Characterization of an eutherian gene cluster generated after transposon domestication identifies Bex3 as relevant for advanced neurological functions

Abstract

Background One of the most unusual sources of phylogenetically restricted genes is the molecular domestication of transposable elements into a host genome as functional genes. Although these kinds of events are sometimes at the core of key macroevolutionary changes, their origin and organismal function are generally poorly understood. Results Here, we identify several previously unreported transposable element domestication events in the human and mouse genomes. Among them, we find a remarkable molecular domestication that gave rise to a multigenic family in placental mammals, the Bex/Tceal gene cluster. These genes, which act as hub proteins within diverse signaling pathways, have been associated with neurological features of human patients carrying genomic microdeletions in chromosome X. The Bex/Tceal genes display neural-enriched patterns and are differentially expressed in human neurological disorders, such as autism and schizophrenia. Two different murine alleles of the cluster member Bex3 display morphological and physiopathological brain modifications, such as reduced interneuron number and hippocampal electrophysiological imbalance, alterations that translate into distinct behavioral phenotypes. Conclusions We provide an in-depth understanding of the emergence of a gene cluster that originated by transposon domestication and gene duplication at the origin of placental mammals, an evolutionary process that transformed a non-functional transposon sequence into novel components of the eutherian genome. These genes were integrated into existing signaling pathways involved in the development, maintenance, and function of the CNS in eutherians. At least one of its members, Bex3, is relevant for higher brain functions in placental mammals and may be involved in human neurological disorders.

S18-phosphorylation of USP7 regulates interaction with TCEAL4 that defines specific complexes and potentially distinct functions

“…We confirmed that GFP-TCEAL4 predominantly localises in the nucleus of U2OS cells (Supplementary Figure S6E) and thus may potentially be involved in nuclear processes such as transcription. However, no TCEAL4 functions have yet been described, and the related BEX proteins are suggested to be hubs that participate in multiple cellular pathways 37 . To investigate further, we immunoprecipitated GFP-TCEAL4 for mass spectrometry (Figure 4A, Supplementary Table 2) and identified several hundred interacting proteins, substantially increasing the list of TCEAL4 interactors collated from high-throughput studies (Figure 4B).…”

New Genes Born-In or Invading Vertebrate Genomes

“…Regarding their expression, according to the available data from adult organs, most genes present a tissue-enriched pattern, with the brain be the organ showing the highest expression levels in most of the paralogs. Navas-Pérez et al (2020) also reported an analysis of the expression via in situ hybridization during mouse development, where they observed that especially the Bex genes were highly and widely expressed with Bex3 strongly expressed in the nervous system.…”

“…Thus, Bex3 would be fine-tuning the regulation of the mTOR pathway and its deregulation was suggested to be related to autism spectrum disorder in humans (Ganesan et al, 2019). Some of the structural features present in BEX and TCEAL families have been detected in the ancestral transposon HAL1b (Navas-Pérez et al, 2020), which indicates that they were preserved along the domestication process., and a positive selection signature can be found in particular cases, suggesting than ancestral genes went through an adaptative process before the diversification of placental mammals. The differences in the neocortex complexity between eutherian and non-eutherian mammals (Cheung et al, 2010) may thus be linked to genomic novelties that emerged during this transition affecting neural development, and maybe, to the appearance of the Bex/Tceal cluster.…”

“…Recently Navas-Pérez et al (2020) presented evidence of the expansion of a domestication event into the Bex/Tceal multigenic family, constituting a cluster of 14 genes in the X chromosome of the ancestor of eutherians, after the divergence of the marsupial-placental clades. The domestication event proposed ( Figure 4 ) consists of six steps: (i) A proto-BGW motif ( Winter and Ponting, 2005 ) existed upstream of the alpha-galactosidase (Gla) promoter (P α) in the X chromosome of the ancestor of eutherians and metatherians; (ii) In the eutherian lineage, a retrotranscribed Hnrnph1 was inserted next to the BGW motif and upstream of Gla, creating the Hnrnph2 retrogene; (iii) The region containing the co-opted BGW motif and Hnrnph2 suffered a duplication and HAL1b and L1ME-like retrotransposons were inserted in the vicinity; (iv) The BGW motif and the ORF created by the insertion of the retrotransposons conformed the proto-Bex/Tceal with the YY1 binding site from HAL1b preserved; (v) The BGW motif and the YY1 binding site of a Bex/Tceal gene duplicated upstream of a retrocopy of the Armc10 gene, giving rise to the ArmcX ancestral gene; and (vi) The Bex/Tceal and ArmcX gene families expanded forming the BGW cluster before the diversification of the placental lineage.…”

“…These disruptive novelties are often accompanied by the apparition of new genes that integrate into the current gene networks ( Lavialle et al, 2013 ; Parrish and Tomonaga, 2018 ; Zhang et al, 2019 ; Navas-Pérez et al, 2020 ; Pascual-Carreras et al, 2020 ). These new genes ( Figure 1 ) can of course be paralogs caused by duplication of genes already present in the genome which could allow the duplicated gene to change its sequence or its regulation ( Ohno, 1970 ; Putnam et al, 2008 ; Jimenez-Delgado et al, 2009 ).…”