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Somatic retrotransposition in the developing rhesus macaque brain

Billon, Victor ; Sanchez-Luque, Francisco J ; Rasmussen, Jay ; Bodea, Gabriela O ; Gerhardt, Daniel J ; Gerdes, Patricia LU orcid ; Cheetham, Seth W ; Schauer, Stephanie N ; Ajjikuttira, Prabha and Meyer, Thomas J , et al. (2022) In Genome Research 32(7). p.1298-1314
Abstract

The retrotransposon LINE-1 (L1) is central to the recent evolutionary history of the human genome and continues to drive genetic diversity and germline pathogenesis. However, the spatiotemporal extent and biological significance of somatic L1 activity are poorly defined and are virtually unexplored in other primates. From a single L1 lineage active at the divergence of apes and Old World monkeys, successive L1 subfamilies have emerged in each descendant primate germline. As revealed by case studies, the presently active human L1 subfamily can also mobilize during embryonic and brain development in vivo. It is unknown whether nonhuman primate L1s can similarly generate somatic insertions in the brain. Here we applied approximately 40×... (More)

The retrotransposon LINE-1 (L1) is central to the recent evolutionary history of the human genome and continues to drive genetic diversity and germline pathogenesis. However, the spatiotemporal extent and biological significance of somatic L1 activity are poorly defined and are virtually unexplored in other primates. From a single L1 lineage active at the divergence of apes and Old World monkeys, successive L1 subfamilies have emerged in each descendant primate germline. As revealed by case studies, the presently active human L1 subfamily can also mobilize during embryonic and brain development in vivo. It is unknown whether nonhuman primate L1s can similarly generate somatic insertions in the brain. Here we applied approximately 40× single-cell whole-genome sequencing (scWGS), as well as retrotransposon capture sequencing (RC-seq), to 20 hippocampal neurons from two rhesus macaques ( Macaca mulatta). In one animal, we detected and PCR-validated a somatic L1 insertion that generated target site duplications, carried a short 5' transduction, and was present in ∼7% of hippocampal neurons but absent from cerebellum and nonbrain tissues. The corresponding donor L1 allele was exceptionally mobile in vitro and was embedded in PRDM4, a gene expressed throughout development and in neural stem cells. Nanopore long-read methylome and RNA-seq transcriptome analyses indicated young retrotransposon subfamily activation in the early embryo, followed by repression in adult tissues. These data highlight endogenous macaque L1 retrotransposition potential, provide prototypical evidence of L1-mediated somatic mosaicism in a nonhuman primate, and allude to L1 mobility in the brain over the past 30 million years of human evolution.

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type
Contribution to journal
publication status
published
subject
keywords
Animals, Brain, DNA-Binding Proteins/genetics, Long Interspersed Nucleotide Elements, Macaca mulatta/genetics, Neurons, Retroelements/genetics, Transcription Factors/genetics
in
Genome Research
volume
32
issue
7
pages
1298 - 1314
publisher
Cold Spring Harbor Laboratory Press (CSHL)
external identifiers
  • pmid:35728967
  • scopus:85135371372
ISSN
1549-5469
DOI
10.1101/gr.276451.121
language
English
LU publication?
no
additional info
© 2022 Billon et al.; Published by Cold Spring Harbor Laboratory Press.
id
e6fefac0-94f7-4c8e-aced-7bd188660862
date added to LUP
2024-06-10 15:15:01
date last changed
2024-06-12 15:28:37
@article{e6fefac0-94f7-4c8e-aced-7bd188660862,
  abstract     = {{<p>The retrotransposon LINE-1 (L1) is central to the recent evolutionary history of the human genome and continues to drive genetic diversity and germline pathogenesis. However, the spatiotemporal extent and biological significance of somatic L1 activity are poorly defined and are virtually unexplored in other primates. From a single L1 lineage active at the divergence of apes and Old World monkeys, successive L1 subfamilies have emerged in each descendant primate germline. As revealed by case studies, the presently active human L1 subfamily can also mobilize during embryonic and brain development in vivo. It is unknown whether nonhuman primate L1s can similarly generate somatic insertions in the brain. Here we applied approximately 40× single-cell whole-genome sequencing (scWGS), as well as retrotransposon capture sequencing (RC-seq), to 20 hippocampal neurons from two rhesus macaques (  Macaca mulatta). In one animal, we detected and PCR-validated a somatic L1 insertion that generated target site duplications, carried a short 5' transduction, and was present in ∼7% of hippocampal neurons but absent from cerebellum and nonbrain tissues. The corresponding donor L1 allele was exceptionally mobile in vitro and was embedded in  PRDM4, a gene expressed throughout development and in neural stem cells. Nanopore long-read methylome and RNA-seq transcriptome analyses indicated young retrotransposon subfamily activation in the early embryo, followed by repression in adult tissues. These data highlight endogenous macaque L1 retrotransposition potential, provide prototypical evidence of L1-mediated somatic mosaicism in a nonhuman primate, and allude to L1 mobility in the brain over the past 30 million years of human evolution. </p>}},
  author       = {{Billon, Victor and Sanchez-Luque, Francisco J and Rasmussen, Jay and Bodea, Gabriela O and Gerhardt, Daniel J and Gerdes, Patricia and Cheetham, Seth W and Schauer, Stephanie N and Ajjikuttira, Prabha and Meyer, Thomas J and Layman, Cora E and Nevonen, Kimberly A and Jansz, Natasha and Garcia-Perez, Jose L and Richardson, Sandra R and Ewing, Adam D and Carbone, Lucia and Faulkner, Geoffrey J}},
  issn         = {{1549-5469}},
  keywords     = {{Animals; Brain; DNA-Binding Proteins/genetics; Long Interspersed Nucleotide Elements; Macaca mulatta/genetics; Neurons; Retroelements/genetics; Transcription Factors/genetics}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{1298--1314}},
  publisher    = {{Cold Spring Harbor Laboratory Press (CSHL)}},
  series       = {{Genome Research}},
  title        = {{Somatic retrotransposition in the developing rhesus macaque brain}},
  url          = {{http://dx.doi.org/10.1101/gr.276451.121}},
  doi          = {{10.1101/gr.276451.121}},
  volume       = {{32}},
  year         = {{2022}},
}