Excited to share our latest work. We introduce an improved version of NanoSeq, a duplex sequencing protocol with <5 errors per billion bp in single DNA molecules, and use it to study the somatic mutation landscape of oral epithelium in >1000 people. 1/n

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An early example is this beautiful study by @MDC_Neville, @R_Rahbari and cols applying exome NanoSeq to sperm and unveiling a rich landscape of selection in the male germline, which explains the high incidence of some de novo developmental disorders. END.

Beyond this study, for us whole-exome NanoSeq is proving a bit like looking down a microscope for the first time. We are seeing fascinating somatic evolution in a range of tissues and diseases, which is changing our perspective on them. 20/n.

A huge thanks to the many friends and colleagues at Sanger and elsewhere who have made this possible. Particular thanks to the brilliant Andrew Lawson, Pan Nicola and Fede Abascal. Stef Lensing on R&D. And the TwinsUK team and donors for making this collection possible. 🙏19/n

The paper packs a few more things for those interested. Including new algorithms, detailed supplementary notes connecting these discoveries in normal tissues with classical multistage models of carcinogenesis, heritability analyses, etc. 18/n

For example, we show that alcohol (a risk factor for oral cancer) is quite mutagenic, but its mutational spectrum is (fortunately) biased towards intronic sequences, reducing the impact on coding sequences per drink unit. 17/n.

Multivariate regression models then enable mutational epidemiology studies on how exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. 16/n

By analysing how the frequency of driver mutations increases with age, we also gained new and unexpected insights into the mode of clonal growth in oral epithelium, which suggests that clonal expansions are highly constrained. 15/n

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. This reveals very interesting patterns of selection within genes. 14/n

For example, we found over 20,000 somatic mutations in NOTCH1 and >7,000 in TP53. For multiple genes, we find many more driver mutations than reported in >40,000 cancer exomes and genomes in the COSMIC database. 13/n.

We found 49 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. 12/n

We then applied deep targeted NanoSeq to 1,042 buccal swabs and 371 samples of blood from a twin cohort. This revealed an unprecedentedly rich landscape of clonal selection. 11/n.

Today we present a new NanoSeq protocol with full genome coverage, compatible with targeted or exome capture, with <5e-9 error rate in single DNA molecules. This yields accurate somatic mutation rates, signatures and driver landscapes from any tissue or cell population. 10/n