Enhancing the power of genomic analysis in the Dog Aging Project

摘要 自犬衰老项目（DAP）开始以来，犬基因组资源已大幅改善， 包括最近发布的一个新的，高连续性的犬参考基因组。DAP当前排序 策略-低通测序后插补-是廉价的，并提供了高密度的 全基因组关联研究所需的基因组变异。然而，它依赖于 单核苷酸变异（SNP）和短插入缺失的估算，这种方法可能会遗漏特定的变异 作为因果候选人特别感兴趣。最值得注意的是，大规模的结构变体（SV），一些 已经与犬的性状有因果关系，不进行额外的测序就不能准确识别。 我们建议更新DAP过程，为每只测序的狗提供更完整的遗传信息， 每只狗不需要额外的费用。我们的具体目标包括：（1）扩展和改进现有的犬种归属 小组，使用最新的犬基因组参考和额外的犬样本;（2）开发一个结构 变体插补面板，以支持从犬短变体中插补犬结构变体;（3） 将靶向高覆盖测序整合到低通测序过程中，使我们能够直接调用 在高优先级基因座的变异，而不插补，并提高我们的敏感性，罕见的，甚至从头变异。 总的来说，这些改进将使狗衰老项目能够更有效地识别基因，调节基因， 与长寿和年龄相关疾病相关的区域和特定变异。通过分享这些 改进与犬研究界，我们将支持正在进行的研究，以广泛的 与年龄有关的疾病，包括神经退行性疾病、器官衰竭和癌症。

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.