Allelic Variation in Human Gene Expression

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Science  16 Aug 2002:
Vol. 297, Issue 5584, pp. 1143
DOI: 10.1126/science.1072545

Understanding the genetic basis of human variation is a vital goal of biomedical research. Studies in other organisms suggest that differences in gene expression levels account for a major part of the variation within and among species (1, 2). To address this in humans, we developed methods to quantitatively evaluate allelic variation in gene expression.

The analysis of variation in gene expression is complicated by the potentially small differences associated with alterations in a single allele as well as by potential variations between individuals that arise from environmental or physiological rather than genetic factors. To circumvent these analytic problems, we compared the relative expression levels of two alleles of the same gene within the same cellular sample. To make these comparisons, we used a fluorescent dideoxy terminator–based method (3) to distinguish the mRNA products of alleles from normal individuals who were heterozygous for a single nucleotide polymorphism (SNP) in the transcript of interest (fig. S1). We estimated that this approach could confidently identify variations when the differences between expression of the two alleles differed by more than 20% (3).

We examined SNPs for 13 genes in 96 individuals from the CEPH families and identified 17 to 37 individuals who were heterozygous for any given gene (Table 1). Their mRNA was then used to assess relative expression of the two alleles. Significant differences in allelic variation were observed in 6 of the 13 genes studied. The fraction of individuals exhibiting such variation ranged from 3% (Catalase) to 30% (p73) (Table 1). In individuals whose alleles were differentially expressed, the ratio of transcripts varied from 1.3:1.0 (FBN1) to 4.3:1.0 (p73). Given that these variations were each observed in only a minority of individuals, it is unlikely that they were due to parental imprinting.

Table 1

Allelic variation in gene expression.

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We next examined the families of nine individuals exhibiting allelic variation. Three families were informative and displayed expression fully consistent with Mendelian inheritance. Two families had allelic variation of Calpain-10 expression, and one family had allelic variation of PKD2 expression (Fig. 1). Altered expression was consistently inherited together with a single haplotype defined by at least two adjacent microsatellite markers. The altered allelic expression ofPKD2 was due to increased expression of the affected allele, whereas in both Calpain-10 families, it was due to decreased expression of the affected allele.

Figure 1

Mendelian inheritance of altered PKD2 orCalpain-10 expression. Only individuals who were heterozygous for the SNP or were used to deduce haplotypes are shown. Red indicates altered fractional allelic expression; arrows indicate probands. An obligate carrier in the PKD2 pedigree who could not be scored is indicated with a red dot within a circle. The results of genotype and expression analyses are shown above each member of the pedigrees. A single Calpain-10 genotype suggesting a recombination is italicized.

Thus, cis-acting inherited variations in gene expression are relatively common among normal individuals. Moreover, these measurements likely represent an underestimate, as additional variations in allelic expression may manifest in a cell type or state-specific manner. These results suggest approaches for connecting genotype to disease susceptibility based on changes in gene expression as opposed to changes in the structure of the encoded protein. Such analyses do not require any assumptions about the genetic structure of the population studied and may yield direct information about the causative gene and its mechanism of action.

Supporting Online Material

Materials and Methods

Fig. S1

  • * To whom correspondence should be addressed. E-mail: kinzlke{at}


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