Defining and Reducing Variant Classification Disparities.

Background: Multiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene of interest. The resulting saturation-style data may help resolve variant classification disparities between populations, especially for variants of uncertain significance (VUS). Methods: We analyzed clinical significance classifications in 213,663 individuals of European-like genetic ancestry versus 206,975 individuals of non-European-like genetic ancestry from All of Us and the Genome Aggregation Database. Then, we incorporated clinically calibrated MAVE data into the Clinical Genome Resource's Variant Curation Expert Panel rules to automate VUS reclassification for BRCA1, TP53, and PTEN . Results: Using two orthogonal statistical approaches, we show a higher prevalence ( p ≤5.95e-06) of VUS in individuals of non-European-like genetic ancestry across all medical specialties assessed in all three databases. Further, in the non-European-like genetic ancestry group, higher rates of Benign or Likely Benign and variants with no clinical designation ( p ≤2.5e-05) were found across many medical specialties, whereas Pathogenic or Likely Pathogenic assignments were higher in individuals of European-like genetic ancestry ( p ≤2.5e-05). Using MAVE data, we reclassified VUS in individuals of non-European-like genetic ancestry at a significantly higher rate in comparison to reclassified VUS from European-like genetic ancestry ( p =9.1e-03) effectively compensating for the VUS disparity. Further, essential code analysis showed equitable impact of MAVE evidence codes but inequitable impact of allele frequency ( p =7.47e-06) and computational predictor ( p =6.92e-05) evidence codes for individuals of non-European-like genetic ancestry. Conclusions: Generation of saturation-style MAVE data should be a priority to reduce VUS disparities and produce equitable training data for future computational predictors.

Large herbivore diversity slows sea ice-associated decline in arctic tundra diversity.

Biodiversity is declining globally in response to multiple human stressors, including climate forcing. Nonetheless, local diversity trends are inconsistent in some taxa, obscuring contributions of local processes to global patterns. Arctic tundra diversity, including plants, fungi, and lichens, declined during a 15-year experiment that combined warming with exclusion of large herbivores known to influence tundra vegetation composition. Tundra diversity declined regardless of experimental treatment, as background growing season temperatures rose with sea ice loss. However, diversity declined slower with large herbivores than without them. This difference was associated with an increase in effective diversity of large herbivores as formerly abundant caribou declined and muskoxen increased. Efforts that promote herbivore diversity, such as rewilding, may help mitigate impacts of warming on tundra diversity.