Targeted_EMSeq___Development

Development of a targeted methylation assay to determine the cell-type composition of a sample.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

2 Datasets 1 Publication

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001015622	Development of a targeted methylation assay to determine the cell-type composition of a sample. As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq), a duplex sequencing method with error rates of less than 5 per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 46 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.	Illumina NovaSeq 6000	1
EGAD00001015623	Development of a targeted methylation assay to determine the cell-type composition of a sample. As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq), a duplex sequencing method with error rates of less than 5 per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 46 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.	Illumina NovaSeq 6000	1

Publications	Citations
Somatic mutation and selection at population scale. Lawson ARJ, Abascal F, Nicola PA, Lensing SV, Roberts AL, Kalantzis G, Baez-Ortega A, Brzozowska N, El-Sayed Moustafa JS, Vaitkute D, Jakupovic B, Nessa A, Wadge S, Österdahl MF, Paterson AL, Rassl DM, Alcantara RE, O'Neill L, Widaa S, Austin-Guest S, Neville MDC, Przybilla MJ, Cheng W, Morra M, Sykes L, Mayho M, Müller-Sienerth N, Williams N, Alexander D, Harvey LMR, Clarke T, Byrne A, Blundell JR, Young MD, Mahbubani KTA, Saeb-Parsy K, Martin HC, Stratton MR, Campbell PJ, Rahbari R, Small KS, Martincorena I. Nature 647: 2025 411-420	2

Publications

Citations

Somatic mutation and selection at population scale.
Lawson ARJ, Abascal F, Nicola PA, Lensing SV, Roberts AL, Kalantzis G, Baez-Ortega A, Brzozowska N, El-Sayed Moustafa JS, Vaitkute D, Jakupovic B, Nessa A, Wadge S, Österdahl MF, Paterson AL, Rassl DM, Alcantara RE, O'Neill L, Widaa S, Austin-Guest S, Neville MDC, Przybilla MJ, Cheng W, Morra M, Sykes L, Mayho M, Müller-Sienerth N, Williams N, Alexander D, Harvey LMR, Clarke T, Byrne A, Blundell JR, Young MD, Mahbubani KTA, Saeb-Parsy K, Martin HC, Stratton MR, Campbell PJ, Rahbari R, Small KS, Martincorena I. Nature 647: 2025 411-420