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The impact of cis-acting polymorphisms on the human phenotype.

ABSTRACT: Cis-acting polymorphisms that affect gene expression are now known to be frequent, although the extent and mechanisms by which such variation affects the human phenotype are, as yet, only poorly understood. Key signatures of cis-acting variation are differences in gene expression that are tightly associated with regulatory SNPs or expression Quantitative Trait Loci (eQTL) and an imbalance of allelic expression (AEI) in heterozygous samples. Such cis-acting sequence differences appear often to have been under selection within and between populations and are also thought to be important in speciation. Here we describe the example of lactase persistence. In medical research, variants that affect regulation in cis have been implicated in both monogenic and polygenic disorders, and in the metabolism of drugs. In this review we suggest that by further understanding common regulatory variations and how they interact with other genetic and environmental variables it will be possible to gain insight into important mechanisms behind complex disease, with the potential to lead to new methods of diagnosis and treatments.

SUBMITTER: Jones BL

PROVIDER: S-EPMC3238023 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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The impact of cis-acting polymorphisms on the human phenotype.

Jones Bryony L BL Swallow Dallas M DM

The HUGO journal 20110720 1-4

Cis-acting polymorphisms that affect gene expression are now known to be frequent, although the extent and mechanisms by which such variation affects the human phenotype are, as yet, only poorly understood. Key signatures of cis-acting variation are differences in gene expression that are tightly associated with regulatory SNPs or expression Quantitative Trait Loci (eQTL) and an imbalance of allelic expression (AEI) in heterozygous samples. Such cis-acting sequence differences appear often to ha ...[more]

PMID: 23205161

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Project description:Simple Summary Epigenetic mechanisms contribute to the regulation of gene expression. However, when they fail, they result in diseases such as cancer. Among these effects is aberrant DNA methylation caused by inherited mutations in cis of the affected gene, referred to as constitutional secondary epimutations. Little is known about this phenomenon, in which hypermethylation promotes transcriptional silencing of tumor suppressor genes in patients with inherited cancers that do not have pathogenic variants in the coding region of cancer susceptibility genes. Here we discuss these hereditary alterations and their effect during the early stages of tumorigenesis, as well as their contribution to disease historically and from a molecular perspective. Abstract Epigenetics affects gene expression and contributes to disease development by alterations known as epimutations. Hypermethylation that results in transcriptional silencing of tumor suppressor genes has been described in patients with hereditary cancers and without pathogenic variants in the coding region of cancer susceptibility genes. Although somatic promoter hypermethylation of these genes can occur in later stages of the carcinogenic process, constitutional methylation can be a crucial event during the first steps of tumorigenesis, accelerating tumor development. Primary epimutations originate independently of changes in the DNA sequence, while secondary epimutations are a consequence of a mutation in a cis or trans-acting factor. Secondary epimutations have a genetic basis in cis of the promoter regions of genes involved in familial cancers. This highlights epimutations as a novel carcinogenic mechanism whose contribution to human diseases is underestimated by the scarcity of the variants described. In this review, we provide an overview of secondary epimutations and present evidence of their impact on cancer. We propose the necessity for genetic screening of loci associated with secondary epimutations in familial cancer as part of prevention programs to improve molecular diagnosis, secondary prevention, and reduce the mortality of these diseases.

Dataset Information

The impact of cis-acting polymorphisms on the human phenotype.

Publications

The impact of cis-acting polymorphisms on the human phenotype.

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