Guryev Victor, Smits Bart M G, van de Belt Jose, Verheul Mark, Hubner Norbert, Cuppen Edwin
Hubrecht Laboratory, Utrecht, The Netherlands.
PLoS Genet. 2006 Jul;2(7):e121. doi: 10.1371/journal.pgen.0020121.
Genetic variation in genomes is organized in haplotype blocks, and species-specific block structure is defined by differential contribution of population history effects in combination with mutation and recombination events. Haplotype maps characterize the common patterns of linkage disequilibrium in populations and have important applications in the design and interpretation of genetic experiments. Although evolutionary processes are known to drive the selection of individual polymorphisms, their effect on haplotype block structure dynamics has not been shown. Here, we present a high-resolution haplotype map for a 5-megabase genomic region in the rat and compare it with the orthologous human and mouse segments. Although the size and fine structure of haplotype blocks are species dependent, there is a significant interspecies overlap in structure and a tendency for blocks to encompass complete genes. Extending these findings to the complete human genome using haplotype map phase I data reveals that linkage disequilibrium values are significantly higher for equally spaced positions in genic regions, including promoters, as compared to intergenic regions, indicating that a selective mechanism exists to maintain combinations of alleles within potentially interacting coding and regulatory regions. Although this characteristic may complicate the identification of causal polymorphisms underlying phenotypic traits, conservation of haplotype structure may be employed for the identification and characterization of functionally important genomic regions.
基因组中的遗传变异以单倍型块的形式组织起来,物种特异性的块结构是由群体历史效应与突变和重组事件的不同贡献所定义的。单倍型图谱描绘了群体中连锁不平衡的常见模式,并在遗传实验的设计和解释中具有重要应用。虽然已知进化过程驱动个体多态性的选择,但尚未显示其对单倍型块结构动态的影响。在此,我们展示了大鼠5兆碱基基因组区域的高分辨率单倍型图谱,并将其与直系同源的人类和小鼠片段进行比较。虽然单倍型块的大小和精细结构因物种而异,但在结构上存在显著的种间重叠,并且块倾向于包含完整的基因。使用单倍型图谱第一阶段数据将这些发现扩展到完整的人类基因组,结果显示,与基因间区域相比,包括启动子在内的基因区域中等距位置的连锁不平衡值显著更高,这表明存在一种选择机制来维持潜在相互作用的编码和调控区域内的等位基因组合。虽然这一特征可能会使识别表型性状背后的因果多态性变得复杂,但单倍型结构的保守性可用于识别和表征功能重要的基因组区域。