Implementation of polygenic risk scores (PRS) may improve disease prevention and management but poses several challenges: the construction of clinically valid assays, interpretation for individual patients, and the development of clinical workflows and resources to support their use in patient care. For the ongoing Veterans Affairs Genomic Medicine at Veterans Affairs (GenoVA) Study we developed a clinical genotype array-based assay for six published PRS. We used data from 36,423 Mass General Brigham Biobank participants and adjustment for population structure to replicate known PRS–disease associations and published PRS thresholds for a disease odds ratio (OR) of 2 (ranging from 1.75 (95% CI: 1.57–1.95) for type 2 diabetes to 2.38 (95% CI: 2.07–2.73) for breast cancer). After confirming the high performance and robustness of the pipeline for use as a clinical assay for individual patients, we analyzed the first 227 prospective samples from the GenoVA Study and found that the frequency of PRS corresponding to published OR > 2 ranged from 13/227 (5.7%) for colorectal cancer to 23/150 (15.3%) for prostate cancer. In addition to the PRS laboratory report, we developed physician- and patient-oriented informational materials to support decision-making about PRS results. Our work illustrates the generalizable development of a clinical PRS assay for multiple conditions and the technical, reporting and clinical workflow challenges for implementing PRS information in the clinic.

Mating success is the main source of fitness variation in males, meaning that males should capitalise on all opportunities for mating. Strong selection on male mating success should also reduce genetic variation in male mating traits relative to other traits. We quantified mating latency, mating duration and productivity in males of the tropical fruitfly, Drosophila birchii, from 30 isofemale lines collected from across two elevational gradients, when they were given opportunities to mate with up to four females consecutively. Male remating rates were low compared to other Drosophila (only 14 – 27% of males achieved a fourth mating), with mean mating durations approximately doubling across successive copulations. However, although successive remating produced progressively fewer offspring, it consistently increased overall male reproductive success, with males that mated four times more than doubling offspring number compared to males mating only once. We also found no reduction in the productivity of sons emerging from later matings, indicating a sustained cumulative fitness benefit to remating. Heritable variation was observed for most traits (H2 = 0.035 – 0.292) except mating latency, but there was no divergence in trait means with elevation. The observed restricted remating ability of male D. birchii, despite the clear benefits of remating, may be due to a low encounter rate with females in the field, leading to high investment per gamete (or ejaculate). However, it remains unclear why genetic variation in these traits is high, given we observe no variation in these traits across elevational gradients known to affect local population density.

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