Whole Genome Sequencing Highlights Genetic Changes Associated with Laboratory Domestication of C. elegans

The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable, suggesting alternative pathways to malignancy. We used whole-genome sequencing (WGS) and transcriptomics to investigate the landscape of sporadic retinoblastomas derived from twenty patients, sought RB1 and other driver mutations and investigated mutational signatures. At least one RB1 mutation was identified in all retinoblastomas, including new mutations in addition to those previously identified by clinical screening. Ten tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. Mutational signature analysis showed predominance of signatures associated with cell division, an absence of ultraviolet-related DNA damage and a profound platinum-related mutational signature in a chemotherapy-exposed tumour. Most RB1 mutations are identifiable by clinical screening. However, the increased resolution and ability to detect otherwise elusive rearrangements by WGS have important repercussions on clinical management and advice on recurrence risks.

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Identification of essential genes in Caenorhabditis elegans through whole genome sequencing of legacy mutant collections

10.1101/2021.06.16.448744 ◽

2021 ◽

Author(s):

Donald G. Moerman ◽

Erica Li-Leger ◽

Stephane Flibotte ◽

Ralf Schnabel ◽

Heinke Holzkamp ◽

...

Keyword(s):

Embryonic Development ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Functional Characterization ◽

Model Organism ◽

Essential Genes ◽

Whole Genome ◽

C Elegans ◽

Novel Alleles ◽

Unknown Male

It has been estimated that 15-30% of the ~20,000 genes in C. elegans are essential, yet many of these genes remain to be identified or characterized. With the goal of identifying unknown essential genes, we performed whole genome sequencing on complementation pairs from legacy collections of maternal-effect lethal and sterile mutants. This approach uncovered maternal genes required for embryonic development and genes with putative sperm-specific functions. In total, 58 essential genes were identified on chromosomes III, IV, and V, of which 49 genes are represented by novel alleles in this collection. Of these 49 genes, 19 (40 alleles) were selected for further functional characterization. The terminal phenotypes of embryos were examined, revealing defects in cell division, morphogenesis, and osmotic integrity of the eggshell. Mating assays with wild-type males revealed previously unknown male-expressed genes required for fertilization and embryonic development. The result of this study is a catalogue of mutant alleles in essential genes that will serve as a resource to guide further study toward a more complete understanding of this important model organism. As many genes and developmental pathways in C. elegans are conserved and essential genes are often linked to human disease, uncovering the function of these genes may also provide insight to further our understanding of human biology.

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Whole genome sequencing reveals within-host genetic changes in paired meningococcal carriage isolates from Ethiopia

BMC Genomics ◽

10.1186/s12864-017-3806-3 ◽

2017 ◽

Vol 18 (1) ◽

Cited By ~ 16

Author(s):

Guro K. Bårnes ◽

Ola Brønstad Brynildsrud ◽

Bente Børud ◽

Bereket Workalemahu ◽

Paul A. Kristiansen ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome ◽

Genetic Changes ◽

Host Genetic

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Faculty Opinions recommendation of Whole-genome sequencing and variant discovery in C. elegans.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1103203.559198 ◽

2008 ◽

Author(s):

Pui-Yan Kwok

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome ◽

C Elegans ◽

Variant Discovery

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Faculty Opinions recommendation of C. elegans mutant identification with a one-step whole-genome-sequencing and SNP mapping strategy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.7049956.7268054 ◽

2010 ◽

Author(s):

Thorsten Hoppe ◽

Alexandra Segref

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome ◽

C Elegans ◽

Mapping Strategy ◽

Snp Mapping ◽

One Step ◽

Mutant Identification

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Decoding human cancer with whole genome sequencing: a review of PCAWG Project studies published in February 2020

Cancer and Metastasis Reviews ◽

10.1007/s10555-021-09969-z ◽

2021 ◽

Author(s):

Simona Giunta

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Cancer Genetics ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Driver Mutations ◽

Causative Mutation ◽

Whole Genome ◽

Genetic Changes ◽

Pan Cancer

AbstractCancer is underlined by genetic changes. In an unprecedented international effort, the Pan-Cancer Analysis of Whole Genomes (PCAWG) of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) sequenced the tumors of over two thousand five hundred patients across 38 different cancer types, as well as the corresponding healthy tissue, with the aim of identifying genome-wide mutations exclusively found in cancer and uncovering new genetic changes that drive tumor formation. What set this project apart from earlier efforts is the use of whole genome sequencing (WGS) that enabled to explore alterations beyond the coding DNA, into cancer’s non-coding genome. WGS of the entire cohort allowed to tease apart driving mutations that initiate and support carcinogenesis from passenger mutations that do not play an overt role in the disease. At least one causative mutation was found in 95% of all cancers, with many tumors showing an average of 5 driver mutations. The PCAWG Project also assessed the transcriptional output altered in cancer and rebuilt the evolutionary history of each tumor showing that initial driver mutations can occur years if not decades prior to a diagnosis. Here, I provide a concise review of the Pan-Cancer Project papers published on February 2020, along with key computational tools and the digital framework generated as part of the project. This represents an historic effort by hundreds of international collaborators, which provides a comprehensive understanding of cancer genetics, with publicly available data and resources representing a treasure trove of information to advance cancer research for years to come.

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