Question

What transcriptional regulation mechanism unique to mammals allows for selective gene expression from one allele only? Explain how this impacts expression of IGF2.

Answer 1

ASE is a powerful approach to study the impact of genetic variations on gene expression [20]. It complements the studies of eQTL (expression quantitative trait loci), which quantifies gene expression differences among people with different genotypes. The eQTL combines measurements of genotype and gene expression in a large number of individuals and correlates genotype with gene expression [21]. The approach is versatile. In many cases, genotype data and gene expression are already available through GWAS and other studies. On the other hand, ASE offers some advantage in certain studies. Here are two examples. First, variation in gene expression among different people can be due to a number of causes. Some are real biological factors while others are caused by experimental noise. Allele-specific gene expression provides an effective way to remove technical noise, since the noise often affects both alleles more or less equally and thus should not affect relative expression between the two alleles. Second, transcription regulatory mechanisms such as negative feedback can conceal the effect of variants on the total expression level, but such an effect can be unmasked by means of allele-specific analysis.

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Allele-specific DNA methylation and chromatin modi.

Igf2 is widely expressed during murine embryonic development and is particularly important in placental growth [18]. As with many genes that regulate placental development, Igf2 is imprinted, or expressed monoallelically, and active only on the paternally inherited allele. Igf2 is highly expressed in the mouse embryo, but levels decline dramatically after birth; in adult mice, Igf2 transcripts are detectable only in the choroid plexus and leptomeninges, where expression is biallelic [14].IGF2 is also imprinted in humans, but is expressed biallelically in the choroid plexus, leptomeninges, and perhaps the developing retina [19]. However, human IGF2 is also expressed in the adult, with transcripts arising from an adult-specific promoter [20]. The corresponding region in the mouse Igf2 gene contains two pseudoexons and what appears to be a remnant of this adult-specific promoter—which may explain whyIgf2 expression ceases after birth in mice but not in humans.