{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:58:31Z","timestamp":1787237911629,"version":"build-2736575974"},"reference-count":61,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T00:00:00Z","timestamp":1611878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Polly and Michael Smith, Edith and Roy Carver, Iris and B. Gerald Cantor Foundation and Max Factor Family"},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01 EY0127363"],"award-info":[{"award-number":["R01 EY0127363"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002806","name":"Discovery Eye Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002806","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Mitochondrial (mt) DNA damage is associated with age-related macular degeneration (AMD) and other human aging diseases. This study was designed to quantify and characterize mtDNA low-frequency heteroplasmy single nucleotide polymorphisms (SNPs) of three different tissues isolated from AMD subjects using Next Generation Sequencing (NGS) technology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>DNA was extracted from neural retina, [RPE+choroid] and blood from three deceased age-related macular degeneration (AMD) subjects. Entire mitochondrial genomes were analyzed for low-frequency heteroplasmy SNPs using NGS technology that independently sequenced both mtDNA strands. This deep sequencing method (average sequencing depth of 30,000; range 1,000\u2013100,000) can accurately differentiate low-frequency heteroplasmy SNPs from DNA modification artifacts. Twenty-three \u2018hot-spot\u2019 heteroplasmy mtDNA SNPs were analyzed in 222 additional blood samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Germline homoplasmy SNPs that defined mtDNA haplogroups were consistent in the three tissues of each subject. Analyses of SNPs with &lt;40% heteroplasmy revealed the blood had significantly greater numbers of heteroplasmy SNPs than retina alone (p\u22640.05) or retina+choroid combined (p = 0.008). Twenty-three \u2018hot-spot\u2019 mtDNA heteroplasmy SNPs were present, with three being non-synonymous (amino acid change). Four \u2018hot-spot\u2019 heteroplasmy SNPs (m.1120C&gt;T, m.1284T&gt;C, m.1556C&gt;T, m.7256C&gt;T) were found in additional samples (n = 222). Five heteroplasmy SNPs (m.4104A&gt;G, m.5320C&gt;T, m.5471G&gt;A, m.5474A&gt;G, m.5498A&gt;G) declined with age. Two heteroplasmy SNPs (m.13095T&gt;C, m.13105A&gt;G) increased in AMD compared to Normal samples. In the heteroplasmy SNPs, very few transversion mutations (purine to pyrimidine or vice versa, associated with oxidative damage) were found and the majority were transition changes (purine to purine or pyrimidine to pyrimidine, associated with replication errors).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Within an individual, the blood, retina and [RPE+choroid] contained identical homoplasmy SNPs representing inherited germline mtDNA haplogroup. NGS methodology showed significantly more mtDNA heteroplasmy SNPs in blood compared to retina and [RPE+choroid], suggesting the latter tissues have substantial protection. Significantly higher heteroplasmy levels of m.13095T&gt;C and m.13105A&gt;G may represent potential AMD biomarkers. Finally, high levels of transition mutations suggest that accumulation of heteroplasmic SNPs may occur through replication errors rather than oxidative damage.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0246114","type":"journal-article","created":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T13:36:30Z","timestamp":1611927390000},"page":"e0246114","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Low frequency mitochondrial DNA heteroplasmy SNPs in blood, retina, and [RPE+choroid] of age-related macular degeneration subjects"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7729-7864","authenticated-orcid":true,"given":"Shari R.","family":"Atilano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitin","family":"Udar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4428-6720","authenticated-orcid":true,"given":"Timothy A.","family":"Satalich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viraat","family":"Udar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn","family":"Chwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Cristina","family":"Kenney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,1,29]]},"reference":[{"key":"pone.0246114.ref001","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1146\/annurev.bi.61.070192.005523","article-title":"Diseases of the mitochondrial DNA","volume":"61","author":"D.C. Wallace","year":"1992","journal-title":"Annu Rev Biochem"},{"issue":"3","key":"pone.0246114.ref002","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/BF00763096","article-title":"Mitochondrial DNA mutations in diseases of energy metabolism","volume":"26","author":"D.C. Wallace","year":"1994","journal-title":"J Bioenerg Biomembr"},{"issue":"2","key":"pone.0246114.ref003","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/j.1365-2796.2008.02066.x","article-title":"Batteries not included: diagnosis and management of mitochondrial disease","volume":"265","author":"R. 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