Data from: Bulk genotyping of biopsies can create spurious evidence for heterogeneity in mutation content

When multiple samples are taken from the neoplastic tissues of a single patient, it is natural to compare their mutation content. This is often done by bulk genotyping of whole biopsies, but the chance that a mutation will be detected in bulk genotyping depends on its local frequency in the sample. When the underlying mutation count per cell is equal, homogenous biopsies will have more high-frequency mutations, and thus more detectable mutations, than heterogeneous ones. Using simulations, we show that bulk genotyping of data simulated under a neutral model of somatic evolution generates strong spurious evidence for non-neutrality, because the pattern of tissue growth systematically generates differences in biopsy heterogeneity. Any experiment which compares mutation content across bulk-genotyped biopsies may therefore suggest mutation rate or selection intensity variation even when these forces are absent. We discuss computational and experimental approaches for resolving this problem.当从同一患者的肿瘤组织中获取多个样本时，对其突变组成进行比较是合乎情理的操作。这类比较通常通过对完整活检标本实施批量基因分型（bulk genotyping）来完成，但批量基因分型中能否检测到某一突变，取决于该突变在样本中的局部频率。当每个细胞的潜在突变数量相同时，均质活检标本相较于异质性活检标本，会携带更多高频突变，因此可检测到的突变数量也更多。本研究通过模拟实验发现，基于体细胞进化（somatic evolution）中性模型生成的数据进行批量基因分型分析时，会产生显著的非中性进化虚假证据——这是因为组织生长模式会系统性地导致活检标本间的异质性差异。因此，任何通过批量基因分型活检标本以比较其突变组成的实验，即便突变率与选择强度并未发生变化，也可能会错误地提示存在这两类参数的差异。我们最后讨论了可用于解决该问题的计算与实验方法。