Program in Human Genetics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Eur J Hum Genet. 2012 Jun;20(6):657-67. doi: 10.1038/ejhg.2011.266. Epub 2012 Jan 25.
A set of Centre d'Étude du Polymorphisme Humain (CEPH) cell lines serves as a large reference collection that has been widely used as a benchmark for allele frequencies in the analysis of genetic variants, to create linkage maps of the human genome, to study the genetics of gene expression, to provide samples to the HapMap and 1000 Genomes projects, and for a variety of other applications. An explicit feature of the CEPH collection is that these multigenerational families represent reference panels of known relatedness, consisting mostly of three-generation pedigrees with large sibships, two parents, and grandparents. We applied identity-by-state (IBS) and identity-by-descent (IBD) methods to high-density genotype data from 186 CEPH individuals in 13 families. We identified unexpected relatedness between nominally unrelated grandparents both within and between pedigrees. For one pair, the estimated Cotterman coefficient of relatedness k1 exceeded 0.2, consistent with one-eighth sharing (eg, first-cousins). Unexpectedly, significant IBD2 values were discovered in both second-degree and parent-child relationships. These were accompanied by regions of homozygosity in the offspring, which corresponded to blocks lacking IBS0 in purportedly unrelated parents, consistent with inbreeding. Our findings support and extend a 1999 report, based on the use of short tandem-repeat polymorphisms, that several CEPH families had regions of homozygosity consistent with autozygosity. We benchmarked our IBD approach (called kcoeff) against both RELPAIR and PREST software packages. Our findings may affect the interpretation of previous studies and the design of future studies that rely on the CEPH resource.
一套 Centre d'Étude du Polymorphisme Humain (CEPH) 细胞系作为一个大型参考集，被广泛用于遗传变异分析中的等位基因频率基准，用于构建人类基因组的连锁图谱，研究基因表达的遗传学，为 HapMap 和 1000 Genomes 项目提供样本，并用于各种其他应用。CEPH 集合的一个明显特征是，这些多代家族代表了已知亲缘关系的参考面板，主要由具有大型兄弟姐妹、父母和祖父母的三代家谱组成。我们应用基于状态的同一性 (IBS) 和基于血统的同一性 (IBD) 方法，对来自 13 个家庭的 186 名 CEPH 个体的高密度基因型数据进行了分析。我们在名义上没有血缘关系的祖孙之间，甚至在同一个家谱内和不同家谱之间，都发现了出人意料的亲缘关系。对于一对祖孙，估计的 Cotterman 相关系数 k1 超过 0.2，与八分之一的共享（例如，表亲）一致。出人意料的是，在二级和亲子关系中都发现了显著的 IBD2 值。这些伴随着后代的纯合区域，与在名义上没有血缘关系的父母中缺乏 IBS0 的区域相对应，这与近亲繁殖一致。我们的发现支持并扩展了 1999 年的一份报告，该报告基于短串联重复多态性的使用，即几个 CEPH 家族的同源区域与自交一致。我们将我们的 IBD 方法（称为 kcoeff）与 RELPAIR 和 PREST 软件包进行了基准测试。我们的发现可能会影响对先前研究的解释和依赖 CEPH 资源的未来研究的设计。
