Cell Lineage Analysis in Human Brain Using Endogenous Retroelements

Gilad D. Evrony, Eunjung Lee, Bhaven K. Mehta, Yuval Benjamini, Robert M. Johnson, Xuyu Cai, Lixing Yang, Psalm Haseley, Hillel S. Lehmann, Peter J. Park*, Christopher A. Walsh

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

177 Scopus citations


Somatic mutations occur during brain development and are increasingly implicated as a cause of neurogenetic disease. However, the patterns in which somatic mutations distribute in the human brain are unknown. We used high-coverage whole-genome sequencing of single neurons from a normal individual to identify spontaneous somatic mutations as clonal marks to track cell lineages in human brain.Somatic mutation analyses in >30 locations throughout the nervous system identified multiple lineages and sublineages of cells marked by different LINE-1 (L1) retrotransposition events and subsequent mutation of poly-A microsatellites within L1. One clone contained thousands of cells limited to the left middle frontal gyrus, whereas a second distinct clone contained millions of cells distributed over the entire left hemisphere. These patterns mirror known somatic mutation disorders of brain development and suggest that focally distributed mutations are also prevalent in normal brains. Single-cell analysis of somatic mutation enables tracing of cell lineage clones in human brain.

Original languageAmerican English
Pages (from-to)49-59
Number of pages11
Issue number1
StatePublished - 7 Jan 2015
Externally publishedYes

Bibliographical note

Funding Information:
We thank Aldo Rozzo for logistical assistance, the Orchestra research computing team at Harvard Medical School for assistance with computing resources, Magda Bienko and Alexander van Oudenaarden for helpful discussions and pilot attempts to detect the somatic insertions in brain tissue using HD-FISH, Alexander Subtelny for assistance analyzing transcriptome poly-A length profiling data ( Note S2 ), and Haig Kazazian and Tara Doucet for helpful discussions regarding activities of source retroelements. We also thank Kim Petro (Bio-Rad) for assistance with droplet digital PCR and Dick Bennett of the Boston Children’s Hospital Molecular Biology core for assistance with capillary electrophoresis. Representative brain image in Figures 3 B, 4 D, and S14 A was adapted with permission from the University of Wisconsin and Michigan State Comparative Mammalian Brain Collections ( http://brainmuseum.org ), supported by the National Science Foundation. Figure 5 was illustrated by Ken Probst (Xavier Studio). Sequencing was performed with support of the Research Connection of Boston Children’s Hospital. G.D.E. is supported by NIH MSTP grant T32GM007753 and the Louis Lange III Scholarship in Translational Research. E.L. is supported in part by the Eleanor and Miles Shore Fellowship. C.A.W. is supported by the Manton Center for Orphan Disease Research and grants from the NINDS (R01 NS079277 and R01 NS032457). C.A.W. is a Distinguished Investigator of the Paul G. Allen Family Foundation and an Investigator of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2015 Elsevier Inc.


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