Non-allelic homologous recombination of Alu and LINE-1 elements generates somatic complexity in human genomes

Millions of Alu and LINE-1 copies in our genomes contribute to evolution and genetic disorders via non-allelic homologous recombination (NAHR), but the somatic extent of these rearrangements has not been systematically investigated. Here we combined high-throughput capture and sequencing of repeat elements with a new bioinformatic pipeline to show that somatic NAHR of Alu and LINE-1 elements is common in human genomes. We describe tissue-specific hallmarks of NAHR, and show that retroelements acting as recombination hotspots are enriched in cancer genes and structural variants. Analysis of recombination in human induced pluripotent stem cells and differentiated neurons revealed a neuron-specific recombination signature suggesting that the emergence of cell type-specific recombination profiles accompanies cell-fate determination. Finally, we found that somatic NAHR profiles are altered in Parkinson’s and Alzheimer’s disease, indicating a link between retroelements recombination and genomic instability in neurodegeneration. This work shows that somatic recombination of repeat elements contributes massively to genomic diversity, and that extensive recombinogenic activity of retroelements may act as a grey eminence in the transition from health to disease.

[1]  E. Swisher,et al.  BRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance , 2019, Nature Communications.

[2]  F. d’Adda di Fagagna,et al.  Functional transcription promoters at DNA double-strand breaks mediate RNA-driven phase separation of damage response factors , 2019, Nature Cell Biology.

[3]  Z. Weng,et al.  Genome-wide analysis of polymerase III–transcribed Alu elements suggests cell-type–specific enhancer function , 2019, Genome research.

[4]  Karim Mekhail,et al.  Phase Separation as a Melting Pot for DNA Repeats. , 2019, Trends in genetics : TIG.

[5]  W. Heyer,et al.  Moving forward one step back at a time: reversibility during homologous recombination , 2019, Current Genetics.

[6]  R. Jaenisch,et al.  Hominoid-Specific Transposable Elements and KZFPs Facilitate Human Embryonic Genome Activation and Control Transcription in Naive Human ESCs , 2019, Cell stem cell.

[7]  T. Misteli,et al.  Extensive Heterogeneity and Intrinsic Variation in Spatial Genome Organization , 2019, Cell.

[8]  Wolf-Dietrich Heyer,et al.  Homologous Recombination and the Formation of Complex Genomic Rearrangements. , 2019, Trends in cell biology.

[9]  A. Valencia,et al.  Intronic CNVs and gene expression variation in human populations , 2019, PLoS genetics.

[10]  C. Cole,et al.  The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers , 2018, Nature Reviews Cancer.

[11]  Anshul Kundaje,et al.  Umap and Bismap: quantifying genome and methylome mappability , 2016, bioRxiv.

[12]  G. Faulkner,et al.  L1 retrotransposition in the soma: a field jumping ahead , 2018, Mobile DNA.

[13]  O. Rando,et al.  LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo , 2017, Nature Genetics.

[14]  D. Frishman,et al.  Genome‐wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma , 2017, International journal of cancer.

[15]  Kiyoshi Asai,et al.  Training alignment parameters for arbitrary sequencers with LAST-TRAIN , 2016, Bioinform..

[16]  Jun Wang,et al.  Evidence for L1-associated DNA rearrangements and negligible L1 retrotransposition in glioblastoma multiforme , 2016, Mobile DNA.

[17]  Jennifer A. Erwin,et al.  L1-associated genomic regions are deleted in somatic cells of the healthy human brain , 2016, Nature Neuroscience.

[18]  J. Goodier.  Restricting retrotransposons: a review , 2016, Mobile DNA.

[19]  J. Vera-Otarola,et al.  Activation of individual L1 retrotransposon instances is restricted to cell-type dependent permissive loci , 2016, eLife.

[20]  C. Feschotte,et al.  Regulatory evolution of innate immunity through co-option of endogenous retroviruses , 2016, Science.

[21]  C. Walsh,et al.  Resolving rates of mutation in the brain using single-neuron genomics , 2016, eLife.

[22]  Robert D. Finn,et al.  The Dfam database of repetitive DNA families , 2015, Nucleic Acids Res..

[23]  Gabor T. Marth,et al.  An integrated map of structural variation in 2,504 human genomes , 2015, Nature.

[24]  M. Frith,et al.  Split-alignment of genomes finds orthologies more accurately , 2015, Genome Biology.

[25]  Benjamin J Raphael,et al.  Detecting non-allelic homologous recombination from high-throughput sequencing data , 2015, Genome Biology.

[26]  P. Deininger,et al.  The Contribution of Alu Elements to Mutagenic DNA Double-Strand Break Repair , 2015, PLoS genetics.

[27]  Michael Q. Zhang,et al.  Integrative analysis of 111 reference human epigenomes , 2015, Nature.

[28]  Anna Gambin,et al.  Genome-wide analyses of LINE–LINE-mediated nonallelic homologous recombination , 2015, Nucleic acids research.

[29]  C. Walsh,et al.  Cell Lineage Analysis in Human Brain Using Endogenous Retroelements , 2015, Neuron.

[30]  Matej Lexa,et al.  Guanine quadruplexes are formed by specific regions of human transposable elements , 2014, BMC Genomics.

[31]  G. Silberberg,et al.  Alu elements shape the primate transcriptome by cis-regulation of RNA editing , 2014, Genome Biology.

[32]  Yan Liu,et al.  Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells , 2013, Nature Protocols.

[33]  C. Morton,et al.  Mechanisms for Structural Variation in the Human Genome , 2013, Current Genetic Medicine Reports.

[34]  Piero Carninci,et al.  Edinburgh Research Explorer Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma , 2022 .

[35]  J. Vermeesch,et al.  Nonallelic homologous recombination between retrotransposable elements is a driver of de novo unbalanced translocations , 2013, Genome research.

[36]  C. Walsh,et al.  Single-Neuron Sequencing Analysis of L1 Retrotransposition and Somatic Mutation in the Human Brain , 2012, Cell.

[37]  K. Kitada,et al.  Alu-Alu Fusion Sequences Identified at Junction Sites of Copy Number Amplified Regions in Cancer Cell Lines , 2012, Cytogenetic and Genome Research.

[38]  B. Faircloth,et al.  Primer3—new capabilities and interfaces , 2012, Nucleic acids research.

[39]  P. Deininger.  Alu elements: know the SINEs , 2011, Genome Biology.

[40]  Steven Salzberg,et al.  BIOINFORMATICS ORIGINAL PAPER , 2004 .

[41]  J. Mattick,et al.  Somatic retrotransposition alters the genetic landscape of the human brain , 2011, Nature.

[42]  J. V. Moran,et al.  LINE-1 elements in structural variation and disease. , 2011, Annual review of genomics and human genetics.

[43]  D. Geschwind,et al.  Neurons show distinctive DNA methylation profile and higher interindividual variations compared with non-neurons. , 2011, Genome research.

[44]  M. Frith,et al.  Adaptive seeds tame genomic sequence comparison. , 2011, Genome research.

[45]  Evan E. Eichler,et al.  LINE-1 Retrotransposition Activity in Human Genomes , 2010, Cell.

[46]  Mariko Sasaki,et al.  Genome destabilization by homologous recombination in the germ line , 2010, Nature Reviews Molecular Cell Biology.

[47]  Aaron R. Quinlan,et al.  Bioinformatics Applications Note Genome Analysis Bedtools: a Flexible Suite of Utilities for Comparing Genomic Features , 2022 .

[48]  M. Hurles,et al.  Copy number variation in human health, disease, and evolution. , 2009, Annual review of genomics and human genetics.

[49]  J. Lupski,et al.  Mechanisms of change in gene copy number , 2009, Nature Reviews Genetics.

[50]  J. Lupski,et al.  Mechanisms for human genomic rearrangements , 2008, PathoGenetics.

[51]  S. Akbarian,et al.  Neuronal nuclei isolation from human postmortem brain tissue. , 2008, Journal of visualized experiments : JoVE.

[52]  Chih-ping Chen,et al.  Gene dosage change of TPTE and BAGE2 and breakpoint analysis in Robertsonian Down syndrome , 2008, Journal of Human Genetics.

[53]  D. Cooper,et al.  Gene conversion: mechanisms, evolution and human disease , 2007, Nature Reviews Genetics.

[54]  Matthew D. Dyer,et al.  Human genomic deletions mediated by recombination between Alu elements. , 2006, American journal of human genetics.

[55]  David W. Russell,et al.  Purification of nucleic acids by extraction with phenol:chloroform. , 2006, CSH protocols.

[56]  Stéphane Boissinot,et al.  Molecular evolution and tempo of amplification of human LINE-1 retrotransposons since the origin of primates. , 2005, Genome research.

[57]  M. Jasin,et al.  Chromosomal translocation mechanisms at intronic alu elements in mammalian cells. , 2005, Molecular cell.

[58]  J. Squire,et al.  The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumors , 2002, Genes, chromosomes & cancer.

[59]  J. V. Moran,et al.  Genomic Deletions Created upon LINE-1 Retrotransposition , 2002, Cell.

[60]  T. Darden,et al.  Biased distribution of inverted and direct Alus in the human genome: implications for insertion, exclusion, and genome stability. , 2001, Genome research.

[61]  J. Jurka,et al.  Inverted Alu repeats unstable in yeast are excluded from the human genome , 2000, The EMBO journal.

[62]  M. Rudnicki,et al.  Simplified mammalian DNA isolation procedure. , 1991, Nucleic acids research.

[63]  R. C. Macridis.  A review , 1963 .