Enhancing the power of genomic analysis in the Dog Aging Project

摘要 自从犬类老化计划(DAP)开始以来，犬类基因组资源有了很大的改善， 包括最近发布的一种新的、高邻接性的犬类参考基因组。DAP的当前序列 该策略--先进行低通测序，然后再进行补偿--成本低廉，并提供了高密度的 基因组变异需要强大的全基因组关联研究。然而，它依赖于 单核苷酸变异(SNPs)和短indels的归属，这是一种可能遗漏特定变异的方法 作为因果候选者特别感兴趣的人。最值得注意的是，更大规模的结构变体(SVS)，一些 已经与犬类特征有因果关系的基因，如果没有额外的测序，就不能准确地识别。 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， 每只狗不收取额外费用。我们的具体目标包括：(1)扩大和完善现有的犬类归责 小组，使用最新的犬类基因组参考和额外的犬类样本；(2)开发一种结构性的 支持从犬类短变体中归类犬类结构变体的变体归类小组；(3) 将有针对性的高覆盖率测序集成到低通测序过程中，使我们能够直接呼叫 高优先级基因座的变异，而不是归罪，并提高我们对罕见甚至从头开始的变异的敏感度。 总的来说，这些改进将使狗老化项目能够更有效地识别基因、监管 与长寿和年龄相关疾病相关的区域和特定变异。通过也分享这些 随着犬类研究社区的改进，我们将支持正在进行的广泛的研究 与年龄相关的疾病，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.