How array design creates SNP ascertainment bias.
How array design creates SNP ascertainment bias.
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DOI：
10.1371/journal.pone.0245178
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Simianer H
中科院分区：
文献类型：
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作者：
Geibel J;Reimer C;Weigend S;Weigend A;Pook T;Simianer H
单核苷酸多态性（SNPs），基因分型芯片，已成为一个广泛使用的标记类型在人群遗传分析在过去的10年。然而，与全基因组重测序数据相比，已知阵列缺乏相当大比例的全球罕见变体，并且倾向于偏向于在相应阵列的开发过程中涉及的群体中存在的变体。这会影响群体遗传估计，称为SNP确定偏倚。我们通过计算机重新设计Axiom™全基因组鸡阵列，并逐步评估等位基因频率谱和杂合性估计值的变化，研究了阵列开发中导致确定偏倚的因素。在发育过程中，罕见等位基因的顺序减少。这主要是由于在有限的一组人群中识别SNP以及在以等距间隔为目标时对常见SNP进行群体内选择造成的。这些影响被证明是不太严重的一个更大的发现面板。此外，对于确定的SNP集，显示出对预期杂合性的普遍大规模高估。在原始阵列的情况下，参与发现过程的人群的这种高估比不参与人群高24%。在重新设计中的SNP发现步骤之后也观察到了同样的情况。然而，在SNP选择期间群体的不平等贡献可以掩盖这种效应，但也增加了不确定性。最后，我们提出了建议，为大规模项目的全基因组重测序技术仍然太昂贵的专业阵列的设计。
Single nucleotide polymorphisms (SNPs), genotyped with arrays, have become a widely used marker type in population genetic analyses over the last 10 years. However, compared to whole genome re-sequencing data, arrays are known to lack a substantial proportion of globally rare variants and tend to be biased towards variants present in populations involved in the development process of the respective array. This affects population genetic estimators and is known as SNP ascertainment bias. We investigated factors contributing to ascertainment bias in array development by redesigning the Axiom™ Genome-Wide Chicken Array in silico and evaluating changes in allele frequency spectra and heterozygosity estimates in a stepwise manner. A sequential reduction of rare alleles during the development process was shown. This was mainly caused by the identification of SNPs in a limited set of populations and a within-population selection of common SNPs when aiming for equidistant spacing. These effects were shown to be less severe with a larger discovery panel. Additionally, a generally massive overestimation of expected heterozygosity for the ascertained SNP sets was shown. This overestimation was 24% higher for populations involved in the discovery process than not involved populations in case of the original array. The same was observed after the SNP discovery step in the redesign. However, an unequal contribution of populations during the SNP selection can mask this effect but also adds uncertainty. Finally, we make suggestions for the design of specialized arrays for large scale projects where whole genome re-sequencing techniques are still too expensive.
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