The Heritability of Pathogen Traits - Definitions and Estimators

Pathogen traits, such as the virulence of an infection, can vary significantly between patients. A major challenge is to measure the extent to which genetic differences between infecting strains explain the observed variation of the trait. This is quantified by the trait’s broad-sense heritability, H 2 . A recent discrepancy between estimates of the heritability of HIV-virulence has opened a debate on the estimators’ accuracy. Here, we show that the discrepancy originates from model limitations and important lifecycle differences between sexually reproducing organisms and transmittable pathogens. In particular, current quantitative genetics methods, such as donor-recipient regression (DR) of surveyed serodiscordant couples and the phylogenetic mixed model (PMM), are prone to underestimate H 2 , because they fail to model the gradual loss of phenotypic resemblance between transmission-related patients in the presence of within-host evolution. We explore two approaches correcting these errors: ANOVA on closest phylogenetic pairs (ANOVA-CPP) and the phylogenetic Ornstein-Uhlenbeck mixed model (POUMM). Empirical analyses reveal that at least 25% of the variation in HIV-virulence is explained by the virus genome both for European and African data. These results confirm the presence of significant factors for HIV virulence in the viral genotype and reject previous hypotheses of negligible viral influence. Beyond HIV, ANOVA-CPP is ideal for slowly evolving protozoa, bacteria and DNA-viruses, while POUMM suits rapidly mutating RNA-viruses, thus, enabling heritability estimation for a broad range of pathogens.