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Rafael Contreras-Galindo, Ph.D.

Description of Research: Rafael Contreras-Galindo

Markers to Study the Role of Centromere Sequence in Human Population and Disease

During every cell cycle, chromosomes, the basic units of inheritance, must be reliably partitioned and delivered to daughter cells.  Failure to do so results in genomic instability and aneuploidy (loss or gain of chromosomes), a hallmark of many birth defects and all late-stage cancers. The centromere, a region of repetitive DNA sequence and unique chromatin composition, is responsible for the faithful segregation of chromosomes.  Sequencing of a very small portion of the centromere of the human X-chromosome indicated that functional human centromere sequences are homogenous repeats of α-satellite DNA, yet the DNA sequence of other centromeres has not been obtained. The repetitive nature of human centromeres has made cloning and assembly of centromere sequences unsuccessful, and therefore centromere sequences have largely not been annotated in the map of the human genome. The virtual absence of centromere DNA information continues to make the study of centromere function and its impact on genetic diseases and cancers challenging. The presence of unique alphoid and non-alphoid repeats in each human centromere would greatly facilitate the study of centromere function, but to date such sequences have not been available.

By studying the RNA from Human Endogenous Retroviruses type K present in the blood of HIV-1-infected individuals we identified several distinct, although evolutionarily-related viral sequences we termed K111, that have arisen from DNA regions not annotated in the reference human genome. We discovered that in modern humans K111 sequences are found in the centromeres of 15 chromosomes. The DNA sequences of these viruses have informative nucleotide substitutions in each human centromere, and thus K111 sequences may serve as unique markers for the study of specific centromeres. To delineate a more complete K111 genome database aimed to establish centromere K111 markers additional sequence and bioinformatics analysis is needed.

We are now taking advantage of the existence of K111 markers as well as specific alphoid repeats to directly assess the role of each human centromere in cancer and genetic disease. We are characterizing K111 retroviruses and alphoid repeats sequences in each human centromere in order to delineate specific DNA markers for each centromere. These centromere markers are allowing us for the first time to study the biology of each individual centromere, will help us to fill the gaps of human centromere sequences, and will potentially be used in studying the role human centromeres play in genetic disorders and carcinogenesis.

Recent Publications:

Contreras-Galindo R, González M, Almodovar S, González-Ramirez S, Lorenzo E, and Yamamura Y.  A new real time-RT-PCR for quantitation of human endogenous retroviruses type K (HERV-K) RNA load in plasma samples: increased HERV-K RNA titers in HIV-1 patients with HAART non-suppressive regimens.  Journal of Virological Methods 2006 Sep;136(1-2):51-7. Epub 2006 May 6. PMID: 16678919

Contreras-Galindo R, Kaplan MH, Markovitz DM, Lorenzo E, and Yamamura Y.  Detection of HERV-K(HML-2) viral RNA in plasma of HIV-1 infected individuals.  AIDS Research and Human Retroviruses. 2006 Oct;22(10):979-84. PMID: 17067267

Contreras-Galindo R, López P, Vélez R, and Yamamura Y.  HIV-1 infection increases the expression of human endogenous retroviruses type K (HERV-K) in vitro. AIDS Research and Human Retroviruses. 2007 Jan;23(1):116-22. PMID: 17263641

Contreras-Galindo R, Almodóvar-Camacho S, González-Ramírez S, Lorenzo E, and Yamamura Y. Comparative longitudinal studies of HERV-K and HIV-1 RNA titers in HIV-1-infected patients receiving successful versus unsuccessful highly active antiretroviral therapy.  AIDS Res Hum Retroviruses. 2007 Sep;23(9):1083-6. PMID: 17919102

Contreras-Galindo R, Kaplan MH, Leissner P, Verjat T, Ferlengui I, Bagnoli F, Giusti F, Dosik MH, Hayes D, Gitlin SD, and Markovitz DM. Human Endogenous Retrovirus-K (HML-2) elements in the plasma of people with lymphoma and breast cancer. Journal of Virology. 2008 Oct;82(19):9329-36. Epub 2008 Jul 16. PMCID: PMC2546968

Dai M, Thompson R, Maher C, Contreras-Galindo R, Kaplan MH, Markovitz DM, Omenn G, and Meng F. NGSQC: Cross-platform quality analysis pipeline for deep sequencing data. BMC Genomics. 2010 Dec 12, 11 Suppl 4:S7. PMCID: PMC3005923

Contreras-Galindo R, Kaplan MH, Contreras-Galindo AC, Gonzalez-Hernandez M, Ferlengui I, Giusti F, Lorenzo E, Gitlin SD, Dosik MH, Yamamura Y, and Markovitz DM. Characterization of Human Endogenous Retroviral elements in the blood of HIV-1-infected individuals. Journal of Virology. 2012 Jan;86(1):262-76. Epub 2011 Oct 26. PMID:22031938

Gonzalez-Hernandez MJ, Swanson MD, Contreras-Galindo R, Cookinham S, King SR, Noel, Jr. RJ, Kaplan MH, and Markovitz DM. Expression of human endogenous retrovirus type-K (HML-2) is activated by the Tat protein of HIV-1. Journal of Virology. 2012. Aug;86(15):7790-805. PMCID: PMC3421662

Monde K, Contreras-Galindo R, Kaplan MH, Markovitz DM, and Ono A, HERV-K Gag coassembles with HIV-1 Gag and reduces the release efficiency and infectivity of HIV-1. Journal of Virology. 2012. Oct;86(20):11194-208. Epub 2012 Aug 1. PMCID: PMC3457174

Contreras-Galindo R, Kaplan MH, He S, Contreras-Galindo A, Gonzalez-Hernandez MJ, Kappes F, Dube D, Chan S, Robinson D, Meng F, Dai M, Gitlin SD, Chinnaiyan AM, Omenn GS, and Markovitz DM. HIV infection reveals wide-spread expansion of novel centromeric human endogenous retroviruses. Genome Research. 2013 Sep;23(9):1505-13. PMCID: PMC3255917



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