Statistical recombinant mapping in extended high-risk Utah pedigrees narrows the 8q24 prostate cancer locus to 2.0 Mb
Statistical recombinant mapping in extended high-risk Utah pedigrees narrows the 8q24 prostate cancer locus to 2.0 Mb
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DOI：
10.1002/pros.20631
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发表时间：
2007-09-15
期刊：
影响因子：
2.8
通讯作者：
Cannon-Albright, Lisa A.
中科院分区：
文献类型：
--
作者：
Camp, Nicola J.;Farnham, James M.;Cannon-Albright, Lisa A.
背景染色体8 q24是前列腺癌（PRCA）的一个令人感兴趣的区域。连锁，协会，和混合物分析最初指出该地区。随后，在8 q24的几个变体被发现与PRCA独立相关。一个令人信服的假设是等位基因异质性，即多个变体影响同一基因的调控。除了潜在的等位基因异质性，8 q24在很远的距离上表现出很强的连锁不平衡，并且容易发生染色体畸变。等位基因异质性和复杂的染色体结构是阻碍利用关联进行基因鉴定的因素。然而，连锁技术是强大的等位基因异质性，因此可以提供重要的定位信息。我们使用了一种基于连锁的定位技术，在8个高危犹他州家系中进行重组定位。使用基于谱系的重组作图，我们在8q24.21-22处鉴定了标记D8 S1774和D8 S557之间的5.7 Mb区域。考虑到我们的区域与先前提出的定位，我们可以将8 q24 PRCA基因座界定为2.0 Mb的一致区间127.5 - 129.5 Mb。我们在扩展的高风险犹他州家系中使用了基于连锁的重组作图技术，成功地缩小了8 q24 PRCA基因座。我们提出的区域一半的95%可信区间先前描述的使用混合物分析，只包含三个注释的基因：FAM 84 B，MYC，和TMEM 75。应该注意的是，LD远远超出了我们描述的区间，因此该区域增加了关于未来在哪里集中精力分离致病变异和潜在基因的重要信息，无论是通过连锁还是关联技术。
BACKGROUND. Chromosome 8q24 is a region of compelling interest for prostate cancer (PRCA). Linkage, association, and admixture analysis initially indicated the region. Subsequently, several variants at 8q24 have been found to independently associate with PRCA. One compelling hypothesis is allelic heterogeneity, whereby multiple variants affect the regulation of the same gene. In addition to potential allelic heterogeneity, 8q24 exhibits strong linkage disequilibrium over vast distances and is prone to chromosomal aberrations.METHODS. Allelic heterogeneity and complex chromosomal structure are factors that hinder progress towards gene identification using association. Linkage techniques, however, are robust to allelic heterogeneity and therefore can contribute important localization information. We have used a linkage-based localization technique to perform recombinant mapping in eight high-risk Utah pedigrees.RESULTS. Using pedigree-based recombinant mapping we identify a 5.7 Mb region at 8q24.21-22, between markers D8S1774 and D8S557. Considering our region with the localization previously presented, we can delimit the 8q24 PRCA locus to a 2.0 Mb consensus interval from 127.5 to 129.5 Mb.CONCLUSION. We have used a linkage-based, recombinant mapping technique in extended high-risk Utah pedigrees to successfully narrow the 8q24 PRCA locus. The region we present halves the 95% credible interval previously described using admixture analysis and contains only three annotated genes: FAM84B, MYC, and TMEM75. It should be noted that LD stretches far beyond the interval we describe, and hence this region adds important information about where to focus future efforts to isolate the causal variants and underlying gene, whether by linkage or association techniques.