Measuring the distribution of fitness effects in somatic evolution by combining clonal dynamics with dN/dS ratios.
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Embargo End Date
ICR Authors
Authors
Williams, MJ
Zapata, L
Werner, B
Barnes, CP
Sottoriva, A
Graham, TA
Zapata, L
Werner, B
Barnes, CP
Sottoriva, A
Graham, TA
Document Type
Journal Article
Date
2020-03-30
Date Accepted
2020-03-09
Abstract
The distribution of fitness effects (DFE) defines how new mutations spread through an evolving population. The ratio of non-synonymous to synonymous mutations (dN/dS) has become a popular method to detect selection in somatic cells. However the link, in somatic evolution, between dN/dS values and fitness coefficients is missing. Here we present a quantitative model of somatic evolutionary dynamics that determines the selective coefficients of individual driver mutations from dN/dS estimates. We then measure the DFE for somatic mutant clones in ostensibly normal oesophagus and skin. We reveal a broad distribution of fitness effects, with the largest fitness increases found for TP53 and NOTCH1 mutants (proliferative bias 1-5%). This study provides the theoretical link between dN/dS values and selective coefficients in somatic evolution, and measures the DFE of mutations in human tissues.
Citation
eLife, 2020, 9
Source Title
Publisher
ELIFE SCIENCES PUBLICATIONS LTD
ISSN
2050-084X
eISSN
2050-084X