Leveraging hologenomic data for phenotypic prediction: potential and pitfalls

Abstract

The microbiota is increasingly recognized as an active component of host biology, influencing various host phenotypes. Advances in high-throughput sequencing and the emergence of the holobiont perspective have raised expectations regarding hologenomic-informed prediction. Yet, whether and under which conditions integrating microbiota and genomic data meaningfully improves phenotypic prediction remains unclear. The biological characteristics of the microbiota, including but not limited to transmission mechanisms, environmental effects and interactions with host genetics, complicate their integration into classical evaluation frameworks. In addition, microbiota datasets are high-dimensional, highly dispersed, sparse and compositional. Finally, analytical choices such as the taxonomic granularity considered for aggregation or the similarity matrix used in prediction models may impact downstream inference and prediction accuracy. Here we explore these challenges using a comprehensive set of transgenerational hologenomic simulations. By generating controlled and contrasted biological scenarios across a broad parameter space, we examine how microbiota granularity, variance structure and host modulation influence (i) the estimation of variance components and (ii) the accuracy of phenotypic prediction. We show that the added value of hologenomic, compared to genomic prediction, is highly context dependent. Our results provide a structured framework to interrogate when and how integrating microbiota may enhance phenotypic prediction in breeding applications.