Enhancing the power of genomic analysis in the Dog Aging Project

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Abstract Canine genomic resources have improved substantially since inception of the Dog Aging Project (DAP), including the recent release of a new, high-contiguity canine reference genome. DAP's current sequencing strategy – low-pass sequencing followed by imputation – is inexpensive and provides the high density of genomic variant calls needed for well-powered genome-wide association studies. However, it relies on imputation of single nucleotide variants (SNPs) and short indels, an approach which may miss specific variants that are of particular interest as causal candidates. Most notably, larger-scale structural variants (SVs), some already causally associated with canine traits, cannot be accurately discerned without additional sequencing. We propose to update DAP processes to yield far more complete genetic information for each dog sequenced, at no additional cost per dog. Our specific aims include: (1) expand and improve the existing canine imputation panel, using the latest canine genome reference and additional canine samples; (2) develop a structural variant imputation panel to support the imputation of canine structural variants from canine short variants; (3) integrate targeted high-coverage sequencing into the low-pass sequencing process, allowing us to directly call variants at high-priority loci without imputation, and improve our sensitivity to rare and even de novo variants. Collectively, these improvements will allow the Dog Aging Project to more effectively identify genes, regulatory regions and specific variants associated with longevity and age-related disease. By also sharing these improvements with the canine research community, we will support ongoing studies into a broad range of age-related diseases, including neurodegenerative diseases, organ failure, and cancer.