Paterson Andrew D, Sun Lei, Liu Xiao-Qing
Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
BMC Genet. 2003 Dec 31;4 Suppl 1(Suppl 1):S48. doi: 10.1186/1471-2156-4-S1-S48.
One implicit assumption in most linkage analysis is that live-born siblings unselected for a phenotype do not share alleles greater than the Mendelian expectation at any particular locus. However, since most families are recruited for genetic studies because of the presence of disease, there is little data available to confirm that this is the case. We hypothesized that loci that behave in a non-Mendelian fashion could be identified using genotype data from the Framingham Heart Study families. We tested the hypothesis that live-born sibs, either stratified by or irrespective of gender, demonstrate excess sharing of alleles on the autosomes, i.e., transmission ratio distortion. Multipoint linkage analysis of siblings either according to gender or not was performed using an allele-sharing method. Such observations may have implications for the mapping of loci for complex disease and quantitative traits in human pedigrees.
No results that reached genome-wide significance were observed. However, four regions demonstrated excess sharing of alleles at p < 0.002 when sibships were stratified by gender-three of which were present in males. Of note, a female-specific locus co-localized with region that is linked to mean systolic blood pressure in the same families. In addition, three other regions demonstrated excess sharing of alleles in sibships irrespective of gender, including a region on chromosome 10p14-p15 (p = 7.5 x 10(-4)).
Although no loci meeting genome-wide significance were detected to demonstrate transmission ratio distortion, loci with suggestive evidence for linkage were detected. These may have implications for the mapping of susceptibility loci for complex disease in human pedigrees.
大多数连锁分析中一个隐含的假设是，未因某种表型而被选择的存活同胞在任何特定基因座上共享的等位基因不会超过孟德尔预期。然而，由于大多数家庭是因为存在疾病而被招募进行基因研究的，几乎没有数据可证实情况确实如此。我们假设可以使用弗雷明汉心脏研究家族的基因型数据来识别表现为非孟德尔方式的基因座。我们检验了这样一个假设，即存活同胞，无论按性别分层与否，在常染色体上表现出等位基因的过度共享，即传递比失真。使用等位基因共享方法对同胞进行了按性别或不按性别分类的多点连锁分析。这些观察结果可能对人类家系中复杂疾病和数量性状的基因座定位有影响。
未观察到达到全基因组显著性的结果。然而，当同胞按性别分层时，有四个区域在p<0.002时表现出等位基因的过度共享——其中三个区域在男性中存在。值得注意的是，一个女性特异性基因座与同一家族中与平均收缩压相关的区域共定位。此外，另外三个区域在无论性别如何的同胞中都表现出等位基因的过度共享，包括染色体10p14 - p15上的一个区域（p = 7.5×10⁻⁴）。
虽然未检测到达到全基因组显著性的基因座来证明传递比失真，但检测到了具有连锁暗示性证据的基因座。这些可能对人类家系中复杂疾病易感基因座的定位有影响。
