CSIRO Livestock Industries, FD McMaster Laboratory Chiswick, Armidale, 2350, NSW, Australia.
Genet Sel Evol. 2010 Aug 12;42(1):34. doi: 10.1186/1297-9686-42-34.
Repeated blocks of genome sequence have been shown to be associated with genetic diversity and disease risk in humans, and with phenotypic diversity in model organisms and domestic animals. Reliable tests are desirable to determine whether individuals are carriers of copy number variants associated with disease risk in humans and livestock, or associated with economically important traits in livestock. In some cases, copy number variants affect the phenotype through a dosage effect but in other cases, allele combinations have non-additive effects. In the latter cases, it has been difficult to develop tests because assays typically return an estimate of the sum of the copy number counts on the maternally and paternally inherited chromosome segments, and this sum does not uniquely determine the allele configuration. In this study, we show that there is an old solution to this new problem: segregation analysis, which has been used for many years to infer alleles in pedigreed populations.
Segregation analysis was used to estimate copy number alleles from assay data on simulated half-sib sheep populations. Copy number variation at the Agouti locus, known to be responsible for the recessive self-colour black phenotype, was used as a model for the simulation and an appropriate penetrance function was derived. The precision with which carriers and non-carriers of the undesirable single copy allele could be identified, was used to evaluate the method for various family sizes, assay strategies and assay accuracies.
Using relationship data and segregation analysis, the probabilities of carrying the copy number alleles responsible for black or white fleece were estimated with much greater precision than by analyzing assay results for animals individually. The proportion of lambs correctly identified as non-carriers of the undesirable allele increased from 7% when the lambs were analysed alone to 80% when the lambs were analysed in half-sib families.
When a quantitative assay is used to estimate copy number alleles, segregation analysis of related individuals can greatly improve the precision of the estimates. Existing software for segregation analysis would require little if any change to accommodate the penetrance function for copy number assay data.
已证实，人类基因组序列的重复片段与遗传多样性和疾病风险有关，与模式生物和家畜的表型多样性有关。需要可靠的测试来确定个体是否携带与人类疾病风险和家畜重要经济性状相关的拷贝数变异。在某些情况下，拷贝数变异通过剂量效应影响表型，但在其他情况下，等位基因组合具有非加性效应。在后一种情况下，开发测试一直很困难，因为检测通常返回母本和父本遗传染色体片段的拷贝数计数的总和估计值，而该总和并不能唯一确定等位基因构型。在这项研究中，我们表明，这个新问题有一个旧的解决方案：分离分析，多年来一直用于推断 pedigreed 群体中的等位基因。
使用分离分析从模拟半同胞绵羊群体的检测数据中估计拷贝数等位基因。Agouti 基因座的拷贝数变异，已知负责隐性自色黑色表型，被用作模拟的模型，并推导出适当的穿透函数。使用不可取的单拷贝等位基因携带者和非携带者的识别精度来评估各种家庭规模、检测策略和检测精度的方法。
使用关系数据和分离分析，携带负责黑色或白色羊毛的拷贝数等位基因的概率的估计精度比单独分析动物的检测结果要高得多。当单独分析羔羊时，未携带不良等位基因的羔羊正确识别的比例从 7%增加到 80%，当在半同胞家庭中分析羔羊时。
当使用定量检测来估计拷贝数等位基因时，相关个体的分离分析可以大大提高估计的精度。现有的分离分析软件几乎不需要任何更改即可适应拷贝数检测数据的穿透函数。
