Modelling population connectivity is central to biodiversity conservation and often relies on resistance surfaces reflecting multi-generational gene flow. ResistanceGA (RGA) is a common optimization framework for parameterizing these surfaces by maximizing the fit between genetic distances and cost distances using maximum likelihood population effect models. As the reliability of this framework has rarely been studied, we investigated the conditions maximizing its accuracy for both prediction and interpretation of landscape features' permeability. We ran demo-genetic simulations in contrasted landscapes for species with distinct dispersal capacities and specialization levels, using corresponding reference cost scenarios. We then optimized resistance surfaces from the simulated genetic distances using RGA. First, we evaluated whether RGA identified the drivers of the genetic patterns, that is, distinguished Isolation-by-Resistance (IBR) patterns from either Isolation-by-Distance or patterns unrelated to ecological distances. We then assessed RGA predictive performance using a cross-validation method, and its ability to recover the reference cost scenarios shaping genetic structure in simulations. IBR patterns were well detected and genetic distances were predicted with great accuracy. This performance depended on the strength of the genetic structuring, sampling design and landscape structure.

Matching the scale of the genetic pattern by focusing on population pairs connected through gene flow and limiting overfitting through cross-validation further enhanced inference reliability. Yet, the optimized cost values often departed from the reference values, making their interpretation and extrapolation potentially dubious. While demonstrating the value of RGA for predictive modelling, we call for caution and provide additional guidance for its optimal use.