以1p31上的PGM1详细分析为例的人类基因组中重组热点和连锁不平衡的区块结构
Recombination hotspots and block structure of linkage disequilibrium in the human genome exemplified by detailed analysis of PGM1 on 1p31.
作者信息
Rana Naheed A, Ebenezer Neil D, Webster Andrew R, Linares Andres R, Whitehouse David B, Povey Sue, Hardcastle Alison J
机构信息
Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK
出版信息
Hum Mol Genet. 2004 Dec 15;13(24):3089-102. doi: 10.1093/hmg/ddh337. Epub 2004 Oct 27.
The distribution of linkage disequilibrium (LD) in the human genome has important consequences for the design of experiments that infer susceptibility genes for complex disease using association studies. Recent studies have shown a non-random distribution of human meiotic recombination associated with intervening tracts of LD. Little is known about the processes, patterns and frequency of reciprocal meiotic recombination in humans. However, this phenomenon can be better understood by the fine structure analysis of several genomic regions by mapping hotspots and characterizing regions with variable LD. Here, we report clustered hotspot activity with intervening blocks of LD within the human PGM1 gene (1p31) using data derived from meiotic and population studies. Earlier work has suggested a high recombination rate in two regions within the PGM1 gene, site A (exons 4-8) and site B (exons 1A-4). Sequencing of eight individuals across 6 kb of targeted regions in site B identified 18 informative SNPs. Individuals from three distinct populations, Caucasian (n=264), Chinese (n=222) and Vietnamese (n=187), were genotyped, and haplotypes were determined using estimate of haplotypes, ldmax and Arlequin. Allelic association and haplotype analysis in these samples revealed variable recombination rates across PGM1, demonstrating the presence of: (i) three hotspots and (ii) three haplotype blocks. The spatial arrangement of haplotype blocks was identical in all populations studied. The pattern of association within PGM1 represents a region decomposed into small blocks of LD, where increased recombination activity has disrupted the ancestral chromosome. Additionally, crossovers in phased data mapped preferentially to regions where LD collapses, which also overlap with sequence motifs.
人类基因组中连锁不平衡(LD)的分布对于利用关联研究推断复杂疾病易感基因的实验设计具有重要意义。最近的研究表明,人类减数分裂重组的分布并非随机,而是与LD的间隔区域相关。目前对于人类减数分裂中相互重组的过程、模式和频率知之甚少。然而,通过绘制热点并对具有可变LD的区域进行特征分析,对几个基因组区域进行精细结构分析,可以更好地理解这一现象。在此,我们利用减数分裂和群体研究的数据,报告了人类PGM1基因(1p31)内存在成簇的热点活性以及LD的间隔区域。早期的研究表明,PGM1基因内的两个区域,即位点A(外显子4 - 8)和位点B(外显子1A - 4),具有较高的重组率。对位点B中6 kb靶向区域的8个个体进行测序,确定了18个信息性单核苷酸多态性(SNP)。对来自三个不同群体,即高加索人(n = 264)、中国人(n = 222)和越南人(n = 187)的个体进行基因分型,并使用单倍型估计、ldmax和Arlequin确定单倍型。这些样本中的等位基因关联和单倍型分析揭示了PGM1基因上不同的重组率,表明存在:(i)三个热点和(ii)三个单倍型区域。在所有研究的群体中,单倍型区域的空间排列是相同的。PGM1基因内的关联模式代表了一个被分解为小LD区域的区域,其中增加的重组活性破坏了祖先染色体。此外,在分型数据中的交叉优先映射到LD崩溃的区域,这些区域也与序列基序重叠。