Deciphering the Ancient and Complex Evolutionary History of Human Arylamine N-Acetyltransferase Genes
The human N-acetyltransferase genes NAT1 and NAT2 encode two phase-II enzymes that metabolize various drugs and carcinogens. Functional variability at these genes has been associated with adverse drug reactions and cancer susceptibility. Mutations in NAT2 leading to the so-called slow-acetylation ph...
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| creator | Patin, Etienne Barreiro, Luis B. Sabeti, Pardis C. Austerlitz, Frédéric Luca, Francesca Sajantila, Antti Behar, Doron M. Semino, Ornella Sakuntabhai, Anavaj Guiso, Nicole Gicquel, Brigitte McElreavey, Ken Harding, Rosalind M. Heyer, Evelyne Quintana-Murci, Lluís |
| description | The human N-acetyltransferase genes
NAT1 and
NAT2 encode two phase-II enzymes that metabolize various drugs and carcinogens. Functional variability at these genes has been associated with adverse drug reactions and cancer susceptibility. Mutations in
NAT2 leading to the so-called slow-acetylation phenotype reach high frequencies worldwide, which questions the significance of altered acetylation in human adaptation. To investigate the role of population history and natural selection in shaping
NATs variation, we characterized genetic diversity through the resequencing and genotyping of
NAT1, NAT2, and the pseudogene
NATP in a collection of 13 different populations with distinct ethnic backgrounds and demographic pasts. This combined study design allowed us to define a detailed map of linkage disequilibrium of the
NATs region as well as to perform a number of sequence-based neutrality tests and the long-range haplotype (LRH) test. Our data revealed distinctive patterns of variability for the two genes: the reduced diversity observed at
NAT1 is consistent with the action of purifying selection, whereas
NAT2 functional variation contributes to high levels of diversity. In addition, the LRH test identified a particular
NAT2 haplotype (
NAT2*5B) under recent positive selection in western/central Eurasians. This haplotype harbors the mutation 341T→C and encodes the “slowest-acetylator” NAT2 enzyme, suggesting a general selective advantage for the slow-acetylator phenotype. Interestingly, the
NAT2*5B haplotype, which seems to have conferred a selective advantage during the past ∼6,500 years, exhibits today the strongest association with susceptibility to bladder cancer and adverse drug reactions. On the whole, the patterns observed for
NAT2 well illustrate how geographically and temporally fluctuating xenobiotic environments may have influenced not only our genome variability but also our present-day susceptibility to disease. |
| doi_str_mv | 10.1086/500614 |
| format | Article |
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NAT1 and
NAT2 encode two phase-II enzymes that metabolize various drugs and carcinogens. Functional variability at these genes has been associated with adverse drug reactions and cancer susceptibility. Mutations in
NAT2 leading to the so-called slow-acetylation phenotype reach high frequencies worldwide, which questions the significance of altered acetylation in human adaptation. To investigate the role of population history and natural selection in shaping
NATs variation, we characterized genetic diversity through the resequencing and genotyping of
NAT1, NAT2, and the pseudogene
NATP in a collection of 13 different populations with distinct ethnic backgrounds and demographic pasts. This combined study design allowed us to define a detailed map of linkage disequilibrium of the
NATs region as well as to perform a number of sequence-based neutrality tests and the long-range haplotype (LRH) test. Our data revealed distinctive patterns of variability for the two genes: the reduced diversity observed at
NAT1 is consistent with the action of purifying selection, whereas
NAT2 functional variation contributes to high levels of diversity. In addition, the LRH test identified a particular
NAT2 haplotype (
NAT2*5B) under recent positive selection in western/central Eurasians. This haplotype harbors the mutation 341T→C and encodes the “slowest-acetylator” NAT2 enzyme, suggesting a general selective advantage for the slow-acetylator phenotype. Interestingly, the
NAT2*5B haplotype, which seems to have conferred a selective advantage during the past ∼6,500 years, exhibits today the strongest association with susceptibility to bladder cancer and adverse drug reactions. On the whole, the patterns observed for
NAT2 well illustrate how geographically and temporally fluctuating xenobiotic environments may have influenced not only our genome variability but also our present-day susceptibility to disease.</description><identifier>ISSN: 0002-9297</identifier><identifier>EISSN: 1537-6605</identifier><identifier>DOI: 10.1086/500614</identifier><identifier>PMID: 16416399</identifier><identifier>CODEN: AJHGAG</identifier><language>eng</language><publisher>Chicago, IL: Elsevier Inc</publisher><subject>Acetylation ; Adaptation, Physiological ; Adaptation, Physiological - genetics ; Amino Acid Sequence ; Arylamine N-Acetyltransferase ; Arylamine N-Acetyltransferase - genetics ; Biological and medical sciences ; Cancer ; Drugs ; Environment and Society ; Environmental Sciences ; Enzymes ; Evolution ; Evolution, Molecular ; Female ; General aspects. Genetic counseling ; Genes ; Genetic Variation ; Geography ; Global Changes ; Haplotypes ; Human health and pathology ; Humans ; Infectious diseases ; Isoenzymes ; Isoenzymes - genetics ; Life Sciences ; Linkage Disequilibrium ; Male ; Medical genetics ; Medical sciences ; Molecular Sequence Data ; Mutation ; Phenotype ; Population ; Population - genetics ; Variation (Genetics)</subject><ispartof>American journal of human genetics, 2006-03, Vol.78 (3), p.423-436</ispartof><rights>2006 The American Society of Human Genetics</rights><rights>2006 INIST-CNRS</rights><rights>Copyright University of Chicago, acting through its Press Mar 2006</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2006 by The American Society of Human Genetics. All rights reserved. 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c531t-19dbc14286fb2e97e9a229673a3dab9bffbef1a504a16abfeb491409ae0bd3a23</citedby><cites>FETCH-LOGICAL-c531t-19dbc14286fb2e97e9a229673a3dab9bffbef1a504a16abfeb491409ae0bd3a23</cites><orcidid>0000-0001-9099-6937 ; 0000-0003-2429-6320 ; 0000-0001-8031-455X ; 0000-0001-6582-1801 ; 0000-0002-0266-3196 ; 0000-0002-9911-4459</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1380286/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0002929707623829$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,3537,27901,27902,53766,53768,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17528512$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16416399$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://pasteur.hal.science/pasteur-00169326$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Patin, Etienne</creatorcontrib><creatorcontrib>Barreiro, Luis B.</creatorcontrib><creatorcontrib>Sabeti, Pardis C.</creatorcontrib><creatorcontrib>Austerlitz, Frédéric</creatorcontrib><creatorcontrib>Luca, Francesca</creatorcontrib><creatorcontrib>Sajantila, Antti</creatorcontrib><creatorcontrib>Behar, Doron M.</creatorcontrib><creatorcontrib>Semino, Ornella</creatorcontrib><creatorcontrib>Sakuntabhai, Anavaj</creatorcontrib><creatorcontrib>Guiso, Nicole</creatorcontrib><creatorcontrib>Gicquel, Brigitte</creatorcontrib><creatorcontrib>McElreavey, Ken</creatorcontrib><creatorcontrib>Harding, Rosalind M.</creatorcontrib><creatorcontrib>Heyer, Evelyne</creatorcontrib><creatorcontrib>Quintana-Murci, Lluís</creatorcontrib><title>Deciphering the Ancient and Complex Evolutionary History of Human Arylamine N-Acetyltransferase Genes</title><title>American journal of human genetics</title><addtitle>Am J Hum Genet</addtitle><description>The human N-acetyltransferase genes
NAT1 and
NAT2 encode two phase-II enzymes that metabolize various drugs and carcinogens. Functional variability at these genes has been associated with adverse drug reactions and cancer susceptibility. Mutations in
NAT2 leading to the so-called slow-acetylation phenotype reach high frequencies worldwide, which questions the significance of altered acetylation in human adaptation. To investigate the role of population history and natural selection in shaping
NATs variation, we characterized genetic diversity through the resequencing and genotyping of
NAT1, NAT2, and the pseudogene
NATP in a collection of 13 different populations with distinct ethnic backgrounds and demographic pasts. This combined study design allowed us to define a detailed map of linkage disequilibrium of the
NATs region as well as to perform a number of sequence-based neutrality tests and the long-range haplotype (LRH) test. Our data revealed distinctive patterns of variability for the two genes: the reduced diversity observed at
NAT1 is consistent with the action of purifying selection, whereas
NAT2 functional variation contributes to high levels of diversity. In addition, the LRH test identified a particular
NAT2 haplotype (
NAT2*5B) under recent positive selection in western/central Eurasians. This haplotype harbors the mutation 341T→C and encodes the “slowest-acetylator” NAT2 enzyme, suggesting a general selective advantage for the slow-acetylator phenotype. Interestingly, the
NAT2*5B haplotype, which seems to have conferred a selective advantage during the past ∼6,500 years, exhibits today the strongest association with susceptibility to bladder cancer and adverse drug reactions. On the whole, the patterns observed for
NAT2 well illustrate how geographically and temporally fluctuating xenobiotic environments may have influenced not only our genome variability but also our present-day susceptibility to disease.</description><subject>Acetylation</subject><subject>Adaptation, Physiological</subject><subject>Adaptation, Physiological - genetics</subject><subject>Amino Acid Sequence</subject><subject>Arylamine N-Acetyltransferase</subject><subject>Arylamine N-Acetyltransferase - genetics</subject><subject>Biological and medical sciences</subject><subject>Cancer</subject><subject>Drugs</subject><subject>Environment and Society</subject><subject>Environmental Sciences</subject><subject>Enzymes</subject><subject>Evolution</subject><subject>Evolution, Molecular</subject><subject>Female</subject><subject>General aspects. Genetic counseling</subject><subject>Genes</subject><subject>Genetic Variation</subject><subject>Geography</subject><subject>Global Changes</subject><subject>Haplotypes</subject><subject>Human health and pathology</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Isoenzymes</subject><subject>Isoenzymes - genetics</subject><subject>Life Sciences</subject><subject>Linkage Disequilibrium</subject><subject>Male</subject><subject>Medical genetics</subject><subject>Medical sciences</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Phenotype</subject><subject>Population</subject><subject>Population - genetics</subject><subject>Variation (Genetics)</subject><issn>0002-9297</issn><issn>1537-6605</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU-P0zAQxSMEYssCHwFZSHAL-E_ixBekqCxbpAoucLYmzmTrVWIHO6not8dVKwo9zcE_vzfzXpa9ZvQDo7X8WFIqWfEkW7FSVLmUtHyarSilPFdcVTfZixgfKWWspuJ5dsNkwaRQapXhZzR22mGw7oHMOySNMxbdTMB1ZO3HacDf5G7vh2W23kE4kI2Ns0_T92SzjOBIEw4DjNYh-ZY3BufDMAdwsccAEck9Oowvs2c9DBFfnedt9vPL3Y_1Jt9-v_-6bra5KQWbc6a61rCC17JvOaoKFXCuZCVAdNCqtu9b7BmUtAAmoe2xLRQrqAKkbSeAi9vs00l3WtoRO5MOCTDoKdgxra49WP3_i7M7_eD3momaJtskkJ8EdlffNs1WTxBnXIJOOUoluNyzxL8_Gwb_a8E469FGg8MADv0SNat4UYryKPz2Cnz0S3ApDM2ZkrSuRX1RM8HHGLD_uwKj-lizPtWcwDf_3nnBzr0m4N0ZgGhg6FMhxsYLV5W8LtkxMHriMLWytxh0PNZvsLMBzaw7b6-9_wAJkMBU</recordid><startdate>20060301</startdate><enddate>20060301</enddate><creator>Patin, Etienne</creator><creator>Barreiro, Luis B.</creator><creator>Sabeti, Pardis C.</creator><creator>Austerlitz, Frédéric</creator><creator>Luca, Francesca</creator><creator>Sajantila, Antti</creator><creator>Behar, Doron M.</creator><creator>Semino, Ornella</creator><creator>Sakuntabhai, Anavaj</creator><creator>Guiso, Nicole</creator><creator>Gicquel, Brigitte</creator><creator>McElreavey, Ken</creator><creator>Harding, Rosalind M.</creator><creator>Heyer, Evelyne</creator><creator>Quintana-Murci, Lluís</creator><general>Elsevier Inc</general><general>University of Chicago Press</general><general>Cell Press</general><general>Elsevier (Cell Press)</general><general>The American Society of Human Genetics</general><scope>6I.</scope><scope>AAFTH</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>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9099-6937</orcidid><orcidid>https://orcid.org/0000-0003-2429-6320</orcidid><orcidid>https://orcid.org/0000-0001-8031-455X</orcidid><orcidid>https://orcid.org/0000-0001-6582-1801</orcidid><orcidid>https://orcid.org/0000-0002-0266-3196</orcidid><orcidid>https://orcid.org/0000-0002-9911-4459</orcidid></search><sort><creationdate>20060301</creationdate><title>Deciphering the Ancient and Complex Evolutionary History of Human Arylamine N-Acetyltransferase Genes</title><author>Patin, Etienne ; Barreiro, Luis B. ; Sabeti, Pardis C. ; Austerlitz, Frédéric ; Luca, Francesca ; Sajantila, Antti ; Behar, Doron M. ; Semino, Ornella ; Sakuntabhai, Anavaj ; Guiso, Nicole ; Gicquel, Brigitte ; McElreavey, Ken ; Harding, Rosalind M. ; Heyer, Evelyne ; Quintana-Murci, Lluís</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c531t-19dbc14286fb2e97e9a229673a3dab9bffbef1a504a16abfeb491409ae0bd3a23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Acetylation</topic><topic>Adaptation, Physiological</topic><topic>Adaptation, Physiological - genetics</topic><topic>Amino Acid Sequence</topic><topic>Arylamine N-Acetyltransferase</topic><topic>Arylamine N-Acetyltransferase - genetics</topic><topic>Biological and medical sciences</topic><topic>Cancer</topic><topic>Drugs</topic><topic>Environment and Society</topic><topic>Environmental Sciences</topic><topic>Enzymes</topic><topic>Evolution</topic><topic>Evolution, Molecular</topic><topic>Female</topic><topic>General aspects. Genetic counseling</topic><topic>Genes</topic><topic>Genetic Variation</topic><topic>Geography</topic><topic>Global Changes</topic><topic>Haplotypes</topic><topic>Human health and pathology</topic><topic>Humans</topic><topic>Infectious diseases</topic><topic>Isoenzymes</topic><topic>Isoenzymes - genetics</topic><topic>Life Sciences</topic><topic>Linkage Disequilibrium</topic><topic>Male</topic><topic>Medical genetics</topic><topic>Medical sciences</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Phenotype</topic><topic>Population</topic><topic>Population - genetics</topic><topic>Variation (Genetics)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Patin, Etienne</creatorcontrib><creatorcontrib>Barreiro, Luis B.</creatorcontrib><creatorcontrib>Sabeti, Pardis C.</creatorcontrib><creatorcontrib>Austerlitz, Frédéric</creatorcontrib><creatorcontrib>Luca, Francesca</creatorcontrib><creatorcontrib>Sajantila, Antti</creatorcontrib><creatorcontrib>Behar, Doron M.</creatorcontrib><creatorcontrib>Semino, Ornella</creatorcontrib><creatorcontrib>Sakuntabhai, Anavaj</creatorcontrib><creatorcontrib>Guiso, Nicole</creatorcontrib><creatorcontrib>Gicquel, Brigitte</creatorcontrib><creatorcontrib>McElreavey, Ken</creatorcontrib><creatorcontrib>Harding, Rosalind M.</creatorcontrib><creatorcontrib>Heyer, Evelyne</creatorcontrib><creatorcontrib>Quintana-Murci, Lluís</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</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>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of human genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Patin, Etienne</au><au>Barreiro, Luis B.</au><au>Sabeti, Pardis C.</au><au>Austerlitz, Frédéric</au><au>Luca, Francesca</au><au>Sajantila, Antti</au><au>Behar, Doron M.</au><au>Semino, Ornella</au><au>Sakuntabhai, Anavaj</au><au>Guiso, Nicole</au><au>Gicquel, Brigitte</au><au>McElreavey, Ken</au><au>Harding, Rosalind M.</au><au>Heyer, Evelyne</au><au>Quintana-Murci, Lluís</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Deciphering the Ancient and Complex Evolutionary History of Human Arylamine N-Acetyltransferase Genes</atitle><jtitle>American journal of human genetics</jtitle><addtitle>Am J Hum Genet</addtitle><date>2006-03-01</date><risdate>2006</risdate><volume>78</volume><issue>3</issue><spage>423</spage><epage>436</epage><pages>423-436</pages><issn>0002-9297</issn><eissn>1537-6605</eissn><coden>AJHGAG</coden><abstract>The human N-acetyltransferase genes
NAT1 and
NAT2 encode two phase-II enzymes that metabolize various drugs and carcinogens. Functional variability at these genes has been associated with adverse drug reactions and cancer susceptibility. Mutations in
NAT2 leading to the so-called slow-acetylation phenotype reach high frequencies worldwide, which questions the significance of altered acetylation in human adaptation. To investigate the role of population history and natural selection in shaping
NATs variation, we characterized genetic diversity through the resequencing and genotyping of
NAT1, NAT2, and the pseudogene
NATP in a collection of 13 different populations with distinct ethnic backgrounds and demographic pasts. This combined study design allowed us to define a detailed map of linkage disequilibrium of the
NATs region as well as to perform a number of sequence-based neutrality tests and the long-range haplotype (LRH) test. Our data revealed distinctive patterns of variability for the two genes: the reduced diversity observed at
NAT1 is consistent with the action of purifying selection, whereas
NAT2 functional variation contributes to high levels of diversity. In addition, the LRH test identified a particular
NAT2 haplotype (
NAT2*5B) under recent positive selection in western/central Eurasians. This haplotype harbors the mutation 341T→C and encodes the “slowest-acetylator” NAT2 enzyme, suggesting a general selective advantage for the slow-acetylator phenotype. Interestingly, the
NAT2*5B haplotype, which seems to have conferred a selective advantage during the past ∼6,500 years, exhibits today the strongest association with susceptibility to bladder cancer and adverse drug reactions. On the whole, the patterns observed for
NAT2 well illustrate how geographically and temporally fluctuating xenobiotic environments may have influenced not only our genome variability but also our present-day susceptibility to disease.</abstract><cop>Chicago, IL</cop><pub>Elsevier Inc</pub><pmid>16416399</pmid><doi>10.1086/500614</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0001-9099-6937</orcidid><orcidid>https://orcid.org/0000-0003-2429-6320</orcidid><orcidid>https://orcid.org/0000-0001-8031-455X</orcidid><orcidid>https://orcid.org/0000-0001-6582-1801</orcidid><orcidid>https://orcid.org/0000-0002-0266-3196</orcidid><orcidid>https://orcid.org/0000-0002-9911-4459</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Acetylation Adaptation, Physiological Adaptation, Physiological - genetics Amino Acid Sequence Arylamine N-Acetyltransferase Arylamine N-Acetyltransferase - genetics Biological and medical sciences Cancer Drugs Environment and Society Environmental Sciences Enzymes Evolution Evolution, Molecular Female General aspects. Genetic counseling Genes Genetic Variation Geography Global Changes Haplotypes Human health and pathology Humans Infectious diseases Isoenzymes Isoenzymes - genetics Life Sciences Linkage Disequilibrium Male Medical genetics Medical sciences Molecular Sequence Data Mutation Phenotype Population Population - genetics Variation (Genetics) |
| title | Deciphering the Ancient and Complex Evolutionary History of Human Arylamine N-Acetyltransferase Genes |
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