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Susanne Tilk
Really excited to share the first chapter of my PhD on how genome-wide linkage in cancer reduces the efficacy of selection via Hill-Robertson interference (HRI), with mentors , and . (1/10)
Introduction Cancer genomes exhibit surprisingly weak signatures of negative selection[1][1],[2][2]. This may be because tumors evolve either under very weak selective pressures (‘weak selection’) or...
bioRxiv bioRxiv @biorxivpreprint
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Susanne Tilk 16. ruj
Odgovor korisniku/ci @SusanneTilk
Here, we try to resolve why signals of negative selection are largely absent in cancer, yet pre-dominant in the human germ-line. (2/10)
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Susanne Tilk 16. ruj
Odgovor korisniku/ci @SusanneTilk
We hypothesized that since tumors evolve asexually, under the constraints of genome-wide linkage, mutations are unable to be removed by negative selection (or favored by positive selection). (3/10)
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Susanne Tilk 16. ruj
Odgovor korisniku/ci @SusanneTilk
Since linkage effects get stronger as mutation rates increase, tumors with elevated mutational burdens should be particularly inefficient at removing deleterious passengers due to genetic hitchhiking and Muller’s Ratchet. (4/10)
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Susanne Tilk 16. ruj
Odgovor korisniku/ci @SusanneTilk
To test this idea, we calculated dN/dS in tumors stratified by their mutational burden and observe that negative and positive selection attenuates as more mutations accumulate in tumors. (5/10)
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Susanne Tilk 16. ruj
Odgovor korisniku/ci @SusanneTilk
We see the same trend in somatic CNAs. Using a dN/dS-style statistic called dE/dI (fractional overlap of CNAs in [E]xonic versus [I]ntergenic/[I]ntronic regions) – we similarly see that selection on CNAs attenuates as the mutational burden increases. (6/10)
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Susanne Tilk 16. ruj
Odgovor korisniku/ci @SusanneTilk
Importantly, we see that attenuated selection on CNAs and SNVs is generic to tumor evolution. This pattern persists across broad and specific tumor sub-type categories. (7/10)
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Susanne Tilk 16. ruj
Odgovor korisniku/ci @SusanneTilk
Finally, we demonstrate that a simple evolutionary model incorporating HRI can explain these observed patterns of selection and allowed us to estimate the mean fitness effects of passengers (~1%) and drivers (~18%) – much larger than previously estimated. (8/10)
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Susanne Tilk 16. ruj
Odgovor korisniku/ci @SusanneTilk
Thus, this allowed us to estimate that in elevated mutational burden tumors (>95% of cancers), deleterious passengers accumulate and confer an individually-weak, but collectively-substantial fitness cost of ~40% that impacts tumor progression. (9/10)
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Susanne Tilk 16. ruj
Odgovor korisniku/ci @SusanneTilk
How successful tumors overcome this deleterious load is an exciting, open question. Similar to constraints in germ-line evolution, we think that preventing protein mis-folding is an important first step. We’d love to hear what you think! (10/10)
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Chris D McFarland 16. ruj
Odgovor korisniku/ci @SusanneTilk @PetrovADmitri i 2 ostali
I also want to thank my graduate advisor , who first got me interested in deleterious passengers and their role in cancer.
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