Whole-exome sequencing of fibroblast and its iPS cell lines derived from a patient diagnosed with xeroderma pigmentosum.

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Because such mutations occur independently in each cell, there is a high degree of mosaicism in patients' tissues. While major mutations that have been expanded in many cognate cells are readily detected by sequencing, minor ones are overlaid with a large depth of non-mutated alleles and are not detected. However, cell cloning enables us to observe such cryptic mutations as well as major mutations. In the present study, we focused on a fibroblastic cell line that is derived from a patient diagnosed with xeroderma pigmentosum (XP), which is an autosomal recessive disorder caused by a deficiency in nucleotide excision repair. By making a list of somatic mutations, we can expect to see a characteristic pattern of mutations caused by the hereditary disorder. We cloned a cell by generating an iPS cell line and performed a whole-exome sequencing analysis of the progenitor and its iPS cell lines. Unexpectedly, we failed to find causal mutations in the XP-related genes, but we identified many other mutations including homozygous deletion of GSTM1 and GSTT1. In addition, we found that the long arm of chromosome 9 formed uniparental disomy in the iPS cell line, which was also confirmed by a structural mutation analysis using a SNP array. Type and number of somatic mutations were different from those observed in XP patients. Taken together, we conclude that the patient might be affected by a different type of the disorder and that some of the mutations that we identified here may be responsible for exhibiting the phenotype. Sequencing and SNP-array data have been submitted to SRA and GEO under accession numbers SRP059858 and GSE55520, respectively.", "claims": [{"id": "claim-data-access", "statement": "Sequencing and SNP-array data have been submitted to SRA and GEO under accession numbers SRP059858 and GSE55520, respectively.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:26697316", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Sequencing and SNP-array data have been submitted to SRA and GEO under accession numbers SRP059858 and GSE55520, respectively."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Whole-exome sequencing of the fibroblast and its iPS-cell lines, using multi-sample variant calling and comparison of inconsistent genotypes, did not identify causal XP-gene mutations but did identify other mutations, including homozygous GSTM1 and GSTT1 deletions and chromosome 9 uniparental disomy; the sequencing and SNP-array data are available through SRA accession SRP059858 and GEO accession GSE55520.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:26697316", "locator": "sections[3] \"Experimental design, materials and methods\" paragraph 5", "quote": "Next, we searched for inconsistent genotypes called with UnifiedGenotyper between the progenitor and its iPS cell lines to identify somatic mutations."}, {"asset": "source:pmid:26697316", "locator": "sections[3] \"Experimental design, materials and methods\" paragraph 3", "quote": "Along with in-house control data, multi-sample calling of single-nucleotide and short indel variations was performed."}, {"asset": "source:pmid:26697316", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Unexpectedly, we failed to find causal mutations in the XP-related genes, but we identified many other mutations including homozygous deletion of GSTM1 and GSTT1."}, {"asset": "source:pmid:26697316", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "In addition, we found that the long arm of chromosome 9 formed uniparental disomy in the iPS cell line, which was also confirmed by a structural mutation analysis using a SNP array."}, {"asset": "source:pmid:26697316", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Sequencing and SNP-array data have been submitted to SRA and GEO under accession numbers SRP059858 and GSE55520, respectively."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Whole-exome sequencing of the fibroblast and its iPS-cell lines, using multi-sample variant calling and comparison of inconsistent genotypes, did not identify causal XP-gene mutations but did identify other mutations, including homozygous GSTM1 and GSTT1 deletions and chromosome 9 uniparental disomy; the sequencing and SNP-array data are available through SRA accession SRP059858 and GEO accession GSE55520.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:26697316"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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