| 1. |
- Behnamian, Sara, et al.
(author)
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Temporal population structure, a genetic dating method for ancient Eurasian genomes from the past 10,000 years
- 2022
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In: Cell reports methods. - : Elsevier BV. - 2667-2375. ; 2:8
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Journal article (peer-reviewed)abstract
- Radiocarbon dating is the gold standard in archeology to estimate the age of skeletons, a key to studying their origins. Many published ancient genomes lack reliable and direct dates, which results in obscure and contradictory reports. We developed the temporal population structure (TPS), a DNA-based dating method for genomes ranging from the Late Mesolithic to today, and applied it to 3,591 ancient and 1,307 modern Eurasians. TPS predictions aligned with the known dates and correctly accounted for kin relationships. TPS dating of poorly dated Eurasian samples resolved conflicting reports in the literature, as illustrated by one test case. We also demonstrated how TPS improved the ability to study phenotypic traits over time. TPS can be used when radiocarbon dating is unfeasible or uncertain or to develop alternative hypotheses for samples younger than 10,000 years ago, a limitation that may be resolved over time as ancient data accumulate.
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| 2. |
- Daneshjou, Roxana, et al.
(author)
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Working toward precision medicine : Predicting phenotypes from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges
- 2017
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In: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 38:9, s. 1182-1192
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Journal article (peer-reviewed)abstract
- Precision medicine aims to predict a patient's disease risk and best therapeutic options by using that individual's genetic sequencing data. The Critical Assessment of Genome Interpretation (CAGI) is a community experiment consisting of genotype-phenotype prediction challenges; participants build models, undergo assessment, and share key findings. For CAGI 4, three challenges involved using exome-sequencing data: Crohn's disease, bipolar disorder, and warfarin dosing. Previous CAGI challenges included prior versions of the Crohn's disease challenge. Here, we discuss the range of techniques used for phenotype prediction as well as the methods used for assessing predictive models. Additionally, we outline some of the difficulties associated with making predictions and evaluating them. The lessons learned from the exome challenges can be applied to both research and clinical efforts to improve phenotype prediction from genotype. In addition, these challenges serve as a vehicle for sharing clinical and research exome data in a secure manner with scientists who have a broad range of expertise, contributing to a collaborative effort to advance our understanding of genotype-phenotype relationships.
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| 3. |
- Fang, Li Tai, et al.
(author)
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Establishing community reference samples, data and call sets for benchmarking cancer mutation detection using whole-genome sequencing
- 2021
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In: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 39:9, s. 1151-1160
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Journal article (peer-reviewed)abstract
- Tumor-normal paired DNA samples from a breast cancer cell line and a matched lymphoblastoid cell line enable calibration of clinical sequencing pipelines and benchmarking 'tumor-only' or 'matched tumor-normal' analyses. The lack of samples for generating standardized DNA datasets for setting up a sequencing pipeline or benchmarking the performance of different algorithms limits the implementation and uptake of cancer genomics. Here, we describe reference call sets obtained from paired tumor-normal genomic DNA (gDNA) samples derived from a breast cancer cell line-which is highly heterogeneous, with an aneuploid genome, and enriched in somatic alterations-and a matched lymphoblastoid cell line. We partially validated both somatic mutations and germline variants in these call sets via whole-exome sequencing (WES) with different sequencing platforms and targeted sequencing with >2,000-fold coverage, spanning 82% of genomic regions with high confidence. Although the gDNA reference samples are not representative of primary cancer cells from a clinical sample, when setting up a sequencing pipeline, they not only minimize potential biases from technologies, assays and informatics but also provide a unique resource for benchmarking 'tumor-only' or 'matched tumor-normal' analyses.
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| 4. |
- Goes, Fernando S, et al.
(author)
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Exome Sequencing of Familial Bipolar Disorder.
- 2016
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In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 73:6, s. 590-7
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Journal article (peer-reviewed)abstract
- Complex disorders, such as bipolar disorder (BD), likely result from the influence of both common and rare susceptibility alleles. While common variation has been widely studied, rare variant discovery has only recently become feasible with next-generation sequencing.
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| 5. |
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| 6. |
- Johannsen, Emma B., et al.
(author)
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The genetics of sudden infant death syndrome—towards a gene reference resource
- 2021
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In: Genes. - : MDPI AG. - 2073-4425. ; 12:2
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Journal article (peer-reviewed)abstract
- Sudden infant death syndrome (SIDS) is the unexpected death of an infant under one year of age that remains unexplained after a thorough investigation. Despite SIDS remaining a diagnosis of exclusion with an unexplained etiology, it is widely accepted that SIDS can be caused by environmental and/or biological factors, with multiple underlying candidate genes. However, the lack of biomarkers raises questions as to why genetic studies on SIDS to date are unable to provide a clearer understanding of the disease etiology. We sought to improve the identification of SIDS-associated genes by reviewing the SIDS genetic literature and objectively categorizing and scoring the reported genes based on the strength of evidence (from C1 (high) to C5 (low)). This was followed by analyses of function, associations between genes, the enrichment of gene ontology (GO) terms, and pathways and gender difference in tissue gene expression. We constructed a curated database for SIDS gene candidates consisting of 109 genes, 14 of which received a category 4 (C4) and 95 genes received the lowest category of C5. That none of the genes was classified into the higher categories indicates the low level of supporting evidence. We found that genes of both scoring categories show distinct networks and are highly diverse in function and involved in many GO terms and pathways, in agreement with the perception of SIDS as a heterogeneous syndrome. Genes of both scoring categories are part of the cardiac system, muscle, and ion channels, whereas immune-related functions showed enrichment for C4 genes. A limited association was found with neural development. Overall, inconsistent reports and missing metadata contribute to the ambiguity of genetic studies. Considering those parameters could help improve the identification of at-risk SIDS genes. However, the field is still far from offering a full-pledged genetic test to identify at-risk infants and is still hampered with methodological challenges and misunderstandings of the vulnerabilities of vital biological mechanisms.
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| 7. |
- Xiao, Wenming, et al.
(author)
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Toward best practice in cancer mutation detection with whole-genome and whole-exome sequencing
- 2021
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In: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 39:9, s. 1141-1150
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Journal article (peer-reviewed)abstract
- Recommendations are given on optimal read coverage and selection of calling algorithm to maximize the reproducibility of cancer mutation detection in whole-genome or whole-exome sequencing. Clinical applications of precision oncology require accurate tests that can distinguish true cancer-specific mutations from errors introduced at each step of next-generation sequencing (NGS). To date, no bulk sequencing study has addressed the effects of cross-site reproducibility, nor the biological, technical and computational factors that influence variant identification. Here we report a systematic interrogation of somatic mutations in paired tumor-normal cell lines to identify factors affecting detection reproducibility and accuracy at six different centers. Using whole-genome sequencing (WGS) and whole-exome sequencing (WES), we evaluated the reproducibility of different sample types with varying input amount and tumor purity, and multiple library construction protocols, followed by processing with nine bioinformatics pipelines. We found that read coverage and callers affected both WGS and WES reproducibility, but WES performance was influenced by insert fragment size, genomic copy content and the global imbalance score (GIV; G > T/C > A). Finally, taking into account library preparation protocol, tumor content, read coverage and bioinformatics processes concomitantly, we recommend actionable practices to improve the reproducibility and accuracy of NGS experiments for cancer mutation detection.
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