Mutational analysis of the mitochondrial tRNA genes and flanking regions in umbilical cord tissue from uninfected infants receiving AZT-based therapies for prophylaxis of HIV-1
A sensitive vertical denaturing gradient gel electrophoresis (DGGE) method, using 13 unipolar psoralen-clamped PCR primer pairs, was developed for detecting sequence variants in the 22 tRNA genes and flanking regions (together spanning ~21%) of the human mitochondrial genome. A study was conducted t...
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| creator | Torres, Salina M Walker, Dale M McCash, Consuelo L Carter, Meghan M Ming, Jessica Cordova, Edmund M Pons, Rachel M Cook, Dennis L. Jr Seilkop, Steven K Copeland, William C Walker, Vernon E |
| description | A sensitive vertical denaturing gradient gel electrophoresis (DGGE) method, using 13 unipolar psoralen-clamped PCR primer pairs, was developed for detecting sequence variants in the 22 tRNA genes and flanking regions (together spanning ~21%) of the human mitochondrial genome. A study was conducted to determine (i) if mitochondrial DNA (mtDNA) polymorphisms and/or mutations were detectable in healthy newborns and (ii) if prepartum 3'-azido-2',3'-dideoxythymidine (AZT) based HIV-1 prophylaxis was associated with significant increases in mtDNA mutations and changes in the degree of heteroplasmy of sequence variants in uninfected infants born to HIV-1-infected mothers. DGGE analysis of umbilical cord tissue (where vascular endothelium and smooth muscle cells are the major source of mtDNA) showed that mtDNA sequence variants were significantly elevated by threefold in AZT-treated infants compared with unexposed controls (P < 0.001), with 24 changes observed in 19/52 (37%) treated newborns (averaging 0.46 changes/subject) versus only eight changes found in 7/55 (13%) unexposed newborns (averaging 0.15 changes/subject). Six distinct sequence variants occurring in unexposed controls were predominately synonymous and homoplasmic, representing previously reported polymorphisms. Uninfected infants exposed to a combination of AZT and 2',3'-dideoxy-3'-thiacytidine and "maternal HIV-1" had a significant shift in the spectrum of mutations (P = 0.04) driven by increases in nonsynonymous heteroplasmic sequence variants at polymorphic sites (10 distinct variants) and novel sites (four distinct variants). While the weight of evidence suggests that prepartum AZT-based prophylaxis produces mtDNA mutations, additional research is needed to determine the degree to which fetal responses to maternal HIV-1 infection, in the absence of antiretroviral treatment, contribute to prenatal mtDNA mutagenesis. Environ. Mol. Mutagen., 2009. |
| doi_str_mv | 10.1002/em.20433 |
| format | Article |
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Jr ; Seilkop, Steven K ; Copeland, William C ; Walker, Vernon E</creator><creatorcontrib>Torres, Salina M ; Walker, Dale M ; McCash, Consuelo L ; Carter, Meghan M ; Ming, Jessica ; Cordova, Edmund M ; Pons, Rachel M ; Cook, Dennis L. Jr ; Seilkop, Steven K ; Copeland, William C ; Walker, Vernon E</creatorcontrib><description>A sensitive vertical denaturing gradient gel electrophoresis (DGGE) method, using 13 unipolar psoralen-clamped PCR primer pairs, was developed for detecting sequence variants in the 22 tRNA genes and flanking regions (together spanning ~21%) of the human mitochondrial genome. A study was conducted to determine (i) if mitochondrial DNA (mtDNA) polymorphisms and/or mutations were detectable in healthy newborns and (ii) if prepartum 3'-azido-2',3'-dideoxythymidine (AZT) based HIV-1 prophylaxis was associated with significant increases in mtDNA mutations and changes in the degree of heteroplasmy of sequence variants in uninfected infants born to HIV-1-infected mothers. DGGE analysis of umbilical cord tissue (where vascular endothelium and smooth muscle cells are the major source of mtDNA) showed that mtDNA sequence variants were significantly elevated by threefold in AZT-treated infants compared with unexposed controls (P < 0.001), with 24 changes observed in 19/52 (37%) treated newborns (averaging 0.46 changes/subject) versus only eight changes found in 7/55 (13%) unexposed newborns (averaging 0.15 changes/subject). Six distinct sequence variants occurring in unexposed controls were predominately synonymous and homoplasmic, representing previously reported polymorphisms. Uninfected infants exposed to a combination of AZT and 2',3'-dideoxy-3'-thiacytidine and "maternal HIV-1" had a significant shift in the spectrum of mutations (P = 0.04) driven by increases in nonsynonymous heteroplasmic sequence variants at polymorphic sites (10 distinct variants) and novel sites (four distinct variants). While the weight of evidence suggests that prepartum AZT-based prophylaxis produces mtDNA mutations, additional research is needed to determine the degree to which fetal responses to maternal HIV-1 infection, in the absence of antiretroviral treatment, contribute to prenatal mtDNA mutagenesis. Environ. Mol. Mutagen., 2009.</description><identifier>ISSN: 0893-6692</identifier><identifier>ISSN: 1098-2280</identifier><identifier>EISSN: 1098-2280</identifier><identifier>DOI: 10.1002/em.20433</identifier><identifier>PMID: 19031409</identifier><identifier>CODEN: EMMUEG</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>3TC ; antiretrovirals ; Antiviral agents ; AZT ; Base Sequence ; Biological and medical sciences ; Case-Control Studies ; DGGE ; DNA Primers ; DNA, Mitochondrial - genetics ; Drug Therapy, Combination ; Fundamental and applied biological sciences. Psychology ; Genetics of eukaryotes. Biological and molecular evolution ; HIV Infections - prevention & control ; HIV-1 ; Human immunodeficiency virus 1 ; Humans ; Infant ; Lamivudine - administration & dosage ; Lamivudine - therapeutic use ; Medical sciences ; mitochondrial DNA mutation ; Mutation ; nucleoside analogs ; Polymorphism, Genetic ; Reverse Transcriptase Inhibitors - administration & dosage ; Reverse Transcriptase Inhibitors - therapeutic use ; RNA, Transfer - genetics ; Toxicology ; transplacental exposure ; tRNA genes ; Umbilical Cord - metabolism ; Zidovudine - administration & dosage ; Zidovudine - therapeutic use</subject><ispartof>Environmental and molecular mutagenesis, 2009, Vol.50 (1), p.10-26</ispartof><rights>Copyright © 2008 Wiley‐Liss, Inc.</rights><rights>2009 INIST-CNRS</rights><rights>2008 Wiley-Liss, Inc. 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5313-a7fca5e46e6ff45619c3773e0d445cfb41187bfb545d69855296184857d4b4803</citedby><cites>FETCH-LOGICAL-c5313-a7fca5e46e6ff45619c3773e0d445cfb41187bfb545d69855296184857d4b4803</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fem.20433$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fem.20433$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,4009,27902,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21055393$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19031409$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Torres, Salina M</creatorcontrib><creatorcontrib>Walker, Dale M</creatorcontrib><creatorcontrib>McCash, Consuelo L</creatorcontrib><creatorcontrib>Carter, Meghan M</creatorcontrib><creatorcontrib>Ming, Jessica</creatorcontrib><creatorcontrib>Cordova, Edmund M</creatorcontrib><creatorcontrib>Pons, Rachel M</creatorcontrib><creatorcontrib>Cook, Dennis L. Jr</creatorcontrib><creatorcontrib>Seilkop, Steven K</creatorcontrib><creatorcontrib>Copeland, William C</creatorcontrib><creatorcontrib>Walker, Vernon E</creatorcontrib><title>Mutational analysis of the mitochondrial tRNA genes and flanking regions in umbilical cord tissue from uninfected infants receiving AZT-based therapies for prophylaxis of HIV-1</title><title>Environmental and molecular mutagenesis</title><addtitle>Environ. Mol. Mutagen</addtitle><description>A sensitive vertical denaturing gradient gel electrophoresis (DGGE) method, using 13 unipolar psoralen-clamped PCR primer pairs, was developed for detecting sequence variants in the 22 tRNA genes and flanking regions (together spanning ~21%) of the human mitochondrial genome. A study was conducted to determine (i) if mitochondrial DNA (mtDNA) polymorphisms and/or mutations were detectable in healthy newborns and (ii) if prepartum 3'-azido-2',3'-dideoxythymidine (AZT) based HIV-1 prophylaxis was associated with significant increases in mtDNA mutations and changes in the degree of heteroplasmy of sequence variants in uninfected infants born to HIV-1-infected mothers. DGGE analysis of umbilical cord tissue (where vascular endothelium and smooth muscle cells are the major source of mtDNA) showed that mtDNA sequence variants were significantly elevated by threefold in AZT-treated infants compared with unexposed controls (P < 0.001), with 24 changes observed in 19/52 (37%) treated newborns (averaging 0.46 changes/subject) versus only eight changes found in 7/55 (13%) unexposed newborns (averaging 0.15 changes/subject). Six distinct sequence variants occurring in unexposed controls were predominately synonymous and homoplasmic, representing previously reported polymorphisms. Uninfected infants exposed to a combination of AZT and 2',3'-dideoxy-3'-thiacytidine and "maternal HIV-1" had a significant shift in the spectrum of mutations (P = 0.04) driven by increases in nonsynonymous heteroplasmic sequence variants at polymorphic sites (10 distinct variants) and novel sites (four distinct variants). While the weight of evidence suggests that prepartum AZT-based prophylaxis produces mtDNA mutations, additional research is needed to determine the degree to which fetal responses to maternal HIV-1 infection, in the absence of antiretroviral treatment, contribute to prenatal mtDNA mutagenesis. Environ. Mol. Mutagen., 2009.</description><subject>3TC</subject><subject>antiretrovirals</subject><subject>Antiviral agents</subject><subject>AZT</subject><subject>Base Sequence</subject><subject>Biological and medical sciences</subject><subject>Case-Control Studies</subject><subject>DGGE</subject><subject>DNA Primers</subject><subject>DNA, Mitochondrial - genetics</subject><subject>Drug Therapy, Combination</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>HIV Infections - prevention & control</subject><subject>HIV-1</subject><subject>Human immunodeficiency virus 1</subject><subject>Humans</subject><subject>Infant</subject><subject>Lamivudine - administration & dosage</subject><subject>Lamivudine - therapeutic use</subject><subject>Medical sciences</subject><subject>mitochondrial DNA mutation</subject><subject>Mutation</subject><subject>nucleoside analogs</subject><subject>Polymorphism, Genetic</subject><subject>Reverse Transcriptase Inhibitors - administration & dosage</subject><subject>Reverse Transcriptase Inhibitors - therapeutic use</subject><subject>RNA, Transfer - genetics</subject><subject>Toxicology</subject><subject>transplacental exposure</subject><subject>tRNA genes</subject><subject>Umbilical Cord - metabolism</subject><subject>Zidovudine - administration & dosage</subject><subject>Zidovudine - therapeutic use</subject><issn>0893-6692</issn><issn>1098-2280</issn><issn>1098-2280</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks1u1DAUhSMEokNB4gnAGxCbFP8n2SANpX9SWxBMB4mN5Tj2jNvEDnZSOm_FI-JhhgEWiI29uN8959j3ZtlTBA8QhPi17g4wpITcyyYIVmWOcQnvZxNYViTnvMJ72aMYryFEiFb4YbaHKkgQhdUk-34xDnKw3skWyHSsoo3AGzAsNejs4NXSuybYVB0-Xk7BQjsdE9gA00p3Y90CBL1I7RFYB8autq1VCVY-NGCwMY4amOA7MDrrjFaDbhJopBtialTa3q4lpl9meS1jqiXbIHubPIwPoA--X65aebfJdHo2z9Hj7IGRbdRPtvd-dnV8NDs8zc_fn5wdTs9zxQgiuSyMkkxTrrkxlHFUKVIURMOGUqZMTREqi9rUjLKGVyVjuOKopCUrGlrTEpL97M1Gtx_rTjdKuyHIVvTBdjKshJdW_F1xdikW_lYQVCVpngRebgWC_zrqOIjORqXb9G_aj1FwXqaRQfhfEENSUETW4KsNqIKPMWizS4OgWO-B0J34uQcJffZn-t_gdvAJeLEFZEwDM0E6ZeOOwwgyRqq1UL7hvtlWr_5pKI4ufhlveRsHfbfjZbgRvCAFE58vT0Tx9t3xBzqfiXnin294I72Qi5AyXH3CMD0XsZJgyMkPGQLkCA</recordid><startdate>2009</startdate><enddate>2009</enddate><creator>Torres, Salina M</creator><creator>Walker, Dale M</creator><creator>McCash, Consuelo L</creator><creator>Carter, Meghan M</creator><creator>Ming, Jessica</creator><creator>Cordova, Edmund M</creator><creator>Pons, Rachel M</creator><creator>Cook, Dennis L. Jr</creator><creator>Seilkop, Steven K</creator><creator>Copeland, William C</creator><creator>Walker, Vernon E</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley-Liss</general><scope>FBQ</scope><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>2009</creationdate><title>Mutational analysis of the mitochondrial tRNA genes and flanking regions in umbilical cord tissue from uninfected infants receiving AZT-based therapies for prophylaxis of HIV-1</title><author>Torres, Salina M ; Walker, Dale M ; McCash, Consuelo L ; Carter, Meghan M ; Ming, Jessica ; Cordova, Edmund M ; Pons, Rachel M ; Cook, Dennis L. Jr ; Seilkop, Steven K ; Copeland, William C ; Walker, Vernon E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5313-a7fca5e46e6ff45619c3773e0d445cfb41187bfb545d69855296184857d4b4803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>3TC</topic><topic>antiretrovirals</topic><topic>Antiviral agents</topic><topic>AZT</topic><topic>Base Sequence</topic><topic>Biological and medical sciences</topic><topic>Case-Control Studies</topic><topic>DGGE</topic><topic>DNA Primers</topic><topic>DNA, Mitochondrial - genetics</topic><topic>Drug Therapy, Combination</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genetics of eukaryotes. Biological and molecular evolution</topic><topic>HIV Infections - prevention & control</topic><topic>HIV-1</topic><topic>Human immunodeficiency virus 1</topic><topic>Humans</topic><topic>Infant</topic><topic>Lamivudine - administration & dosage</topic><topic>Lamivudine - therapeutic use</topic><topic>Medical sciences</topic><topic>mitochondrial DNA mutation</topic><topic>Mutation</topic><topic>nucleoside analogs</topic><topic>Polymorphism, Genetic</topic><topic>Reverse Transcriptase Inhibitors - administration & dosage</topic><topic>Reverse Transcriptase Inhibitors - therapeutic use</topic><topic>RNA, Transfer - genetics</topic><topic>Toxicology</topic><topic>transplacental exposure</topic><topic>tRNA genes</topic><topic>Umbilical Cord - metabolism</topic><topic>Zidovudine - administration & dosage</topic><topic>Zidovudine - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Torres, Salina M</creatorcontrib><creatorcontrib>Walker, Dale M</creatorcontrib><creatorcontrib>McCash, Consuelo L</creatorcontrib><creatorcontrib>Carter, Meghan M</creatorcontrib><creatorcontrib>Ming, Jessica</creatorcontrib><creatorcontrib>Cordova, Edmund M</creatorcontrib><creatorcontrib>Pons, Rachel M</creatorcontrib><creatorcontrib>Cook, Dennis L. Jr</creatorcontrib><creatorcontrib>Seilkop, Steven K</creatorcontrib><creatorcontrib>Copeland, William C</creatorcontrib><creatorcontrib>Walker, Vernon E</creatorcontrib><collection>AGRIS</collection><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Environmental and molecular mutagenesis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Torres, Salina M</au><au>Walker, Dale M</au><au>McCash, Consuelo L</au><au>Carter, Meghan M</au><au>Ming, Jessica</au><au>Cordova, Edmund M</au><au>Pons, Rachel M</au><au>Cook, Dennis L. Jr</au><au>Seilkop, Steven K</au><au>Copeland, William C</au><au>Walker, Vernon E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mutational analysis of the mitochondrial tRNA genes and flanking regions in umbilical cord tissue from uninfected infants receiving AZT-based therapies for prophylaxis of HIV-1</atitle><jtitle>Environmental and molecular mutagenesis</jtitle><addtitle>Environ. Mol. Mutagen</addtitle><date>2009</date><risdate>2009</risdate><volume>50</volume><issue>1</issue><spage>10</spage><epage>26</epage><pages>10-26</pages><issn>0893-6692</issn><issn>1098-2280</issn><eissn>1098-2280</eissn><coden>EMMUEG</coden><abstract>A sensitive vertical denaturing gradient gel electrophoresis (DGGE) method, using 13 unipolar psoralen-clamped PCR primer pairs, was developed for detecting sequence variants in the 22 tRNA genes and flanking regions (together spanning ~21%) of the human mitochondrial genome. A study was conducted to determine (i) if mitochondrial DNA (mtDNA) polymorphisms and/or mutations were detectable in healthy newborns and (ii) if prepartum 3'-azido-2',3'-dideoxythymidine (AZT) based HIV-1 prophylaxis was associated with significant increases in mtDNA mutations and changes in the degree of heteroplasmy of sequence variants in uninfected infants born to HIV-1-infected mothers. DGGE analysis of umbilical cord tissue (where vascular endothelium and smooth muscle cells are the major source of mtDNA) showed that mtDNA sequence variants were significantly elevated by threefold in AZT-treated infants compared with unexposed controls (P < 0.001), with 24 changes observed in 19/52 (37%) treated newborns (averaging 0.46 changes/subject) versus only eight changes found in 7/55 (13%) unexposed newborns (averaging 0.15 changes/subject). Six distinct sequence variants occurring in unexposed controls were predominately synonymous and homoplasmic, representing previously reported polymorphisms. Uninfected infants exposed to a combination of AZT and 2',3'-dideoxy-3'-thiacytidine and "maternal HIV-1" had a significant shift in the spectrum of mutations (P = 0.04) driven by increases in nonsynonymous heteroplasmic sequence variants at polymorphic sites (10 distinct variants) and novel sites (four distinct variants). While the weight of evidence suggests that prepartum AZT-based prophylaxis produces mtDNA mutations, additional research is needed to determine the degree to which fetal responses to maternal HIV-1 infection, in the absence of antiretroviral treatment, contribute to prenatal mtDNA mutagenesis. Environ. Mol. Mutagen., 2009.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>19031409</pmid><doi>10.1002/em.20433</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Environmental and molecular mutagenesis, 2009, Vol.50 (1), p.10-26 |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | 3TC antiretrovirals Antiviral agents AZT Base Sequence Biological and medical sciences Case-Control Studies DGGE DNA Primers DNA, Mitochondrial - genetics Drug Therapy, Combination Fundamental and applied biological sciences. Psychology Genetics of eukaryotes. Biological and molecular evolution HIV Infections - prevention & control HIV-1 Human immunodeficiency virus 1 Humans Infant Lamivudine - administration & dosage Lamivudine - therapeutic use Medical sciences mitochondrial DNA mutation Mutation nucleoside analogs Polymorphism, Genetic Reverse Transcriptase Inhibitors - administration & dosage Reverse Transcriptase Inhibitors - therapeutic use RNA, Transfer - genetics Toxicology transplacental exposure tRNA genes Umbilical Cord - metabolism Zidovudine - administration & dosage Zidovudine - therapeutic use |
| title | Mutational analysis of the mitochondrial tRNA genes and flanking regions in umbilical cord tissue from uninfected infants receiving AZT-based therapies for prophylaxis of HIV-1 |
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