Eisenbarth I, Striebel A M, Moschgath E, Vogel W, Assum G
Abteilung Humangenetik, Universität Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany.
Hum Mol Genet. 2001 Nov 15;10(24):2833-9. doi: 10.1093/hmg/10.24.2833.
Association studies, the most powerful tool for the identification of genes underlying complex traits, depend on the observation of linkage disequilibrium (LD) between marker alleles and the trait. The LD pattern of the human genome which determines the regional density of required markers is non-uniform, with regions of long-range LD over several hundred kilobases and regions where LD extends only over a few kilobases. Studying LD in the NF1 gene region we encountered a transition from long-range to short-range LD which coincides with a switch in the isochore pattern. This observation prompted us to investigate the regional variation in the extent of LD more systematically and we selected an isochore transition within the MN1/PITPNB gene region on chromosome 22q12.1. Long-range LD characterizes the GC-poor (40% GC) parts of the sequences. No LD can be observed between closely spaced markers throughout the whole range of the GC-rich (50% GC) parts. In both cases, the NF1 and the MN1/PITPNB gene region, a clear-cut transition of the long-range GC content precisely coincides with a change in the extent of observable LD. The results can be explained by a 72-fold lower recombination frequency in the GC-poor, compared to the GC-rich isochores. Although recombination is not the only factor governing LD, our findings can help to predict levels of LD and marker densities required for association studies on the basis of regional GC content.
关联研究是识别复杂性状潜在基因的最有力工具，它依赖于对标记等位基因与性状之间连锁不平衡（LD）的观察。决定所需标记区域密度的人类基因组LD模式是不均匀的，存在数百千碱基的长程LD区域和LD仅延伸几千碱基的区域。在研究NF1基因区域的LD时，我们遇到了从长程LD到短程LD的转变，这与等容线模式的转变相吻合。这一观察促使我们更系统地研究LD程度的区域差异，我们选择了22q12.1染色体上MN1/PITPNB基因区域内的一个等容线转变。长程LD表征了序列中GC含量低（40%GC）的部分。在富含GC（50%GC）的部分整个范围内，紧密间隔的标记之间未观察到LD。在NF1和MN1/PITPNB基因区域这两种情况下，长程GC含量的明显转变恰好与可观察到的LD程度的变化相吻合。结果可以用GC含量低的区域与富含GC的等容线相比重组频率低72倍来解释。虽然重组不是决定LD的唯一因素，但我们的发现有助于根据区域GC含量预测关联研究所需的LD水平和标记密度。
