Local Adaptive Mapping of Karyotype Fitness Landscapes

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 novel 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 validated 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 alterations (CNAs); (2) Environmental context and cisplatin treatment significantly modulate the fitness impact of these alterations; (3) Fitness consequences of CNAs are contingent upon parental karyotype; and (4) Chromosome mis-segregation rates strongly influence the predominant karyotypes in evolving populations.