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Abstract Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in the All of Us cohort. The European ancestry subgroup showed the highest overall rate of pathogenic variation, with 2.26% of participants having a pathogenic variant. Other ancestry groups had lower rates of pathogenic variation, including 1.62% for the African ancestry group and 1.32% in the Latino/Admixed American ancestry group. Pathogenic variants were most frequently observed in genes related to Breast/Ovarian Cancer or Hypercholesterolemia. Variant frequencies in many genes were consistent with the data from the public gnomAD database, with some notable exceptions resolved using gnomAD subsets. Differences in pathogenic variant frequency observed between ancestral groups generally indicate biases of ascertainment of knowledge about those variants, but some deviations may be indicative of differences in disease prevalence. This work will allow targeted precision medicine efforts at revealed disparities.

The domestic dog is an important model organism for our understanding of cancer and other diseases. Here the authors conduct a genome-wide association study across multiple breeds and identify novel loci significantly associated with several complex diseases and morphological traits.

The domesticated horse has played a unique role in human history, serving not just as a source of animal protein, but also as a catalyst for long-distance migration and military conquest. As a result, the horse developed unique physiological adaptations to meet the demands of both their climatic environment and their relationship with man. Completed in 2009, the first domesticated horse reference genome assembly (EquCab 2.0) produced most of the publicly available genetic variations annotations in this species. Yet, there are around 400 geographically and physiologically diverse breeds of horse. To enrich the current collection of genetic variants in the horse, we sequenced whole genomes from six horses of six different breeds: an American Miniature, a Percheron, an Arabian, a Mangalarga Marchador, a Native Mongolian Chakouyi, and a Tennessee Walking Horse, and mapped them to EquCab3.0 genome. Aside from extreme contrasts in body size, these breeds originate from diverse global locations and each possess unique adaptive physiology. A total of 1.3 billion reads were generated for the six horses with coverage between 15x to 24x per horse. After applying rigorous filtration, we identified and functionally annotated 17,514,723 Single Nucleotide Polymorphisms (SNPs), and 1,923,693 Insertions/Deletions (INDELs), as well as an average of 1,540 Copy Number Variations (CNVs) and 3,321 Structural Variations (SVs) per horse. Our results revealed putative functional variants including genes associated with size variation like LCORL gene (found in all horses), ZFAT in the Arabian, American Miniature and Percheron horses and ANKRD1 in the Native Mongolian Chakouyi horse. We detected a copy number variation in the Latherin gene that may be the result of evolutionary selection impacting thermoregulation by sweating, an important component of athleticism and heat tolerance. The newly discovered variants were formatted into user-friendly browser tracks and will provide a foundational database for future studies of the genetic underpinnings of diverse phenotypes within the horse.