Probability of detection of genotyping errors and mutations as inheritance inconsistencies in nuclear-family data
Probability of detection of genotyping errors and mutations as inheritance inconsistencies in nuclear-family data
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DOI：
10.1086/338919
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发表时间：
2002-02-01
影响因子：
9.8
通讯作者：
Boehnke, M
中科院分区：
文献类型：
--
作者：
Douglas, JA;Skol, AD;Boehnke, M
基因图谱研究通常依赖于检查系谱中标记等位基因的孟德尔传递，作为筛选基因分型错误和突变的手段，隐含的假设是，如果系谱符合孟德尔遗传定律，那么就没有基因分型错误。然而，仅遗传不一致的发生率不能充分衡量基因分型错误的数量，因为发生率取决于基因分型系谱成员的数量和关系、错误的类型以及标记-等位基因频率的分布。在这篇文章中，我们计算的预期概率检测基因分型错误或突变的遗传不一致的核心家庭数据，作为一个功能的基因分型父母和后代的数量和标记等位基因频率分布。通过计算机模拟，我们探讨了我们的分析计算的敏感性的基本误差模型。在随机等位基因错误模型下，我们发现多等位基因标记的检出率为51%-77%，双等位基因标记的检出率为13%-75%;当错误发生在父母身上时，检出率通常低于后代，除非大量后代进行基因分型。错误是特别难以检测的双等位基因标记具有相同频率的等位基因，即使当父母双方的基因型，在这种情况下，最高检出率是34%的四人核心家庭。在父母没有基因分型的家庭中，错误检测是有限的，即使是多等位基因标记。鉴于这些结果，我们建议额外的错误检查（e。例如，在一个实施例中，在多点分析的基础上）进行，超出了孟德尔一致性的常规检查。此外，我们的研究结果允许一个家庭的遗传不一致的观察到的数量的可解释性的评估，允许检测可能的谱系，而不是基因分型错误的早期阶段的基因组扫描。这样的早期评估是有价值的，无论是针对家庭的恢复或中断基因分型。
Gene-mapping studies routinely rely on checking for Mendelian transmission of marker alleles in a pedigree, as a means of screening for genotyping errors and mutations, with the implicit assumption that, if a pedigree is consistent with Mendel's laws of inheritance, then there are no genotyping errors. However, the occurrence of inheritance inconsistencies alone is an inadequate measure of the number of genotyping errors, since the rate of occurrence depends on the number and relationships of genotyped pedigree members, the type of errors, and the distribution of marker-allele frequencies. In this article, we calculate the expected probability of detection of a genotyping error or mutation as an inheritance inconsistency in nuclear-family data, as a function of both the number of genotyped parents and offspring and the marker-allele frequency distribution. Through computer simulation, we explore the sensitivity of our analytic calculations to the underlying error model. Under a random-allele-error model, we find that detection rates are 51%-77% for multiallelic markers and 13%-75% for biallelic markers; detection rates are generally lower when the error occurs in a parent than in an offspring, unless a large number of offspring are genotyped. Errors are especially difficult to detect for biallelic markers with equally frequent alleles, even when both parents are genotyped; in this case, the maximum detection rate is 34% for four-person nuclear families. Error detection in families in which parents are not genotyped is limited, even with multiallelic markers. Given these results, we recommend that additional error checking (e. g., on the basis of multipoint analysis) be performed, beyond routine checking for Mendelian consistency. Furthermore, our results permit assessment of the plausibility of an observed number of inheritance inconsistencies for a family, allowing the detection of likely pedigree-rather than genotyping-errors in the early stages of a genome scan. Such early assessments are valuable in either the targeting of families for resampling or discontinued genotyping.