Single-Neuron Sequencing Analysis of L1 Retrotransposition and Somatic Mutation in the Human Brain
A major unanswered question in neuroscience is whether there exists genomic variability between individual neurons of the brain, contributing to functional diversity or to an unexplained burden of neurological disease. To address this question, we developed a method to amplify genomes of single neur...
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| Veröffentlicht in: | Cell 2012-10, Vol.151 (3), p.483-496 |
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| creator | Evrony, Gilad D. Cai, Xuyu Lee, Eunjung Hills, L. Benjamin Elhosary, Princess C. Lehmann, Hillel S. Parker, J.J. Atabay, Kutay D. Gilmore, Edward C. Poduri, Annapurna Park, Peter J. Walsh, Christopher A. |
| description | A major unanswered question in neuroscience is whether there exists genomic variability between individual neurons of the brain, contributing to functional diversity or to an unexplained burden of neurological disease. To address this question, we developed a method to amplify genomes of single neurons from human brains. Because recent reports suggest frequent LINE-1 (L1) retrotransposition in human brains, we performed genome-wide L1 insertion profiling of 300 single neurons from cerebral cortex and caudate nucleus of three normal individuals, recovering >80% of germline insertions from single neurons. While we find somatic L1 insertions, we estimate |
| doi_str_mv | 10.1016/j.cell.2012.09.035 |
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▸ Whole-genome amplification and sequencing of single neurons from human brains ▸ Single-neuron genome-wide analysis of somatic L1 retrotransposition ▸ Somatic L1 insertions are infrequent in cerebral cortex and caudate nucleus ▸ Single-cell analysis of a somatic mutation causing malformation of the brain
Whole-genome sequencing of individual neurons from human brain shows that retrotransposition of the L1 element is infrequent. L1 insertions may thus generate some somatic mutations but are unlikely to account for neuronal diversity.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2012.09.035</identifier><identifier>PMID: 23101622</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Caudate Nucleus - cytology ; Caudate Nucleus - metabolism ; cerebral cortex ; Cerebral Cortex - cytology ; Cerebral Cortex - metabolism ; Child ; children ; Chromosomes, Human, Pair 18 ; cortex ; functional diversity ; genome ; Genome-Wide Association Study ; genomes ; genomics ; germ cells ; Humans ; Long Interspersed Nucleotide Elements ; Male ; Malformations of Cortical Development - genetics ; Malformations of Cortical Development - pathology ; Mosaicism ; Mutation ; nervous system diseases ; neurons ; Neurons - metabolism ; neurophysiology ; Proto-Oncogene Proteins c-akt - genetics ; sequence analysis ; Single-Cell Analysis ; somatic mutation ; Trisomy</subject><ispartof>Cell, 2012-10, Vol.151 (3), p.483-496</ispartof><rights>2012 Elsevier Inc.</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><rights>2012 Elsevier Inc. All rights reserved. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c578t-5efea7e85c77e0b1420299286193a8b4fe677378be0412a089f96ee58a7a85073</citedby><cites>FETCH-LOGICAL-c578t-5efea7e85c77e0b1420299286193a8b4fe677378be0412a089f96ee58a7a85073</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0092867412011828$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23101622$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Evrony, Gilad D.</creatorcontrib><creatorcontrib>Cai, Xuyu</creatorcontrib><creatorcontrib>Lee, Eunjung</creatorcontrib><creatorcontrib>Hills, L. Benjamin</creatorcontrib><creatorcontrib>Elhosary, Princess C.</creatorcontrib><creatorcontrib>Lehmann, Hillel S.</creatorcontrib><creatorcontrib>Parker, J.J.</creatorcontrib><creatorcontrib>Atabay, Kutay D.</creatorcontrib><creatorcontrib>Gilmore, Edward C.</creatorcontrib><creatorcontrib>Poduri, Annapurna</creatorcontrib><creatorcontrib>Park, Peter J.</creatorcontrib><creatorcontrib>Walsh, Christopher A.</creatorcontrib><title>Single-Neuron Sequencing Analysis of L1 Retrotransposition and Somatic Mutation in the Human Brain</title><title>Cell</title><addtitle>Cell</addtitle><description>A major unanswered question in neuroscience is whether there exists genomic variability between individual neurons of the brain, contributing to functional diversity or to an unexplained burden of neurological disease. To address this question, we developed a method to amplify genomes of single neurons from human brains. Because recent reports suggest frequent LINE-1 (L1) retrotransposition in human brains, we performed genome-wide L1 insertion profiling of 300 single neurons from cerebral cortex and caudate nucleus of three normal individuals, recovering >80% of germline insertions from single neurons. While we find somatic L1 insertions, we estimate <0.6 unique somatic insertions per neuron, and most neurons lack detectable somatic insertions, suggesting that L1 is not a major generator of neuronal diversity in cortex and caudate. We then genotyped single cortical cells to characterize the mosaicism of a somatic AKT3 mutation identified in a child with hemimegalencephaly. Single-neuron sequencing allows systematic assessment of genomic diversity in the human brain.
[Display omitted]
▸ Whole-genome amplification and sequencing of single neurons from human brains ▸ Single-neuron genome-wide analysis of somatic L1 retrotransposition ▸ Somatic L1 insertions are infrequent in cerebral cortex and caudate nucleus ▸ Single-cell analysis of a somatic mutation causing malformation of the brain
Whole-genome sequencing of individual neurons from human brain shows that retrotransposition of the L1 element is infrequent. L1 insertions may thus generate some somatic mutations but are unlikely to account for neuronal diversity.</description><subject>Caudate Nucleus - cytology</subject><subject>Caudate Nucleus - metabolism</subject><subject>cerebral cortex</subject><subject>Cerebral Cortex - cytology</subject><subject>Cerebral Cortex - metabolism</subject><subject>Child</subject><subject>children</subject><subject>Chromosomes, Human, Pair 18</subject><subject>cortex</subject><subject>functional diversity</subject><subject>genome</subject><subject>Genome-Wide Association Study</subject><subject>genomes</subject><subject>genomics</subject><subject>germ cells</subject><subject>Humans</subject><subject>Long Interspersed Nucleotide Elements</subject><subject>Male</subject><subject>Malformations of Cortical Development - genetics</subject><subject>Malformations of Cortical Development - pathology</subject><subject>Mosaicism</subject><subject>Mutation</subject><subject>nervous system diseases</subject><subject>neurons</subject><subject>Neurons - metabolism</subject><subject>neurophysiology</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>sequence analysis</subject><subject>Single-Cell Analysis</subject><subject>somatic mutation</subject><subject>Trisomy</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFv1DAQhS0EokvhD3AAH7kkjJ04tiWEVCpKkRaQWHq2nOxk61ViL3ZSqf8ep1squMDJ0vibpzfvEfKSQcmANW_3ZYfDUHJgvARdQiUekRUDLYuaSf6YrAA0L1Qj6xPyLKU9ACghxFNywqtFgPMVaTfO7wYsvuIcg6cb_Dmj7_KMnnk73CaXaOjpmtHvOMUwRevTISQ3uQxbv6WbMNrJdfTLPNm7ofN0ukZ6OY_W0w_ROv-cPOntkPDF_XtKri4-_ji_LNbfPn0-P1sXnZBqKgT2aCUq0UmJ0LKaA9eaq4bpyqq27rGRspKqRagZt6B0rxtEoay0SoCsTsn7o-5hbkfcduiz3cEcohttvDXBOvP3j3fXZhduTCVyRDXLAm_uBWLIMaTJjC4tEVuPYU6G5wCBqaqG_6KMcd5wXesmo_yIdjGkFLF_cMTALDWYvVk2zdKjAW1yj3np1Z-3PKz8Li4Dr49Ab4Oxu-iSudpkhWbx2Ai9SLw7Epgzv3EYTepc7ha3LmI3mW1w_3LwC6NPuCM</recordid><startdate>20121026</startdate><enddate>20121026</enddate><creator>Evrony, Gilad D.</creator><creator>Cai, Xuyu</creator><creator>Lee, Eunjung</creator><creator>Hills, L. Benjamin</creator><creator>Elhosary, Princess C.</creator><creator>Lehmann, Hillel S.</creator><creator>Parker, J.J.</creator><creator>Atabay, Kutay D.</creator><creator>Gilmore, Edward C.</creator><creator>Poduri, Annapurna</creator><creator>Park, Peter J.</creator><creator>Walsh, Christopher A.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</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>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20121026</creationdate><title>Single-Neuron Sequencing Analysis of L1 Retrotransposition and Somatic Mutation in the Human Brain</title><author>Evrony, Gilad D. ; Cai, Xuyu ; Lee, Eunjung ; Hills, L. Benjamin ; Elhosary, Princess C. ; Lehmann, Hillel S. ; Parker, J.J. ; Atabay, Kutay D. ; Gilmore, Edward C. ; Poduri, Annapurna ; Park, Peter J. ; Walsh, Christopher A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c578t-5efea7e85c77e0b1420299286193a8b4fe677378be0412a089f96ee58a7a85073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Caudate Nucleus - cytology</topic><topic>Caudate Nucleus - metabolism</topic><topic>cerebral cortex</topic><topic>Cerebral Cortex - cytology</topic><topic>Cerebral Cortex - metabolism</topic><topic>Child</topic><topic>children</topic><topic>Chromosomes, Human, Pair 18</topic><topic>cortex</topic><topic>functional diversity</topic><topic>genome</topic><topic>Genome-Wide Association Study</topic><topic>genomes</topic><topic>genomics</topic><topic>germ cells</topic><topic>Humans</topic><topic>Long Interspersed Nucleotide Elements</topic><topic>Male</topic><topic>Malformations of Cortical Development - genetics</topic><topic>Malformations of Cortical Development - pathology</topic><topic>Mosaicism</topic><topic>Mutation</topic><topic>nervous system diseases</topic><topic>neurons</topic><topic>Neurons - metabolism</topic><topic>neurophysiology</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>sequence analysis</topic><topic>Single-Cell Analysis</topic><topic>somatic mutation</topic><topic>Trisomy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Evrony, Gilad D.</creatorcontrib><creatorcontrib>Cai, Xuyu</creatorcontrib><creatorcontrib>Lee, Eunjung</creatorcontrib><creatorcontrib>Hills, L. Benjamin</creatorcontrib><creatorcontrib>Elhosary, Princess C.</creatorcontrib><creatorcontrib>Lehmann, Hillel S.</creatorcontrib><creatorcontrib>Parker, J.J.</creatorcontrib><creatorcontrib>Atabay, Kutay D.</creatorcontrib><creatorcontrib>Gilmore, Edward C.</creatorcontrib><creatorcontrib>Poduri, Annapurna</creatorcontrib><creatorcontrib>Park, Peter J.</creatorcontrib><creatorcontrib>Walsh, Christopher A.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Evrony, Gilad D.</au><au>Cai, Xuyu</au><au>Lee, Eunjung</au><au>Hills, L. Benjamin</au><au>Elhosary, Princess C.</au><au>Lehmann, Hillel S.</au><au>Parker, J.J.</au><au>Atabay, Kutay D.</au><au>Gilmore, Edward C.</au><au>Poduri, Annapurna</au><au>Park, Peter J.</au><au>Walsh, Christopher A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Single-Neuron Sequencing Analysis of L1 Retrotransposition and Somatic Mutation in the Human Brain</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2012-10-26</date><risdate>2012</risdate><volume>151</volume><issue>3</issue><spage>483</spage><epage>496</epage><pages>483-496</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><abstract>A major unanswered question in neuroscience is whether there exists genomic variability between individual neurons of the brain, contributing to functional diversity or to an unexplained burden of neurological disease. To address this question, we developed a method to amplify genomes of single neurons from human brains. Because recent reports suggest frequent LINE-1 (L1) retrotransposition in human brains, we performed genome-wide L1 insertion profiling of 300 single neurons from cerebral cortex and caudate nucleus of three normal individuals, recovering >80% of germline insertions from single neurons. While we find somatic L1 insertions, we estimate <0.6 unique somatic insertions per neuron, and most neurons lack detectable somatic insertions, suggesting that L1 is not a major generator of neuronal diversity in cortex and caudate. We then genotyped single cortical cells to characterize the mosaicism of a somatic AKT3 mutation identified in a child with hemimegalencephaly. Single-neuron sequencing allows systematic assessment of genomic diversity in the human brain.
[Display omitted]
▸ Whole-genome amplification and sequencing of single neurons from human brains ▸ Single-neuron genome-wide analysis of somatic L1 retrotransposition ▸ Somatic L1 insertions are infrequent in cerebral cortex and caudate nucleus ▸ Single-cell analysis of a somatic mutation causing malformation of the brain
Whole-genome sequencing of individual neurons from human brain shows that retrotransposition of the L1 element is infrequent. L1 insertions may thus generate some somatic mutations but are unlikely to account for neuronal diversity.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23101622</pmid><doi>10.1016/j.cell.2012.09.035</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Caudate Nucleus - cytology Caudate Nucleus - metabolism cerebral cortex Cerebral Cortex - cytology Cerebral Cortex - metabolism Child children Chromosomes, Human, Pair 18 cortex functional diversity genome Genome-Wide Association Study genomes genomics germ cells Humans Long Interspersed Nucleotide Elements Male Malformations of Cortical Development - genetics Malformations of Cortical Development - pathology Mosaicism Mutation nervous system diseases neurons Neurons - metabolism neurophysiology Proto-Oncogene Proteins c-akt - genetics sequence analysis Single-Cell Analysis somatic mutation Trisomy |
| title | Single-Neuron Sequencing Analysis of L1 Retrotransposition and Somatic Mutation in the Human Brain |
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