SNP Haplotype Mapping in a Small ALS Family
SNP Haplotype Mapping in a Small ALS Family
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DOI：
10.1371/journal.pone.0005687
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发表时间：
2009-05-25
期刊：
影响因子：
3.7
通讯作者：
Ranum, Laura P. W.
中科院分区：
文献类型：
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作者：
Krueger, Katherine A. Dick;Tsuji, Shoji;Ranum, Laura P. W.
单基因疾病的基因鉴定已被证明对了解人类疾病机制、途径和基因功能非常有效。然而，尽管数千种孟德尔疾病尚未被绘制出来，但已经出现了一种远离研究单基因疾病的趋势。在某种程度上，这是由于许多剩余的单基因家族不够大，无法将疾病位点定位到基因组中的单个位点。需要新的工具和方法来让研究人员有效地挖掘这个基因金矿。为了实现这一目标，我们使用单倍体细胞系实验验证高密度单核苷酸多态性（SNP）阵列的使用，以一个小的肌萎缩性侧索硬化症（ALS）家族为原型，定义全基因组单倍型和候选区域。具体来说，我们使用单倍体细胞系来确定高密度SNP阵列是否准确地预测了整个染色体的单倍型，并表明单倍型信息显着增强了小家族的遗传信息。生成单倍体细胞系，进行5厘米（cM）短串联重复多态性（STRP）基因组扫描。实验获得的整个染色体的单倍型用于直接鉴定5个受影响个体的基因组同源区域。实验确定的单倍型和通过SNP阵列预测的单倍型的比较表明，二倍体DNA的SNP分析准确地预测了染色体的单倍型。这些方法精确地确定了12个候选区间，这些区间由所有5个受影响的个体共享。我们的研究说明了如何利用现成的工具最大限度地获取遗传信息，作为绘制小家庭单基因疾病图谱的第一步。
The identification of genes for monogenic disorders has proven to be highly effective for understanding disease mechanisms, pathways and gene function in humans. Nevertheless, while thousands of Mendelian disorders have not yet been mapped there has been a trend away from studying single-gene disorders. In part, this is due to the fact that many of the remaining single-gene families are not large enough to map the disease locus to a single site in the genome. New tools and approaches are needed to allow researchers to effectively tap into this genetic gold-mine. Towards this goal, we have used haploid cell lines to experimentally validate the use of high-density single nucleotide polymorphism (SNP) arrays to define genome-wide haplotypes and candidate regions, using a small amyotrophic lateral sclerosis (ALS) family as a prototype. Specifically, we used haploid-cell lines to determine if high-density SNP arrays accurately predict haplotypes across entire chromosomes and show that haplotype information significantly enhances the genetic information in small families. Panels of haploid-cell lines were generated and a 5 centimorgan (cM) short tandem repeat polymorphism (STRP) genome scan was performed. Experimentally derived haplotypes for entire chromosomes were used to directly identify regions of the genome identical-by-descent in 5 affected individuals. Comparisons between experimentally determined and in silico haplotypes predicted from SNP arrays demonstrate that SNP analysis of diploid DNA accurately predicted chromosomal haplotypes. These methods precisely identified 12 candidate intervals, which are shared by all 5 affected individuals. Our study illustrates how genetic information can be maximized using readily available tools as a first step in mapping single-gene disorders in small families.