Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.
Genetics. 2012 May;191(1):215-32. doi: 10.1534/genetics.112.139576. Epub 2012 Feb 29.
Children of a heterozygous parent are expected to carry either allele with equal probability. Exceptions can occur, however, due to meiotic drive, competition among gametes, or viability selection, which we collectively term "transmission distortion" (TD). Although there are several well-characterized examples of these phenomena, their existence in humans remains unknown. We therefore performed a genome-wide scan for TD by applying the transmission disequilibrium test (TDT) genome-wide to three large sets of human pedigrees of European descent: the Framingham Heart Study (FHS), a founder population of European origin (HUTT), and a subset of the Autism Genetic Resource Exchange (AGRE). Genotyping error is an important confounder in this type of analysis. In FHS and HUTT, despite extensive quality control, we did not find sufficient evidence to exclude genotyping error in the strongest signals. In AGRE, however, many signals extended across multiple SNPs, a pattern highly unlikely to arise from genotyping error. We identified several candidate regions in this data set, notably a locus in 10q26.13 displaying a genome-wide significant TDT in combined female and male transmissions and a signature of recent positive selection, as well as a paternal TD signal in 6p21.1, the same region in which a significant TD signal was previously observed in 30 European males. Neither region replicated in FHS, however, and the paternal signal was not visible in sperm competition assays or as allelic imbalance in sperm. In maternal transmissions, we detected no strong signals near centromeres or telomeres, the regions predicted to be most susceptible to female-specific meiotic drive, but we found a significant enrichment of top signals among genes involved in cell junctions. These results illustrate both the potential benefits and the challenges of using the TDT to study transmission distortion and provide candidates for investigation in future studies.
杂合子父母的子女携带任一等位基因的概率相等。然而，由于减数分裂驱动、配子竞争或存活选择，这种情况可能会出现例外，我们将这些现象统称为“传递偏倚”（TD）。尽管有几个此类现象的特征得到了很好的描述，但它们在人类中的存在仍然未知。因此，我们通过对三个具有欧洲血统的大型人类家系（弗雷明汉心脏研究（FHS）、一个欧洲起源的创始人群体（HUTT）和自闭症遗传资源交换（AGRE）的子集）进行全基因组扫描，应用传递不平衡测试（TDT）进行全基因组分析，来寻找 TD。在这种类型的分析中，基因分型错误是一个重要的混杂因素。尽管在 FHS 和 HUTT 中进行了广泛的质量控制，但我们没有找到足够的证据来排除最强信号中的基因分型错误。然而，在 AGRE 中，许多信号跨越多个 SNP 延伸，这种模式极不可能是由基因分型错误引起的。在这个数据集，我们确定了几个候选区域，特别是在 10q26.13 上的一个基因座，在女性和男性的联合传递中显示出全基因组显著的 TDT，以及最近正选择的特征，以及在 6p21.1 上的父系 TD 信号，该区域之前在 30 名欧洲男性中观察到显著的 TD 信号。然而，这两个区域在 FHS 中均未复制，父系信号在精子竞争试验或精子等位基因失衡中也不可见。在母系传递中，我们在着丝粒或端粒附近没有检测到强烈的信号，这些区域预计最容易受到雌性特异性减数分裂驱动的影响，但我们发现，在参与细胞连接的基因中，TOP 信号显著富集。这些结果既说明了使用 TDT 研究传递偏倚的潜在优势，也说明了其中的挑战，并为未来研究提供了候选基因。
