Allele-Specific KRT1 Expression Is a Complex Trait

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Abstract
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.