ALFA-K: Local adaptive mapping of karyotype fitness landscapes
Nature CommunicationsTL;DR
Imagine a tumor is a team of players in a video game, where each player's character build (their set of chromosomes) is slightly different. Some builds are strong and fast, while others are weak. This study created a computer program, ALFA-K, that watches the game and creates a 'map' of the game world. The hills on the map represent powerful character builds that help the team win (high fitness), and the valleys are weak builds that get eliminated. ALFA-K is so smart it can not only map the builds it sees, but it can also predict which new, unseen builds are likely to be powerful. This helps scientists understand the rules of cancer's 'game' and how it adapts to challenges like chemotherapy.
Despite its critical role in tumor evolution, a detailed quantitative understanding of the evolutionary dynamics of aneuploidy remains elusive. Here we introduce ALFA-K (Adaptive Local Fitness landscapes for Aneuploid Karyotypes), a method that infers chromosome-level karyotype fitness landscapes from longitudinal single-cell data. ALFA-K estimates fitness of thousands of karyotypes closely related to observed populations, enabling robust prediction of emergent karyotypes not yet experimentally detected. We validate ALFA-K’s performance using synthetic data from an agent-based model and empirical data from in vitro and in vivo passaged cell lines. Analysis of fitted landscapes suggests several key insights: (1) Whole genome doubling facilitates aneuploidy evolution by narrowing the spectrum of deleterious copy-number changes; (2) Environmental context and cisplatin treatment significantly modulate the fitness impact of these changes; (3) Fitness effects of copy-number changes depend on parental karyotype; and (4) Chromosome mis-segregation rates strongly influence the predominant karyotypes in evolving populations.
- 1Whole genome doubling facilitates aneuploidy evolution by narrowing the spectrum of deleterious copy-number changes.
- 2Environmental context and cisplatin treatment significantly modulate the fitness impact of copy-number changes.
- 3Fitness effects of copy-number changes depend on parental karyotype.
- 4Chromosome mis-segregation rates strongly influence the predominant karyotypes in evolving populations.
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