Brand Colin M, Capra John A
Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
bioRxiv. 2025 May 23:2025.05.19.654975. doi: 10.1101/2025.05.19.654975.
The ability to observe the genomes of past human populations using ancient DNA provides an extraordinary perspective on many fundamental questions in human genetics, including understanding the evolutionary history of variants that underlie human disease and other phenotypes. However, ancient DNA is often damaged and degraded, yielding low-coverage of most nucleotides. Further, many publicly available genotypes for ancient humans are limited to ~1.23 million specific loci. Thus, variants of interest often fall outside these specific positions, limiting the ability of ancient DNA to shed light on many loci. Here, we address this challenge by quantifying linkage disequilibrium (LD) between modern variants and ancient genotyped variants (AGVs) to generate a catalog enabling rapid identification of proxy variants. We identified 260,732,675 pairs of AGVs and modern variants with a minimum LD threshold hold of ≥ 0.2. Even at ≥ 0.9, ≥ 60% of common variants were linked to an AGV in non-African ancestry groups, as were 34% of common variants in Africans. We evaluated the accuracy of the genotypes inferred from proxy variants in two high-coverage ancient genomes finding that > 90% of genotypes were correctly predicted, even in a 45,000 year old individual. We also find that AGVs are significantly older than expected and that many likely are evolving neutrally. We integrate these results in a database that researchers can easily query to identify ancient proxy variants if their variant of interest is not directly genotyped in ancient humans.
利用古DNA观察过去人类群体基因组的能力，为人类遗传学中的许多基本问题提供了非凡的视角，包括理解构成人类疾病和其他表型基础的变异的进化历史。然而，古DNA往往受损且降解，导致大多数核苷酸的覆盖度较低。此外，许多公开可用的古代人类基因型仅限于约123万个特定位点。因此，感兴趣的变异通常落在这些特定位置之外，限制了古DNA阐明许多位点的能力。在这里，我们通过量化现代变异与古代基因分型变异（AGV）之间的连锁不平衡（LD）来应对这一挑战，以生成一个目录，从而能够快速识别代理变异。我们鉴定出260,732,675对AGV和现代变异，其最小LD阈值为≥0.2。即使在≥0.9时，非非洲血统群体中≥60%的常见变异与一个AGV相关联，非洲人中这一比例为34%。我们在两个高覆盖度的古代基因组中评估了从代理变异推断出的基因型的准确性，发现即使在一个45000年前的个体中，>90%的基因型也能被正确预测。我们还发现AGV比预期的要古老得多，而且许多可能正在中性进化。我们将这些结果整合到一个数据库中，研究人员如果其感兴趣的变异在古代人类中没有直接进行基因分型，就可以轻松查询该数据库以识别古代代理变异。
