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To test the performance of a new sequencing platform, develop an updated somatic calling pipeline and establish a reference for future benchmarking experiments, we performed whole-genome sequencing of 3 common cancer cell lines (COLO-829, HCC-1143 and HCC-1187) along with their matched normal cell lines to great sequencing depths (up to 278x coverage) on both Illumina HiSeqX and NovaSeq sequencing instruments. Somatic calling was generally consistent between the two platforms despite minor differences at the read level. We designed and implemented a novel pipeline for the analysis of tumor-normal samples, using multiple variant callers. We show that coupled with a high-confidence filtering strategy, the use of combination of tools improves the accuracy of somatic variant calling. We also demonstrate the utility of the dataset by creating an artificial purity ladder to evaluate the somatic pipeline and benchmark methods for estimating purity and ploidy from tumor-normal pairs. The data and results of the pipeline are made accessible to the cancer genomics community.

Background Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. Studies have correlated risk of CRC development with dietary habits and environmental conditions. Gene signatures for any disease can identify the key biological processes, which is especially useful in studying cancer development. Such processes can be used to evaluate potential drug targets. Though recognition of CRC gene-signatures across populations is crucial to better understanding potential novel treatment options for CRC, it remains a challenging task. Results We developed a topological and biological feature-based network approach for identifying the gene signatures across populations. In this work, we propose a novel approach of using cliques to understand the variability within population. Cliques are more conserved and co-expressed, therefore allowing identification and comparison of cliques across a population which can help researchers study gene variations. Our study was based on four publicly available expression datasets belonging to four different populations across the world. We identified cliques of various sizes (0 to 7) across the four population networks. Cliques of size seven were further analyzed across populations for their commonality and uniqueness. Forty-nine common cliques of size seven were identified. These cliques were further analyzed based on their connectivity profiles. We found associations between the cliques and their connectivity profiles across networks. With these clique connectivity profiles (CCPs), we were able to identify the divergence among the populations, important biological processes (cell cycle, signal transduction, and cell differentiation), and related gene pathways. Therefore the genes identified in these cliques and their connectivity profiles can be defined as the gene-signatures across populations. In this work we demonstrate the power and effectiveness of cliques to study CRC across populations. Conclusions We developed a new approach where cliques and their connectivity profiles helped elucidate the variation and similarity in CRC gene profiles across four populations with unique dietary habits.

ABSTRACT The 1000 Genomes Project (1kGP), launched in 2008, is the largest fully open resource of whole genome sequencing (WGS) data consented for public distribution of raw sequence data without access or use restrictions. The final (phase 3) 2015 release of 1kGP included 2,504 unrelated samples from 26 populations, representing five continental regions of the world and was based on a combination of technologies including low coverage WGS (mean depth 7.4X), high coverage whole exome sequencing (mean depth 65.7X), and microarray genotyping. Here, we present a new, high coverage WGS resource encompassing the original 2,504 1kGP samples, as well as an additional 698 related samples that result in 602 complete trios in the 1kGP cohort. We sequenced this expanded 1kGP cohort of 3,202 samples to a targeted depth of 30X using Illumina NovaSeq 6000 instruments. We performed SNV/INDEL calling against the GRCh38 reference using GATK’s HaplotypeCaller, and generated a comprehensive set of SVs by integrating multiple analytic methods through a sophisticated machine learning model, upgrading the 1kGP dataset to current state-of-the-art standards. Using this strategy, we defined over 111 million SNVs, 14 million INDELs, and ∼170 thousand SVs across the entire cohort of 3,202 samples with estimated false discovery rate (FDR) of 0.3%, 1.0%, and 1.8%, respectively. By comparison to the low-coverage phase 3 callset, we observed substantial improvements in variant discovery and estimated FDR that were facilitated by high coverage re-sequencing and expansion of the cohort. Specifically, we called 7% more SNVs, 59% more INDELs, and 170% more SVs per genome than the phase 3 callset. Moreover, we leveraged the presence of families in the cohort to achieve superior haplotype phasing accuracy and we demonstrate improvements that the high coverage panel brings especially for INDEL imputation. We make all the data generated as part of this project publicly available and we envision this updated version of the 1kGP callset to become the new de facto public resource for the worldwide scientific community working on genomics and genetics. Competing Interest Statement M.C.Z. is a shareholder in Merck & Co and Thermo Fisher Scientific. P.F. is a member of the scientific advisory boards of Fabric Genomics, Inc., and Eagle Genomics, Ltd. J.L. is an employee and shareholder of Bionano Genomics.

To test the performance of a new sequencing platform, develop an updated somatic calling pipeline and establish a reference for future benchmarking experiments, we sequenced 3 common cancer cell lines along with their matched normal cell lines to great sequencing depths (up to 278X coverage) on both Illumina HiSeqX and NovaSeq sequencing instruments. Somatic calling was generally consistent between the two platforms despite minor differences at the read level. We designed and implemented a novel pipeline for the analysis of tumor-normal samples, using multiple variant callers. We show that coupled with a high-confidence filtering strategy, it improves the accuracy of somatic calls. We also demonstrate the utility of the dataset by creating an artificial purity ladder to evaluate the somatic pipeline and benchmark methods for estimating purity and ploidy from tumor-normal pairs. The data and results of the pipeline are made accessible to the cancer genomics community. Footnotes * https://www.nygenome.org/bioinformatics/3-cancer-cell-lines-on-2-sequencers/