Recombination of repeat elements generates somatic complexity in human genomes

Delighted to share our paper https://www.cell.com/cell/fulltext/S0092-8674(22)00784-X, finally out in?@CellCellPress, which reports and discusses unexpected recombination mediated by repeat elements in somatic genomes. Details also in the thread of Giovanni @muju79.

The genome contains the blueprint with the instructions to construct all the cells and tissues of the human body and is generally believed to be constant in all cells, except well-known exceptions such some immune cells and cancers. Giovanni, @muju79 was interested in studying somatic genome variation in brain and the role of retrotransposon elements, repeated sequences like ALU and LINE that are known to sometimes jump in the genome by retrotransposon from RNA intermediates. We redeveloped a method, called retrotransposon capture-sequencing, to enrich and sequence genomic regions enriched in SINE and LINE sequences, which were candidates for possible retrotransposition, in order to link them to pathologies.??Then we applied this method to neuron and non-neurons from three regions of the brain cortex, and two control tissues (kidney and liver) from postmortem donors. Samples included also 10 Alzheimer’s and 10 Parkinson’s disease donors.?

While we were looking for retrotransposition, as seen before as altering the landscape of human brain (https://www.nature.com/articles/nature10531), we serendipitously identify something different: recombination occurring on these elements.?

The genome undergoes continuous breaks and repair. Repeat elements may confuse?the?typical?homology-based repair mechanism, which fixes?DNA double-strand breaks (DSBs), here causing?non-allelic homologous recombination (NAHR). A big surprise was the type and extent of the NAHR events: NAHR happening on?inverted repeats generates?inversions;?NAHR of direct repeats cause deletions and duplications. We estimate that there are several events per cells.?

The data suggests that genome in most of the cells harbors deletions, duplications, inversions; there are specific patterns, discussed by @muju79 that are specific for brain, including patterns specific for #Alzheimers and #Parkinsons.?

There are also hotspots as in in pericentromeric regions or localized on genes involved in cancer. We could recapitulate NAHR also in neurons differentiating from iPS cells, which deserve further studies, including implications on applications. We spend considerable efforts to validate, by resequencing with Sanger and finally by sequencing non-PCR amplified genomic DNA with @nanopore #PromethION, which confirmed a number of original finding and identified more events.??While I hope that you can read the final version, the paper originated from this manuscript: https://www.biorxiv.org/content/10.1101/2020.07.02.163816v2, which will be available to everyone.?

As often, this study opens many more questions, in particular on how widespread genome recombination is in somatic cells, when is this originated, how the cells cope with NAHR challenges and the role in disease and aging.?

Special thanks to key collaborators @SGustincich for many discussion about the concept of stability, copy numbers and retrotransposition of LINE elements;?Martin Frith at @UTokyo_News_en?for the?https://gitlab.com/mcfrith/te-rex; big thanks also to Yutaka Suzuki (https://www.cbms.k.u-tokyo.ac.jp/english/lab/suzuki.html) for the #Promethion, Shigeo Murayama for the postmortem human samples: https://www.tmig.or.jp/eresearch/a23.html and to??all colleagues at @RIKEN_IMS, @riken_en, @RIKEN_JP, @humantechnopole.?