title: Differential L1 regulation in pluripotent stem cells of humans and apes.
abstract: Identifying cellular and molecular differences between human and non-human primates (NHPs) is essential to the basic understanding of the evolution and diversity of our own species. Until now, preserved tissues have been the main source for most comparative studies between humans, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). However, these tissue samples do not fairly represent the distinctive traits of live cell behaviour and are not amenable to genetic manipulation. We propose that induced pluripotent stem (iPS) cells could be a unique biological resource to determine relevant phenotypical differences between human and NHPs, and that those differences could have potential adaptation and speciation value. Here we describe the generation and initial characterization of iPS cells from chimpanzees and bonobos as new tools to explore factors that may have contributed to great ape evolution. Comparative gene expression analysis of human and NHP iPS cells revealed differences in the regulation of long interspersed element-1 (L1, also known as LINE-1) transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution. Decreased levels of L1-restricting factors APOBEC3B (also known as A3B) and PIWIL2 (ref. 7) in NHP iPS cells correlated with increased L1 mobility and endogenous L1 messenger RNA levels. Moreover, results from the manipulation of A3B and PIWIL2 levels in iPS cells supported a causal inverse relationship between levels of these proteins and L1 retrotransposition. Finally, we found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in NHPs is not limited to iPS cells in culture and may have also occurred in the germ line or embryonic cells developmentally upstream to germline specification during primate evolution. We propose that differences in L1 mobility may have differentially shaped the genomes of humans and NHPs and could have continuing adaptive significance.
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Maria C N
authors.initials: MCN
authors.lastname: Marchetto
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Narvaiza
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Ahmet M
authors.initials: AM
authors.lastname: Denli
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Benner
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Lazzarini
authors.affiliation: University of California San Diego, Department of Cellular and Molecular Medicine, Stem Cell Program, Institute for Genomic Medicine. Sanford Consortium for Regenerative Medicine. 2880 Torrey Pines Scenic Dr. Room 3805, La Jolla, CA 92037.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Nathanson
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Apuã C M
authors.initials: ACM
authors.lastname: Paquola
authors.affiliation: University of California San Diego, Division of Biological Sciences. 9500 Gilman Dr. La Jolla, CA 92093.
authors.forename: Keval N
authors.initials: KN
authors.lastname: Desai
authors.affiliation: University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, 2880 Torrey Pines Scenic Road - Sanford Consortium, La Jolla, CA 92093, MC 0695, USA.
authors.forename: Roberto H
authors.initials: RH
authors.lastname: Herai
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine and Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Weitzman
authors.affiliation: University of California San Diego, Department of Cellular and Molecular Medicine, Stem Cell Program, Institute for Genomic Medicine. Sanford Consortium for Regenerative Medicine. 2880 Torrey Pines Scenic Dr. Room 3805, La Jolla, CA 92037.
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.affiliation: University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, 2880 Torrey Pines Scenic Road - Sanford Consortium, La Jolla, CA 92093, MC 0695, USA.|Center for Academic Research and Training in Anthropogeny (CARTA).
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.|Center for Academic Research and Training in Anthropogeny (CARTA).
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D002460:Cell Line; D048430:Cell Shape; D003564:Cytidine Deaminase / Q000378:metabolism; D019143:Evolution, Molecular; D015894:Genome, Human / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007621:Karyotyping; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008819:Mice, Nude; D015778:Minor Histocompatibility Antigens; D019974:Pan paniscus / Q000235:genetics* / Q000378:metabolism; D002679:Pan troglodytes / Q000235:genetics* / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D017423:Sequence Analysis, RNA; D013045:Species Specificity
chemical_list: D060565:Argonaute Proteins; D015778:Minor Histocompatibility Antigens; C486868:PIWIL2 protein, human; D012333:RNA, Messenger; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase