detected for schizophrenia, bipolar disorder, and restless leg syndrome risk variants, in line with the circadian component of these conditions.Conclusions
Our results suggest that human populations adapted to life at different latitudes by tuning their circadian clock systems. This process also involves risk variants for neuropsychiatric conditions, suggesting possible genetic modulators for chronotherapies and candidates for interaction analysis with photoperiod-related environmental variables, such as season of birth, country of residence, shift-work or lifestyle habits.Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0499-7) contains supplementary material, which is available to authorized users. 相似文献4.
Chang-Ki Yoon Nayoung K. D. Kim Je-Gun Joung Joo Young Shin Jung Hyun Park Hye-Hyun Eum Hae-ock Lee Woong-Yang Park Hyeong Gon Yu 《BMC genomics》2015,16(1)
Background
Identification of the causative genes of retinitis pigmentosa (RP) is important for the clinical care of patients with RP. However, a comprehensive genetic study has not been performed in Korean RP patients. Moreover, the genetic heterogeneity found in sensorineural genetic disorders makes identification of pathogenic mutations challenging. Therefore, high throughput genetic testing using massively parallel sequencing is needed.Results
Sixty-two Korean patients with nonsyndromic RP (46 patients from 18 families and 16 simplex cases) who consented to molecular genetic testing were recruited in this study and targeted exome sequencing was applied on 53 RP-related genes. Causal variants were characterised by selecting exonic and splicing variants, selecting variants with low allele frequency (below 1 %), and discarding the remaining variants with quality below 20. The variants were additionally confirmed by an inheritance pattern and cosegregation test of the families, and the rest of the variants were prioritised using in-silico prediction tools. Finally, causal variants were detected from 10 of 18 familial cases (55.5 %) and 7 of 16 simplex cases (43.7 %) in total. Novel variants were detected in 13 of 20 (65 %) candidate variants. Compound heterozygous variants were found in four of 7 simplex cases.Conclusion
Panel-based targeted re-sequencing can be used as an effective molecular diagnostic tool for RP.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1723-x) contains supplementary material, which is available to authorized users. 相似文献5.
Objective
To determine whether information from genetic risk variants for diabetes is associated with cardiovascular events incidence.Methods
From the about 30 known genes associated with diabetes, we genotyped single-nucleotide polymorphisms at the 10 loci most associated with type-2 diabetes in 425 subjects from the MASS-II Study, a randomized study in patients with multi-vessel coronary artery disease. The combined genetic information was evaluated by number of risk alleles for diabetes. Performance of genetic models relative to major cardiovascular events incidence was analyzed through Kaplan-Meier curve comparison and Cox Hazard Models and the discriminatory ability of models was assessed for cardiovascular events by calculating the area under the ROC curve.Results
Genetic information was able to predict 5-year incidence of major cardiovascular events and overall-mortality in non-diabetic individuals, even after adjustment for potential confounders including fasting glycemia. Non-diabetic individuals with high genetic risk had a similar incidence of events then diabetic individuals (cumulative hazard of 33.0 versus 35.1% of diabetic subjects). The addition of combined genetic information to clinical predictors significantly improved the AUC for cardiovascular events incidence (AUC = 0.641 versus 0.610).Conclusions
Combined information of genetic variants for diabetes risk is associated to major cardiovascular events incidence, including overall mortality, in non-diabetic individuals with coronary artery disease.Clinical Trial Registration Information
Medicine, Angioplasty, or Surgery Study (MASS II). Unique identifier: ISRCTN66068876 URL. 相似文献6.
Zhongxue Chen 《BMC genomics》2014,15(1)
Background
Current robust association tests for case–control genome-wide association study (GWAS) data are mainly based on the assumption of some specific genetic models. Due to the richness of the genetic models, this assumption may not be appropriate. Therefore, robust but powerful association approaches are desirable.Results
In this paper, we propose a new approach to testing for the association between the genotype and phenotype for case–control GWAS. This method assumes a generalized genetic model and is based on the selected disease allele to obtain a p-value from the more powerful one-sided test. Through a comprehensive simulation study we assess the performance of the new test by comparing it with existing methods. Some real data applications are also used to illustrate the use of the proposed test.Conclusions
Based on the simulation results and real data application, the proposed test is powerful and robust.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-358) contains supplementary material, which is available to authorized users. 相似文献7.
Background
Recent advances in deep digital sequencing have unveiled an unprecedented degree of clonal heterogeneity within a single tumor DNA sample. Resolving such heterogeneity depends on accurate estimation of fractions of alleles that harbor somatic mutations. Unlike substitutions or small indels, structural variants such as deletions, duplications, inversions and translocations involve segments of DNAs and are potentially more accurate for allele fraction estimations. However, no systematic method exists that can support such analysis.Results
In this paper, we present a novel maximum-likelihood method that estimates allele fractions of structural variants integratively from various forms of alignment signals. We develop a tool, BreakDown, to estimate the allele fractions of most structural variants including medium size (from 1 kilobase to 1 megabase) deletions and duplications, and balanced inversions and translocations.Conclusions
Evaluation based on both simulated and real data indicates that our method systematically enables structural variants for clonal heterogeneity analysis and can greatly enhance the characterization of genomically instable tumors.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2105-15-299) contains supplementary material, which is available to authorized users. 相似文献8.
Background
Like other structural variants, transposable element insertions can be highly polymorphic across individuals. Their functional impact, however, remains poorly understood. Current genome-wide approaches for genotyping insertion-site polymorphisms based on targeted or whole-genome sequencing remain very expensive and can lack accuracy, hence new large-scale genotyping methods are needed.Results
We describe a high-throughput method for genotyping transposable element insertions and other types of structural variants that can be assayed by breakpoint PCR. The method relies on next-generation sequencing of multiplex, site-specific PCR amplification products and read count-based genotype calls. We show that this method is flexible, efficient (it does not require rounds of optimization), cost-effective and highly accurate.Conclusions
This method can benefit a wide range of applications from the routine genotyping of animal and plant populations to the functional study of structural variants in humans.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1700-4) contains supplementary material, which is available to authorized users. 相似文献9.
Vilson Mirdita Guozheng Liu Yusheng Zhao Thomas Miedaner C. Friedrich H. Longin Manje Gowda Michael Florian Mette Jochen C. Reif 《BMC genomics》2015,16(1)
Background
Fusarium head blight (FHB) and Septoria tritici blotch (STB) severely impair wheat production. With the aim to further elucidate the genetic architecture underlying FHB and STB resistance, we phenotyped 1604 European wheat hybrids and their 135 parental lines for FHB and STB disease severities and determined genotypes at 17,372 single-nucleotide polymorphic loci.Results
Cross-validated association mapping revealed the absence of large effect QTL for both traits. Genomic selection showed a three times higher prediction accuracy for FHB than STB disease severity for test sets largely unrelated to the training sets.Conclusions
Our findings suggest that the genetic architecture is less complex and, hence, can be more properly tackled to perform accurate prediction for FHB than STB disease severity. Consequently, FHB disease severity is an interesting model trait to fine-tune genomic selection models exploiting beyond relatedness also knowledge of the genetic architecture.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1628-8) contains supplementary material, which is available to authorized users. 相似文献10.
Xu Han Lixuan Gui Bing Liu Jing Wang Yaru Li Xiayun Dai Jun Li Binyao Yang Gaokun Qiu Jing Feng Xiaomin Zhang Tangchun Wu Meian He 《BMC genetics》2015,16(1)
Background
Multiple studies investigated the associations between serum uric acid and coronary heart disease (CHD) risk. However, further investigations still remain to be carried out to determine whether there exists a causal relationship between them. We aim to explore the associations between genetic variants in uric acid related loci of SLC2A9 and ABCG2 and CHD risk in a Chinese population.Results
A case–control study including 1,146 CHD cases and 1,146 controls was conducted. Association analysis between two uric acid related variants (SNP rs11722228 in SLC2A9 and rs4148152 in ABCG2) and CHD risk was performed by logistic regression model. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Compared with subjects with A allele of rs4148152, those with G allele had a decreased CHD risk and the association remained significant in a multivariate model. However, it altered to null when BMI was added into the model. No significant association was observed between rs11722228 and CHD risk. The distribution of CHD risk factors was not significantly different among different genotypes of both SNPs. Among subjects who did not consume alcohol, the G allele of rs4148152 showed a moderate protective effect. However, no significant interactions were observed between SNP by CHD risk factors on CHD risk.Conclusions
There might be no association between the two uric acid related SNPs with CHD risk. Further studies were warranted to validate these results.Electronic supplementary material
The online version of this article (doi:10.1186/s12863-015-0162-7) contains supplementary material, which is available to authorized users. 相似文献11.
Matthew T. Webster Nona Kamgari Michele Perloski Marc P. Hoeppner Erik Axelsson ?ke Hedhammar Gerli Pielberg Kerstin Lindblad-Toh 《BMC genomics》2015,16(1)
Background
The domestic dog is a rich resource for mapping the genetic components of phenotypic variation due to its unique population history involving strong artificial selection. Genome-wide association studies have revealed a number of chromosomal regions where genetic variation associates with morphological characters that typify dog breeds. A region on chromosome 10 is among those with the highest levels of genetic differentiation between dog breeds and is associated with body mass and ear morphology, a common motif of animal domestication. We characterised variation in this region to uncover haplotype structure and identify candidate functional variants.Results
We first identified SNPs that strongly associate with body mass and ear type by comparing sequence variation in a 3 Mb region between 19 breeds with a variety of phenotypes. We next genotyped a subset of 123 candidate SNPs in 288 samples from 46 breeds to identify the variants most highly associated with phenotype and infer haplotype structure. A cluster of SNPs that associate strongly with the drop ear phenotype is located within a narrow interval downstream of the gene MSRB3, which is involved in human hearing. These SNPs are in strong genetic linkage with another set of variants that correlate with body mass within the gene HMGA2, which affects human height. In addition we find evidence that this region has been under selection during dog domestication, and identify a cluster of SNPs within MSRB3 that are highly differentiated between dogs and wolves.Conclusions
We characterise genetically linked variants that potentially influence ear type and body mass in dog breeds, both key traits that have been modified by selective breeding that may also be important for domestication. The finding that variants on long haplotypes have effects on more than one trait suggests that genetic linkage can be an important determinant of the phenotypic response to selection in domestic animals.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1702-2) contains supplementary material, which is available to authorized users. 相似文献12.
Arnaud Sartelet Wanbo Li Eric Pailhoux Christophe Richard Nico Tamma Latifa Karim Corinne Fasquelle Tom Druet Wouter Coppieters Michel Georges Carole Charlier 《BMC genomics》2015,16(1)
Background
Cattle populations are characterized by regular outburst of genetic defects as a result of the extensive use of elite sires. The causative genes and mutations can nowadays be rapidly identified by means of genome-wide association studies combined with next generation DNA sequencing, provided that the causative mutations are conventional loss-of-function variants. We show in this work how the combined use of next generation DNA and RNA sequencing allows for the rapid identification of otherwise difficult to identify splice-site variants.Results
We report the use of haplotype-based association mapping to identify a locus on bovine chromosome 10 that underlies autosomal recessive arthrogryposis in Belgian Blue Cattle. We identify 31 candidate mutations by resequencing the genome of four cases and 15 controls at ~10-fold depth. By analyzing RNA-Seq data from a carrier fetus, we observe skipping of the second exon of the PIGH gene, which we confirm by RT-PCR to be fully penetrant in tissues from affected calves. We identify - amongst the 31 candidate variants - a C-to-G transversion in the first intron of the PIGH gene (c211-10C > G) that is predicted to affect its acceptor splice-site. The resulting PIGH protein is likely to be non-functional as it lacks essential domains, and hence to cause arthrogryposis.Conclusions
This work illustrates how the growing arsenal of genome exploration tools continues to accelerate the identification of an even broader range of disease causing mutations, therefore improving the management and control of genetic defects in livestock.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1528-y) contains supplementary material, which is available to authorized users. 相似文献13.
Roel Hermsen Joep de Ligt Wim Spee Francis Blokzijl Sebastian Sch?fer Eleonora Adami Sander Boymans Stephen Flink Ruben van Boxtel Robin H van der Weide Tim Aitman Norbert Hübner Marieke Simonis Boris Tabakoff Victor Guryev Edwin Cuppen 《BMC genomics》2015,16(1)
Background
Since the completion of the rat reference genome in 2003, whole-genome sequencing data from more than 40 rat strains have become available. These data represent the broad range of strains that are used in rat research including commonly used substrains. Currently, this wealth of information cannot be used to its full extent, because the variety of different variant calling algorithms employed by different groups impairs comparison between strains. In addition, all rat whole genome sequencing studies to date used an outdated reference genome for analysis (RGSC3.4 released in 2004).Results
Here we present a comprehensive, multi-sample and uniformly called set of genetic variants in 40 rat strains, including 19 substrains. We reanalyzed all primary data using a recent version of the rat reference assembly (RGSC5.0 released in 2012) and identified over 12 million genomic variants (SNVs, indels and structural variants) among the 40 strains. 28,318 SNVs are specific to individual substrains, which may be explained by introgression from other unsequenced strains and ongoing evolution by genetic drift. Substrain SNVs may have a larger predicted functional impact compared to older shared SNVs.Conclusions
In summary we present a comprehensive catalog of uniformly analyzed genetic variants among 40 widely used rat inbred strains based on the RGSC5.0 assembly. This represents a valuable resource, which will facilitate rat functional genomic research. In line with previous observations, our genome-wide analyses do not show evidence for contribution of multiple ancestral founder rat subspecies to the currently used rat inbred strains, as is the case for mouse. In addition, we find that the degree of substrain variation is highly variable between strains, which is of importance for the correct interpretation of experimental data from different labs.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1594-1) contains supplementary material, which is available to authorized users. 相似文献14.
Background
Domestication has shaped the horse and lead to a group of many different types. Some have been under strong human selection while others developed in close relationship with nature. The aim of our study was to perform next generation sequencing of breed and non-breed horses to provide an insight into genetic influences on selective forces.Results
Whole genome sequencing of five horses of four different populations revealed 10,193,421 single nucleotide polymorphisms (SNPs) and 1,361,948 insertion/deletion polymorphisms (indels). In comparison to horse variant databases and previous reports, we were able to identify 3,394,883 novel SNPs and 868,525 novel indels. We analyzed the distribution of individual variants and found significant enrichment of private mutations in coding regions of genes involved in primary metabolic processes, anatomical structures, morphogenesis and cellular components in non-breed horses and in contrast to that private mutations in genes affecting cell communication, lipid metabolic process, neurological system process, muscle contraction, ion transport, developmental processes of the nervous system and ectoderm in breed horses.Conclusions
Our next generation sequencing data constitute an important first step for the characterization of non-breed in comparison to breed horses and provide a large number of novel variants for future analyses. Functional annotations suggest specific variants that could play a role for the characterization of breed or non-breed horses.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-562) contains supplementary material, which is available to authorized users. 相似文献15.
Stuart J Lucas Bala An? Akp?nar Hana ?imková Marie Kubaláková Jaroslav Dole?el Hikmet Budak 《BMC genomics》2014,15(1)
Background
The ~17 Gb hexaploid bread wheat genome is a high priority and a major technical challenge for genomic studies. In particular, the D sub-genome is relatively lacking in genetic diversity, making it both difficult to map genetically, and a target for introgression of agriculturally useful traits. Elucidating its sequence and structure will therefore facilitate wheat breeding and crop improvement.Results
We generated shotgun sequences from each arm of flow-sorted Triticum aestivum chromosome 5D using 454 FLX Titanium technology, giving 1.34× and 1.61× coverage of the short (5DS) and long (5DL) arms of the chromosome respectively. By a combination of sequence similarity and assembly-based methods, ~74% of the sequence reads were classified as repetitive elements, and coding sequence models of 1314 (5DS) and 2975 (5DL) genes were generated. The order of conserved genes in syntenic regions of previously sequenced grass genomes were integrated with physical and genetic map positions of 518 wheat markers to establish a virtual gene order for chromosome 5D.Conclusions
The virtual gene order revealed a large-scale chromosomal rearrangement in the peri-centromeric region of 5DL, and a concentration of non-syntenic genes in the telomeric region of 5DS. Although our data support the large-scale conservation of Triticeae chromosome structure, they also suggest that some regions are evolving rapidly through frequent gene duplications and translocations.Sequence accessions
EBI European Nucleotide Archive, Study no. ERP002330Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1080) contains supplementary material, which is available to authorized users. 相似文献16.
Li Jiang Xuan Liu Jie Yang Haifei Wang Jicai Jiang Lili Liu Sang He Xiangdong Ding Jianfeng Liu Qin Zhang 《BMC genomics》2014,15(1)
Background
Genome wide association study (GWAS) has been proven to be a powerful tool for detecting genomic variants associated with complex traits. However, the specific genes and causal variants underlying these traits remain unclear.Results
Here, we used target-enrichment strategy coupled with next generation sequencing technique to study target regions which were found to be associated with milk production traits in dairy cattle in our previous GWAS. Among the large amount of novel variants detected by targeted resequencing, we selected 200 SNPs for further association study in a population consisting of 2634 cows. Sixty six SNPs distributed in 53 genes were identified to be associated significantly with on milk production traits. Of the 53 genes, 26 were consistent with our previous GWAS results. We further chose 20 significant genes to analyze their mRNA expression in different tissues of lactating cows, of which 15 were specificly highly expressed in mammary gland.Conclusions
Our study illustrates the potential for identifying causal mutations for milk production traits using target-enrichment resequencing and extends the results of GWAS by discovering new and potentially functional mutations.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1105) contains supplementary material, which is available to authorized users. 相似文献17.
Li Jiang Stefan M Edwards Bo Thomsen Christopher T Workman Bernt Guldbrandtsen Peter S?rensen 《BMC bioinformatics》2014,15(1)
Background
Prioritizing genetic variants is a challenge because disease susceptibility loci are often located in genes of unknown function or the relationship with the corresponding phenotype is unclear. A global data-mining exercise on the biomedical literature can establish the phenotypic profile of genes with respect to their connection to disease phenotypes. The importance of protein-protein interaction networks in the genetic heterogeneity of common diseases or complex traits is becoming increasingly recognized. Thus, the development of a network-based approach combined with phenotypic profiling would be useful for disease gene prioritization.Results
We developed a random-set scoring model and implemented it to quantify phenotype relevance in a network-based disease gene-prioritization approach. We validated our approach based on different gene phenotypic profiles, which were generated from PubMed abstracts, OMIM, and GeneRIF records. We also investigated the validity of several vocabulary filters and different likelihood thresholds for predicted protein-protein interactions in terms of their effect on the network-based gene-prioritization approach, which relies on text-mining of the phenotype data. Our method demonstrated good precision and sensitivity compared with those of two alternative complex-based prioritization approaches. We then conducted a global ranking of all human genes according to their relevance to a range of human diseases. The resulting accurate ranking of known causal genes supported the reliability of our approach. Moreover, these data suggest many promising novel candidate genes for human disorders that have a complex mode of inheritance.Conclusion
We have implemented and validated a network-based approach to prioritize genes for human diseases based on their phenotypic profile. We have devised a powerful and transparent tool to identify and rank candidate genes. Our global gene prioritization provides a unique resource for the biological interpretation of data from genome-wide association studies, and will help in the understanding of how the associated genetic variants influence disease or quantitative phenotypes.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2105-15-315) contains supplementary material, which is available to authorized users. 相似文献18.
So-Young Bang Young-Ji Na Kwangwoo Kim Young Bin Joo Youngho Park Jaemoon Lee Sun-Young Lee Adnan A Ansari Junghee Jung Hwanseok Rhee Jong-Young Lee Bok-Ghee Han Sung-Min Ahn Sungho Won Hye-Soon Lee Sang-Cheol Bae 《Arthritis research & therapy》2014,16(5)
Introduction
Although it has been suggested that rare coding variants could explain the substantial missing heritability, very few sequencing studies have been performed in rheumatoid arthritis (RA). We aimed to identify novel functional variants with rare to low frequency using targeted exon sequencing of RA in Korea.Methods
We analyzed targeted exon sequencing data of 398 genes selected from a multifaceted approach in Korean RA patients (n = 1,217) and controls (n = 717). We conducted a single-marker association test and a gene-based analysis of rare variants. For meta-analysis or enrichment tests, we also used ethnically matched independent samples of Korean genome-wide association studies (GWAS) (n = 4,799) or immunochip data (n = 4,722).Results
After stringent quality control, we analyzed 10,588 variants of 398 genes from 1,934 Korean RA case controls. We identified 13 nonsynonymous variants with nominal association in single-variant association tests. In a meta-analysis, we did not find any novel variant with genome-wide significance for RA risk. Using a gene-based approach, we identified 17 genes with nominal burden signals. Among them, VSTM1 showed the greatest association with RA (P = 7.80 × 10−4). In the enrichment test using Korean GWAS, although the significant signal appeared to be driven by total genic variants, we found no evidence for enriched association of coding variants only with RA.Conclusions
We were unable to identify rare coding variants with large effect to explain the missing heritability for RA in the current targeted resequencing study. Our study raises skepticism about exon sequencing of targeted genes for complex diseases like RA.Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0447-7) contains supplementary material, which is available to authorized users. 相似文献19.
Eva C Berglund Carl M?rten Lindqvist Shahina Hayat Elin ?vern?s Niklas Henriksson Jessica Nordlund Per Wahlberg Erik Forestier Gudmar L?nnerholm Ann-Christine Syv?nen 《BMC genomics》2013,14(1)
Background
Target enrichment and resequencing is a widely used approach for identification of cancer genes and genetic variants associated with diseases. Although cost effective compared to whole genome sequencing, analysis of many samples constitutes a significant cost, which could be reduced by pooling samples before capture. Another limitation to the number of cancer samples that can be analyzed is often the amount of available tumor DNA. We evaluated the performance of whole genome amplified DNA and the power to detect subclonal somatic single nucleotide variants in non-indexed pools of cancer samples using the HaloPlex technology for target enrichment and next generation sequencing.Results
We captured a set of 1528 putative somatic single nucleotide variants and germline SNPs, which were identified by whole genome sequencing, with the HaloPlex technology and sequenced to a depth of 792–1752. We found that the allele fractions of the analyzed variants are well preserved during whole genome amplification and that capture specificity or variant calling is not affected. We detected a large majority of the known single nucleotide variants present uniquely in one sample with allele fractions as low as 0.1 in non-indexed pools of up to ten samples. We also identified and experimentally validated six novel variants in the samples included in the pools.Conclusion
Our work demonstrates that whole genome amplified DNA can be used for target enrichment equally well as genomic DNA and that accurate variant detection is possible in non-indexed pools of cancer samples. These findings show that analysis of a large number of samples is feasible at low cost, even when only small amounts of DNA is available, and thereby significantly increases the chances of indentifying recurrent mutations in cancer samples.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-14-856) contains supplementary material, which is available to authorized users. 相似文献20.
Miaofei Xu Yufeng Qin Jianhua Qu Chuncheng Lu Ying Wang Wei Wu Ling Song Shoulin Wang Feng Chen Hongbing Shen Jiahao Sha Zhibin Hu Yankai Xia Xinru Wang 《PloS one》2013,8(11)