Response to Mitr and Pollack.
Response to Mitr and Pollack.
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对 Mitr 和 Pollack 的回应。
DOI：
10.1093/jnci/djac133
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Asmann,YanW
中科院分区：
文献类型：
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作者：
Wickland,DanielP;Sherman,MarkE;Radisky,DerekC;Mansfield,AaronS;Asmann,YanW
我们首先要澄清的是，在我们的整个手稿中，“测序覆盖率”和“测序深度”可以互换使用。因此，没有人试图对报道进行深入的解释。我们没有将3种癌症类型(前列腺癌[PRAD]、肺腺癌[LUAD]和结肠腺癌[COAD])的较低测序覆盖率归因于参考基因组中的种族偏见。我们的研究得出结论，“对于其他3种癌症，非洲祖先外显子的测序覆盖率较低的原因尚不清楚。”除了测序深度或覆盖率，我们报告的第二个差异是，即使有类似的测序覆盖率或深度，非洲祖先患者的外显子组在统计上显著丰富，与欧洲人相比，覆盖率较低的位置。在此背景下，讨论了人类参考基因组中的种族偏见作为一个潜在因素。Mitr等人(1)正确地指出，一个单身男性贡献了用于构建参考基因组的大约70%的序列，这使得美国纽约州布法罗的种族构成变得无关紧要。这个人的基因混合体大约50%是非洲人，50%是欧洲人(2-4)。来自主要有东亚血统的个体的DNA占参考序列的第二大部分(占总数的5.5%)，其余序列来自主要有欧洲血统的捐赠者(3)。总体而言，来自非洲人的序列约占人类参考基因组的三分之一，这使得人类参考基因组的欧洲偏见并不像我们所说的那样重要，但仍然是一个因素。来自欧洲的序列贡献了大约60%的参考基因组，因此捕获试剂盒的设计基本上是有偏见的。
We would like to first clarify that throughout our manuscript,“sequencing coverage” and “sequencing depth” were used interchangeably. Therefore, there was no attempt to explain the coverage with depth. We did not attribute the lower sequencing coverage of 3 cancer types (Prostate Adenocarcinoma [PRAD], Lung Adenocarcinoma [LUAD], and Colon Adenocarcinoma [COAD]) to racial bias in the reference genome. Our study concluded that “For the other 3 cancers, the reasons of lower sequencing coverage of ancestrally African exomes remain unknown.” Besides the sequencing depths or coverages, the second disparity we reported was that even with comparable sequencing coverages or depths, exomes from ancestrally African patients were statistically significantly enriched with positions with less than sufficient coverages compared with those from Europeans. The racial bias in the human reference genome as a potential factor was discussed in this context. Mitr et al.(1) correctly pointed out that a single male contributed approximately 70% of the sequences used to construct the reference genome, which makes the racial makeup of Buffalo, NY, USA irrelevant. The genetic admixture of this individual was approximately 50% African and 50% European (2-4). DNA from an individual with primarily East Asian ancestry represents the second largest fraction of the reference (5.5% of the total), and the remaining sequences originated from donors with primarily European ancestry (3). In total, sequences from Africans constitute approximately one-third of the human reference genome, which makes the European bias of the human reference genome not as substantial as we suggested but still a factor. Sequences from Europeans contributed to approximately 60% of the reference genome, and therefore the capture kit design is substantially biased.