HIV infection reveals widespread expansion of novel centromeric human endogenous retroviruses
- Rafael Contreras-Galindo1,
- Mark H. Kaplan1,
- Shirley He1,
- Angie C. Contreras-Galindo1,
- Marta J. Gonzalez-Hernandez1,
- Ferdinand Kappes2,
- Derek Dube1,
- Susana M. Chan1,
- Dan Robinson3,4,
- Fan Meng5,6,
- Manhong Dai5,
- Scott D. Gitlin1,4,7,
- Arul M. Chinnaiyan3,4,8,
- Gilbert S. Omenn9 and
- David M. Markovitz1,4,10
- 1Department of Internal Medicine, and Programs in Immunology, Cancer Biology, and Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109, USA;
- 2Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany;
- 3Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
- 4Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
- 5Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan 48109, USA;
- 6Department of Psychiatry, University of Michigan, Ann Arbor, Michigan 48109, USA;
- 7Veteran Affairs Health System, Ann Arbor, Michigan 48105, USA;
- 8Howard Hughes Medical Institute,
- 9Departments of Computational Medicine and Bioinformatics, Internal Medicine, and Human Genetics, and School of Public Health, University of Michigan, Ann Arbor, Michigan 48109, USA
Abstract
Human endogenous retroviruses (HERVs) make up 8% of the human genome. The HERV-K (HML-2) family is the most recent group of these viruses to have inserted into the genome, and we have detected the activation of HERV-K (HML-2) proviruses in the blood of patients with HIV-1 infection. We report that HIV-1 infection activates expression of a novel HERV-K (HML-2) provirus, termed K111, present in multiple copies in the centromeres of chromosomes throughout the human genome yet not annotated in the most recent human genome assembly. Infection with HIV-1 or stimulation with the HIV-1 Tat protein leads to the activation of K111 proviruses. K111 is present as a single copy in the genome of the chimpanzee, yet K111 is not found in the genomes of other primates. Remarkably, K111 proviruses appear in the genomes of the extinct Neanderthal and Denisovan, while modern humans have at least 100 K111 proviruses spread across the centromeres of 15 chromosomes. Our studies suggest that the progenitor K111 integrated before the Homo-Pan divergence and expanded in copy number during the evolution of hominins, perhaps by recombination. The expansion of K111 provides sequence evidence suggesting that recombination between the centromeres of various chromosomes took place during the evolution of humans. K111 proviruses show significant sequence variations in each individual centromere, which may serve as markers in future efforts to annotate human centromere sequences. Further, this work is an example of the potential to discover previously unknown genomic sequences through the analysis of nucleic acids found in the blood of patients.
Footnotes
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↵10 Corresponding author
E-mail dmarkov{at}umich.edu
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.144303.112.
Freely available online through the Genome Research Open Access option.
- Received June 6, 2012.
- Accepted April 30, 2013.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
