Morte e ressurreição do gene IRGM humano

Death and Resurrection of the HumanIRGM Gene

Cemalettin Bekpen1,2, Tomas Marques-Bonet1,3, Can Alkan1,2, Francesca Antonacci1, Maria Bruna Leogrande4, Mario Ventura4, Jeffrey M. Kidd1, Priscillia Siswara1, Jonathan C. Howard5, Evan E. Eichler1,2*

1 Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America, 2 Howard Hughes Medical Institute, Seattle, Washington, United States of America, 3Institut de Biologia Evolutiva (UPF-CSIC), Barcelona, Spain, 4 Universita' degli Studi di Bari, Bari, Italy, 5 Institute of Genetics, University of Cologne, Cologne, Germany

Abstract

Immunity-related GTPases (IRG) play an important role in defense against intracellular pathogens. One member of this gene family in humans, IRGM, has been recently implicated as a risk factor for Crohn's disease. We analyzed the detailed structure of this gene family among primates and showed that most of the IRG gene cluster was deleted early in primate evolution, after the divergence of the anthropoids from prosimians ( about 50 million years ago). Comparative sequence analysis of New World and Old World monkey species shows that the single-copy IRGM gene became pseudogenized as a result of an Alu retrotransposition event in the anthropoid common ancestor that disrupted the open reading frame (ORF). We find that the ORF was reestablished as a part of a polymorphic stop codon in the common ancestor of humans and great apes. Expression analysis suggests that this change occurred in conjunction with the insertion of an endogenous retrovirus, which altered the transcription initiation, splicing, and expression profile of IRGM. These data argue that the gene became pseudogenized and was then resurrected through a series of complex structural events and suggest remarkable functional plasticity where alleles experience diverse evolutionary pressures over time. Such dynamism in structure and evolution may be critical for a gene family locked in an arms race with an ever-changing repertoire of intracellular parasites.

Author Summary

The IRG gene family plays an important role in defense against intracellular bacteria, and genome-wide association studies have implicated structural variants of the single-copy human IRGM locus as a risk factor for Crohn's disease. We reconstruct the evolutionary history of this region among primates and show that the ancestral tandem gene family contracted to a single pseudogene within the ancestral lineage of apes and monkeys. Phylogenetic analyses support a model where the gene has been “dead” for at least 25 million years of human primate evolution but whose ORF became restored in all human and great ape lineages. We suggest that the rebirth or restoration of the gene coincided with the insertion of an endogenous retrovirus, which now serves as the functional promoter driving human gene expression. We suggest that either the gene is not functional in humans or this represents one of the first documented examples of gene death and rebirth.

Citation: Bekpen C, Marques-Bonet T, Alkan C, Antonacci F, Leogrande MB, et al.
(2009) Death and Resurrection of the Human IRGM Gene. PLoS Genet 5(3): e1000403. doi:10.1371/journal.pgen.1000403

Editor: Mikkel H. Schierup, University of Aarhus, Denmark

Received: October 23, 2008; Accepted: January 20, 2009; Published: March 6, 2009

Copyright: © 2009 Bekpen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported in part by Deutsche Forschungsgemeinschaft grant SFB680 to JCH and by NIH grants GM058815 and HG002385 to EEE. TM-B is supported by a Marie Curie fellowship. EEE is an investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: eee@gs.washington.edu

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