Population-scale genetic control of alternative polyadenylation and its association with human diseases

Abstract

Background: Genome-wide association studies (GWAS) have identified thousands of genomic non-coding variants statistically associated with many human traits and diseases, including cancer. However, the functional interpretation of these non-coding variants remains a significant challenge in the post-GWAS era. Alternative polyadenylation (APA) plays an essential role in post-transcriptional regulation for most human genes. By employing different poly(A) sites, genes can either shorten or extend the 3′-UTRs that contain cis-regulatory elements such as miRNAs or RNA-binding protein binding sites. Therefore, APA can affect the mRNA stability, translation, and cellular localization of proteins. Population-scale studies have revealed many inherited genetic variants that potentially impact APA to further influence disease susceptibility and phenotypic diversity, but systematic computational investigations to delineate the connections are in their earliest states.

Results: Here, we discuss the evolving definitions of the genetic basis of APA and the modern genomics tools to identify, characterize, and validate the genetic influences of APA events in human populations. We also explore the emerging and surprisingly complex molecular mechanisms that regulate APA and summarize the genetic control of APA that is associated with complex human diseases and traits.

Conclusion: APA is an intermediate molecular phenotype that can translate human common non-coding variants to individual phenotypic variability and disease susceptibility.

Author summary

Genome-wide association studies (GWAS) have identified hundreds of inherited single-nucleotide polymorphisms (SNPs) associated with human diseases. However, they fall short of linking SNPs with dysregulation of specific genes and the molecular mechanisms responsible for disease/traits. By investigating the genetic basis of alternative polyadenylation we may gain insight into how GWAS non-coding variants influence complex diseases.

Graphical abstract

Keywords

GWAS / eQTL / disease / alternative polyadenylation

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ACKNOWLEDGEMENTS

The authors apologize to those colleagues whose relevant studies were not cited due to spacing limits. We thank members of the Wei Li lab for helpful discussions. The Wagner lab acknowledges support from the National Institutes of Health grant R01-GM134539 (E.J.W).

COMPLIANCE WITH ETHICS GUIDELINES

The authors Lei Li, Yumei Li, Xudong Zou, Fuduan Peng, Ya Cui, Eric J. Wagner and Wei Li declare no competing financial interests. All procedures performed in studies were in accordance with the ethical standards of the institution or practice at which the studies were conducted, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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