The sequencing and interpretation of the genome obtained from a Serbian individual

Recent genetic studies and whole-genome sequencing projects have greatly improved our understanding of human variation and clinically actionable genetic information. Smaller ethnic populations, however, remain underrepresented in both individual and large-scale sequencing efforts and hence present an opportunity to discover new variants of biomedical and demographic significance. This report describes the sequencing and analysis of a genome obtained from an individual of Serbian origin, introducing tens of thousands of previously unknown variants to the currently available pool. Ancestry analysis places this individual in close proximity to Central and Eastern European populations; i.e., closest to Croatian, Bulgarian and Hungarian individuals and, in terms of other Europeans, furthest from Ashkenazi Jewish, Spanish, Sicilian and Baltic individuals. Our analysis confirmed gene flow between Neanderthal and ancestral pan-European populations, with similar contributions to the Serbian genome as those observed in other European groups. Finally, to assess the burden of potentially disease-causing/clinically relevant variation in the sequenced genome, we utilized manually curated genotype-phenotype association databases and variant-effect predictors. We identified several variants that have previously been associated with severe early-onset disease that is not evident in the proband, as well as putatively impactful variants that could yet prove to be clinically relevant to the proband over the next decades. The presence of numerous private and low-frequency variants, along with the observed and predicted disease-causing mutations in this genome, exemplify some of the global challenges of genome interpretation, especially in the context of under-studied ethnic groups.

近年来，遗传学研究与全基因组测序（whole-genome sequencing）项目极大地提升了我们对人类遗传变异及临床可操作遗传信息的认知水平。然而，小型族群在个体水平及大规模测序研究中的样本代表性仍显著不足，这为发掘兼具生物医学与人口统计学意义的新型遗传变异提供了重要契机。本报告详述了一例塞尔维亚血统个体的基因组测序与分析工作，为现有变异集合新增了数万种此前未被收录的遗传变异。祖先分析结果显示，该个体与中东欧人群亲缘关系紧密：与克罗地亚、保加利亚及匈牙利个体的亲缘关系最近；而在欧洲人群中，与德系犹太人、西班牙人、西西里人及波罗的海人群的遗传距离最远。我们的分析证实了尼安德特人（Neanderthal）与泛欧洲祖先人群间存在基因交流，该塞尔维亚基因组所获得的遗传贡献比例与其他欧洲族群基本一致。最后，为评估本次测序基因组中潜在致病/临床相关变异的负载情况，我们采用了经人工整理注释的基因型-表型关联数据库（genotype-phenotype association databases）与变异效应预测工具（variant-effect predictors）。我们鉴定出数种此前被报道与早发性重症疾病相关的变异，但先证者（proband）并未表现出此类疾病的临床症状；同时还发现了若干潜在致病变异，它们可能在未来数十年内被证实与该先证者的临床健康相关。本基因组中存在大量私有低频变异，以及经观测与预测的致病突变，这凸显了基因组解读所面临的部分全球性挑战，尤其是在研究不足的族群研究背景下。