Widespread establishment and regulatory impact of Alu exons in human genes

Shihao Shen; Lan Lin; James J Cai; Peng Jiang; Elizabeth J Kenkel; Mallory R Stroik; Seiko Sato; Beverly L Davidson; Yi Xing

doi:10.1073/pnas.1012834108

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Widespread establishment and regulatory impact of Alu exons in human genes

Journal article

Open access

Peer reviewed

Widespread establishment and regulatory impact of Alu exons in human genes

Shihao Shen, Lan Lin, James J Cai, Peng Jiang, Elizabeth J Kenkel, Mallory R Stroik, Seiko Sato, Beverly L Davidson and Yi Xing

Proceedings of the National Academy of Sciences - PNAS, Vol.108(7), pp.2837-2842

02/15/2011

DOI: 10.1073/pnas.1012834108

PMCID: PMC3041063

PMID: 21282640

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Abstract

The Alu element has been a major source of new exons during primate evolution. Thousands of human genes contain spliced exons derived from Alu elements. However, identifying Alu exons that have acquired genuine biological functions remains a major challenge. We investigated the creation and establishment of Alu exons in human genes, using transcriptome profiles of human tissues generated by high-throughput RNA sequencing (RNA-Seq) combined with extensive RT-PCR analysis. More than 25% of Alu exons analyzed by RNA-Seq have estimated transcript inclusion levels of at least 50% in the human cerebellum, indicating widespread establishment of Alu exons in human genes. Genes encoding zinc finger transcription factors have significantly higher levels of Alu exonization. Importantly, Alu exons with high splicing activities are strongly enriched in the 5'-UTR, and two-thirds (10/15) of 5'-UTR Alu exons tested by luciferase reporter assays significantly alter mRNA translational efficiency. Mutational analysis reveals the specific molecular mechanisms by which newly created 5'-UTR Alu exons modulate translational efficiency, such as the creation or elongation of upstream ORFs that repress the translation of the primary ORFs. This study presents genomic evidence that a major functional consequence of Alu exonization is the lineage-specific evolution of translational regulation. Moreover, the preferential creation and establishment of Alu exons in zinc finger genes suggest that Alu exonization may have globally affected the evolution of primate and human transcriptomes by regulating the protein production of master transcriptional regulators in specific lineages.

Computational Biology

Alternative Splicing - genetics

Alu Elements - genetics

Cerebellum - metabolism

DNA Mutational Analysis

Evolution, Molecular

Exons - genetics

Gene Expression Profiling - methods

Gene Expression Regulation - genetics

Humans

Luciferases

Reverse Transcriptase Polymerase Chain Reaction

Transcription Factors - genetics

Zinc Fingers - genetics

Details

Title: Subtitle: Widespread establishment and regulatory impact of Alu exons in human genes
Creators: Shihao Shen - University of Iowa
Lan Lin
James J Cai
Peng Jiang
Elizabeth J Kenkel
Mallory R Stroik
Seiko Sato
Beverly L Davidson
Yi Xing
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.108(7), pp.2837-2842
DOI: 10.1073/pnas.1012834108
PMID: 21282640
PMCID: PMC3041063
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Grant note: R01 HG004634 / NHGRI NIH HHS R01 GM088342 / NIGMS NIH HHS P01 NS050210 / NINDS NIH HHS R01HG004634 / NHGRI NIH HHS R01 GM088342-02 / NIGMS NIH HHS P01NS050210 / NINDS NIH HHS R01 GM088342-01A1 / NIGMS NIH HHS R01GM088342 / NIGMS NIH HHS
Language: English
Date published: 02/15/2011
Academic Unit: Internal Medicine
Record Identifier: 9984259411602771

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