Identification of mobile retrocopies during genetic testing: Consequences for routine diagnosis

Chatron, Nicolas; Cassinari, Kévin; Quenez, Olivier; Baert‐Desurmont, Stéphanie; Bardel, Claire; Buisine, Marie‐Pierre; Calpena, Eduardo; Capri, Yline; Galbany, Jordi Corominas; Diguet, Flavie; Edery, Patrick; Isidor, Bertrand; Labalme, Audrey; Caignec, Cédric Le; Lévy, Jonathan; Lecoquierre, François; Livet, Pierre; Pichon, Olivier; Rollat‐Farnier, Pierre‐Antoine; Simonet, Thomas; Saugier‐Veber, Pascale; Tabet, Anne‐Claude; Toutain, Annick; Wilkie, Andrew; Lesca, Gaëtan; Sanlaville, Damien; Nicolas, Gaël; Schluth-Bolard, Caroline

doi:10.1002/humu.23845

Cited by 4 publications

(7 citation statements)

References 39 publications

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“…We found this CNV was a retropseudogene of the CTH. The retrocopy of one gene could insert in a non-functional sequence, disrupt a gene or form a fusion transcript with unpredictable consequences [52]. A previous study reported that the HIV resistance of owl monkeys caused by the insertion of a Cyclophilin A cDNA into the TRIM5 gene [53].…”

Section: Discussionmentioning

confidence: 99%

Comparative analyses of copy number variations between Bos taurus and Bos indicus

Xia

et al. 2020

BMC Genomics

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Background Bos taurus and Bos indicus are two main sub-species of cattle. However, the differential copy number variations (CNVs) between them are not yet well studied. Results Based on the new high-quality cattle reference genome ARS-UCD1.2, we identified 13,234 non-redundant CNV regions (CNVRs) from 73 animals of 10 cattle breeds (4 Bos taurus and 6 Bos indicus), by integrating three detection strategies. While 6990 CNVRs (52.82%) were shared by Bos taurus and Bos indicus, large CNV differences were discovered between them and these differences could be used to successfully separate animals into two subspecies. We found that 2212 and 538 genes uniquely overlapped with either indicine-specific CNVRs and or taurine-specific CNVRs, respectively. Based on FST, we detected 16 candidate lineage-differential CNV segments (top 0.1%) under selection, which overlapped with eight genes (CTNNA1, ENSBTAG00000004415, PKN2, BMPER, PDE1C, DNAJC18, MUSK, and PLCXD3). Moreover, we obtained 1.74 Mbp indicine-specific sequences, which could only be mapped on the Bos indicus reference genome UOA_Brahman_1. We found these sequences and their associated genes were related to heat resistance, lipid and ATP metabolic process, and muscle development under selection. We further analyzed and validated the top significant lineage-differential CNV. This CNV overlapped genes related to muscle cell differentiation, which might be generated from a retropseudogene of CTH but was deleted along Bos indicus lineage. Conclusions This study presents a genome wide CNV comparison between Bos taurus and Bos indicus. It supplied essential genome diversity information for understanding of adaptation and phenotype differences between the Bos taurus and Bos indicus populations.

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Section: Discussionmentioning

confidence: 99%

Comparative analyses of copy number variations between Bos taurus and Bos indicus

Xia

et al. 2020

BMC Genomics

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“…While next generation sequencing allows for the detection of polymorphic gene retrocopies, they often go unidentified or misidentified by common variant calling methods [ 40 ]. However, more careful analysis of discordant Illumina paired-end reads has shown they are more common than previously thought [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Multiple FGF4 Retrocopies Recently Derived within Canids

Batcher

Dickinson

Maciejczyk

et al. 2020

Genes

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Two transcribed retrocopies of the fibroblast growth factor 4 (FGF4) gene have previously been described in the domestic dog. An FGF4 retrocopy on chr18 is associated with disproportionate dwarfism, while an FGF4 retrocopy on chr12 is associated with both disproportionate dwarfism and intervertebral disc disease (IVDD). In this study, whole-genome sequencing data were queried to identify other FGF4 retrocopies that could be contributing to phenotypic diversity in canids. Additionally, dogs with surgically confirmed IVDD were assayed for novel FGF4 retrocopies. Five additional and distinct FGF4 retrocopies were identified in canids including a copy unique to red wolves (Canis rufus). The FGF4 retrocopies identified in domestic dogs were identical to domestic dog FGF4 haplotypes, which are distinct from modern wolf FGF4 haplotypes, indicating that these retrotransposition events likely occurred after domestication. The identification of multiple, full length FGF4 retrocopies with open reading frames in canids indicates that gene retrotransposition events occur much more frequently than previously thought and provide a mechanism for continued genetic and phenotypic diversity in canids.

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Section: The Biology Of Retropositionmentioning

confidence: 99%

“…A recent study in mice suggested that the actual rate of retrocopy generation in extant populations is even higher and possibly similar between humans and mice [40], and hence, it is not surprising that retrocopy variation is detected in medical contexts [65,66]. However, it is also suggested that due to the use of unoptimized analytical pipelines, many retrocopies have often been overlooked in routine genetic testing [40,65]. At present, there are several documented cases of retrocopy emergence related to diseases in animals [49,65,67], and one case of pathogenic retrocopy in humans [49,65,68,69], but more could potentially be discovered [40].…”

Section: The Biology Of Retropositionmentioning

confidence: 99%

mRNA Vaccines: Why Is the Biology of Retroposition Ignored?

Domazet-Lošo

2022

Genes

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The major advantage of mRNA vaccines over more conventional approaches is their potential for rapid development and large-scale deployment in pandemic situations. In the current COVID-19 crisis, two mRNA COVID-19 vaccines have been conditionally approved and broadly applied, while others are still in clinical trials. However, there is no previous experience with the use of mRNA vaccines on a large scale in the general population. This warrants a careful evaluation of mRNA vaccine safety properties by considering all available knowledge about mRNA molecular biology and evolution. Here, I discuss the pervasive claim that mRNA-based vaccines cannot alter genomes. Surprisingly, this notion is widely stated in the mRNA vaccine literature but never supported by referencing any primary scientific papers that would specifically address this question. This discrepancy becomes even more puzzling if one considers previous work on the molecular and evolutionary aspects of retroposition in murine and human populations that clearly documents the frequent integration of mRNA molecules into genomes, including clinical contexts. By performing basic comparisons, I show that the sequence features of mRNA vaccines meet all known requirements for retroposition using L1 elements—the most abundant autonomously active retrotransposons in the human genome. In fact, many factors associated with mRNA vaccines increase the possibility of their L1-mediated retroposition. I conclude that is unfounded to a priori assume that mRNA-based therapeutics do not impact genomes and that the route to genome integration of vaccine mRNAs via endogenous L1 retroelements is easily conceivable. This implies that we urgently need experimental studies that would rigorously test for the potential retroposition of vaccine mRNAs. At present, the insertional mutagenesis safety of mRNA-based vaccines should be considered unresolved.

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Identification of mobile retrocopies during genetic testing: Consequences for routine diagnosis

Cited by 4 publications

References 39 publications

Comparative analyses of copy number variations between Bos taurus and Bos indicus

Comparative analyses of copy number variations between Bos taurus and Bos indicus

Multiple FGF4 Retrocopies Recently Derived within Canids

mRNA Vaccines: Why Is the Biology of Retroposition Ignored?

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