Browsing by Subject "COPY NUMBER VARIATIONS"

Sort by: Order: Results:

Now showing items 1-2 of 2
  • Jones, W; Gong, BS; Novoradovskaya, N; Li, D; Kusko, R; Richmond, TA; Johann, DJ; Bisgin, H; Sahraeian, SME; Bushel, PR; Pirooznia, M; Wilkins, K; Chierici, M; Bao, WJ; Basehore, LS; Lucas, AB; Burgess, D; Butler, DJ; Cawley, S; Chang, CJ; Chen, GC; Chen, T; Chen, YC; Craig, DJ; Del Pozo, A; Foox, J; Francescatto, M; Fu, YT; Furlanello, C; Giorda, K; Grist, KP; Guan, MJ; Hao, YY; Happe, S; Hariani, G; Haseley, N; Jasper, J; Jurman, G; Kreil, DP; Labaj, P; Lai, K; Li, JY; Li, QZ; Li, YL; Li, ZG; Liu, ZC; Lopez, MS; Miclaus, K; Miller, R; Mittal, VK; Mohiyuddin, M; Pabon-Pena, C; Parsons, BL; Qiu, FJ; Scherer, A; Shi, TL; Stiegelmeyer, S; Suo, C; Tom, N; Wang, D; Wen, ZN; Wu, LH; Xiao, WZ; Xu, C; Yu, Y; Zhang, JY; Zhang, YF; Zhang, ZH; Zheng, YT; Mason, CE; Willey, JC; Tong, WD; Shi, LM; Xu, J (2021)
    BackgroundOncopanel genomic testing, which identifies important somatic variants, is increasingly common in medical practice and especially in clinical trials. Currently, there is a paucity of reliable genomic reference samples having a suitably large number of pre-identified variants for properly assessing oncopanel assay analytical quality and performance. The FDA-led Sequencing and Quality Control Phase 2 (SEQC2) consortium analyze ten diverse cancer cell lines individually and their pool, termed Sample A, to develop a reference sample with suitably large numbers of coding positions with known (variant) positives and negatives for properly evaluating oncopanel analytical performance.ResultsIn reference Sample A, we identify more than 40,000 variants down to 1% allele frequency with more than 25,000 variants having less than 20% allele frequency with 1653 variants in COSMIC-related genes. This is 5-100x more than existing commercially available samples. We also identify an unprecedented number of negative positions in coding regions, allowing statistical rigor in assessing limit-of-detection, sensitivity, and precision. Over 300 loci are randomly selected and independently verified via droplet digital PCR with 100% concordance. Agilent normal reference Sample B can be admixed with Sample A to create new samples with a similar number of known variants at much lower allele frequency than what exists in Sample A natively, including known variants having allele frequency of 0.02%, a range suitable for assessing liquid biopsy panels.ConclusionThese new reference samples and their admixtures provide superior capability for performing oncopanel quality control, analytical accuracy, and validation for small to large oncopanels and liquid biopsy assays.
  • Guo, Michael H.; Nandakumar, Satish K.; Ulirsch, Jacob C.; Zekavat, Seyedeh M.; Buenrostro, Jason D.; Natarajan, Pradeep; Salem, Rany M.; Chiarle, Roberto; Mitt, Mario; Kals, Mart; Pärn, Kalle; Fischer, Krista; Milani, Lili; Magi, Reedik; Palta, Priit; Gabriel, Stacey B.; Metspalu, Andres; Lander, Eric S.; Kathiresan, Sekar; Hirschhorn, Joel N.; Esko, Tonu; Sankaran, Vijay G. (2017)
    Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA. The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.