Allele-specific KRT1 expression is a complex trait.
Allele-specific KRT1 expression is a complex trait.
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等位基因特异性的KRT1表达是一个复杂的性状。
DOI：
10.1371/journal.pgen.0020093
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发表时间：
2006-06
期刊：
影响因子：
4.5
通讯作者：
Frazer, Kelly A.
中科院分区：
文献类型：
--
作者：
Tao, Heng;Cox, David R.;Frazer, Kelly A.
等位基因的差异表达在人类中普遍存在，可能是表型性状遗传差异的重要遗传因素。因此，了解等位基因表达差异的分子基础是一个重要的挑战。虽然许多基因已被证明显示差异等位基因表达，这是第一个研究，详细检查负责等位基因特异性表达差异的多个顺式调节多态性的累积效应。我们已经使用了各种实验方法来确定和表征负责极端等位基因特异性角蛋白-1（KRT 1）在人类白色血细胞中的表达差异的顺式调节多态性。从我们的分析组合的数据提供了强有力的证据表明，KRT 1等位基因的表达差异的单倍型组合和相互作用的5个顺式调节单核苷酸多态性（SNP），其等位基因不同的亲和力结合转录因子和调节KRT 1启动子活性。这些顺式调节SNP中的两个结合转录激活因子，其中高表达KRT 1单倍型模式上的等位基因具有比低表达单倍型模式上的等位基因更高的亲和力。相比之下，其他三个顺式调节SNP结合转录抑制剂，其中低表达单倍型模式上的等位基因具有比高表达单倍型模式上的等位基因更高的亲和力。我们的研究提供了重要的新的见解的复杂程度，负责等位基因特异性转录调控的顺式调控序列。这些数据表明，等位基因表达差异的累积贡献的多个DNA序列多态性，每个有一个小的影响，因此，等位基因特异性表达可以被视为一个复杂的性状。尽管所有人都有几乎相同的DNA序列，但个体在遗传特征上表现出巨大的差异，如身高，体重和皮肤纹理。最近的证据表明，基因的不同拷贝（等位基因）之间的表达水平差异有助于这些观察到的遗传性状的差异。目前，对等位基因表达水平差异的机制还知之甚少。在这份报告中，作者确定并表征了一组五个单核苷酸多态性（SNP），这些SNP导致人类角蛋白-1（KRT 1）等位基因之间的极端表达差异。这五个SNP中的每一个都存在于KRT 1附近的不同调控序列中。SNP导致五种调控序列的不同拷贝在其结合控制KRT 1表达的转录因子的亲和力上不同。极端的KRT 1等位基因表达水平差异是由这五个SNP的累积贡献造成的，这五个SNP在两个常见的固定集合（低表达集合和高表达集合）中紧密连锁和遗传。这项研究为等位基因表达水平差异的复杂机制提供了重要的新见解。这些复杂性可能解释了研究人员在试图发现与遗传研究中的遗传性状相关的间隔中的“致病SNP”时经常遇到的困难。
The differential expression of alleles occurs commonly in humans and is likely an important genetic factor underlying heritable differences in phenotypic traits. Understanding the molecular basis of allelic expression differences is thus an important challenge. Although many genes have been shown to display differential allelic expression, this is the first study to examine in detail the cumulative effects of multiple cis-regulatory polymorphisms responsible for allele-specific expression differences. We have used a variety of experimental approaches to identify and characterize cis-regulatory polymorphisms responsible for the extreme allele-specific expression differences of keratin-1 (KRT1) in human white blood cells. The combined data from our analyses provide strong evidence that the KRT1 allelic expression differences result from the haplotypic combinations and interactions of five cis-regulatory single nucleotide polymorphisms (SNPs) whose alleles differ in their affinity to bind transcription factors and modulate KRT1 promoter activity. Two of these cis-regulatory SNPs bind transcriptional activators with the alleles on the high-expressing KRT1 haplotype pattern having a higher affinity than the alleles on the low-expressing haplotype pattern. In contrast, the other three cis-regulatory SNPs bind transcriptional inhibitors with the alleles on the low-expressing haplotype pattern having a higher affinity than the alleles on the high-expressing haplotype pattern. Our study provides important new insights into the degree of complexity that the cis-regulatory sequences responsible for allele-specific transcriptional regulation have. These data suggest that allelic expression differences result from the cumulative contribution of multiple DNA sequence polymorphisms, with each having a small effect, and that allele-specific expression can thus be viewed as a complex trait. Despite the fact that all humans share nearly identical DNA sequences, individuals exhibit tremendous variation in heritable traits, such as height, weight, and skin texture. Recent evidence suggests that expression level differences between different copies (alleles) of a gene contribute to these observed differences in heritable traits. Currently, the mechanisms underlying allele-expression level differences are poorly understood. In this report the authors identified and characterized a set of five single nucleotide polymorphisms (SNPs) contributing to extreme expression differences between keratin-1 (KRT1) alleles in humans. Each of the five SNPs is found in a different regulatory sequence in the proximity of KRT1. The SNPs cause different copies of the five regulatory sequences to differ in their affinities to bind transcription factors controlling KRT1 expression. The extreme KRT1 allele-expression level differences result from the cumulative contributions of these five SNPs which are tightly linked and inherited in two common fixed sets, a low- and a high-expressing set. The study provides important new insights into the complexities of the mechanisms underlying allele-expression level differences. These complexities may explain the difficulties researchers frequently encounter when trying to discover the “causative SNP” in an interval identified as associated with an inherited trait in a genetic study.
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影响因子：
5.3
作者：
Bray, NJ;Buckland, PR;O'Donovan, MC
通讯作者：
O'Donovan, MC
影响因子：
14.9
作者：
Crinelli, R;Bianchi, M;Magnani, M
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Magnani, M
影响因子：
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作者：
LEVANON, D;NEGREANU, V;GRONER, Y
通讯作者：
GRONER, Y
影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0830998100
发表时间：
2003-04-15
影响因子：
11.1
作者：
Grooteclaes, M;Deveraux, Q;Frisch, SM
通讯作者：
Frisch, SM