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Background  New strategies to combat the global scourge of schistosomiasis may be revealed by increased understanding of the mechanisms by which the obligate snail host can resist the schistosome parasite. However, few molecular markers linked to resistance have been identified and characterized in snails.    Methodology/Principal Findings  Here we test six independent genetic loci for their influence on resistance to  Schistosoma mansoni  strain PR1 in the 13-16-R1 strain of the snail  Biomphalaria glabrata . We first identify a genomic region,  RADres , showing the highest differentiation between susceptible and resistant inbred lines among 1611 informative restriction-site associated DNA (RAD) markers, and show that it significantly influences resistance in an independent set of 439 outbred snails. The additive effect of each  RADres  resistance allele is 2-fold, similar to that of the previously identified resistance gene  sod1 . The data fit a model in which both loci contribute independently and additively to resistance, such that the odds of infection in homozygotes for the resistance alleles at both loci (13% infected) is 16-fold lower than the odds of infection in snails without any resistance alleles (70% infected). Genome-wide linkage disequilibrium is high, with both  sod1  and  RADres  residing on haplotype blocks >2Mb, and with other markers in each block also showing significant effects on resistance; thus the causal genes within these blocks remain to be demonstrated. Other candidate loci had no effect on resistance, including the Guadeloupe Resistance Complex and three genes ( aif ,  infPhox , and  prx1)  with immunological roles and expression patterns tied to resistance, which must therefore be trans-regulated.    Conclusions/Significance  The loci  RADres  and  sod1  both have strong effects on resistance to  S .  mansoni . Future approaches to control schistosomiasis may benefit from further efforts to characterize and harness this natural genetic variation.

Genome-Wide Scan and Test of Candidate Genes in the Snail Biomphalaria glabrata Reveal New Locus Influencing Resistance to Schistosoma mansoni