De novo genes with an lncRNA origin encode unique human brain developmental functionality

Abstract

Human de novo genes can originate from neutral long non-coding RNA (lncRNA) loci and are evolutionarily significant in general, yet how and why this all-or-nothing transition to functionality happens remains unclear. Here, in 74 human/hominoid-specific de novo genes, we identified distinctive U1 elements and RNA splice-related sequences accounting for RNA nuclear export, differentiating mRNAs from lncRNAs, and driving the origin of de novo genes from lncRNA loci. The polymorphic sites facilitating the lncRNA–mRNA conversion through regulating nuclear export are selectively constrained, maintaining a boundary that differentiates mRNAs from lncRNAs. The functional new genes actively passing through it thus showed a mode of pre-adaptive origin, in that they acquire functions along with the achievement of their coding potential. As a proof of concept, we verified the regulations of splicing and U1 recognition on the nuclear export efficiency of one of these genes, the ENSG00000205704, in human neural progenitor cells. Notably, knock-out or over-expression of this gene in human embryonic stem cells accelerates or delays the neuronal maturation of cortical organoids, respectively. The transgenic mice with ectopically expressed ENSG00000205704 showed enlarged brains with cortical expansion. We thus demonstrate the key roles of nuclear export in de novo gene origin. These newly originated genes should reflect the novel uniqueness of human brain development.

Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames

“… 3 Many human microproteins have been selected for functional characterization based on high inter-species conservation 2 , 4 and a minimum amino acid (aa) size. However, evolutionarily young microproteins can have biological roles and have for instance been implicated in cell survival, 5 , 6 , 7 human brain development, 8 and cancer. 9 , 10 , 11 Similarly, a lower size cutoff for protein investigations seems unjustified: peptides as small as 11 aa can control morphogenetic development in insects 12 , 13 , 14 and muscle metabolism in humans, 15 respectively, and short bioactive peptides cleaved from bigger precursor proteins can function as peptide hormones.…”

Origin of functional de novo genes in humans from “hopeful monsters”

“…Notably, the recently originated de novo genes in the human lineage show brain-and testis-biased expression profiles (An et al, 2023;D. D. Wu et al, 2011;Xie et al, 2012;Y.…”

“…Taken together, although there is a consensus for the definition of de novo genes in the field, the list of de novo genes in humans has expanded with the introduction of new genomic technologies. Starting from the initial reports of three human‐specific de novo genes ( CLLU1 , C22orf45 , and DNAH10OS ) by Knowles and McLysaght (2009) and C20orf203 by C. Y. Li et al (2010), dozens of human‐ or hominoid‐specific de novo genes have since been reported, with new genomic technologies such as transcriptome sequencing and ribosome profiling providing evidence of the expression of these new genes (An et al, 2023; J. Y. Chen et al, 2015; Knowles & McLysaght, 2009; C. Y. Li et al, 2010; Ruiz‐Orera et al, 2015; Y. Shao et al, 2019; Vakirlis et al, 2021; D. D. Wu et al, 2011; Xie et al, 2012). According to a recent review by Luuk et al, 82 de novo genes originated recently in the human lineage during the primate evolution (Broeils et al, 2023).…”

“…As a special note, the regulatory roles of these new genes in preventing apoptosis and improving cell survival in spermatocytes (Gubala et al, 2017; Rivard et al, 2021), as well as their roles in the maintenance of the progenitor pool (An et al, 2023; Qi et al, 2023), motivated us to consider their cancer‐promoting roles. Indeed, a quick survey has associated the expression of these new genes with tumor development and prognosis, and several case studies have implicated some of these de novo genes in tumorigenesis, such as the roles of NCYM in promoting multiple types of human cancers (Kaneko et al, 2015; Suenaga et al, 2014; J. Yu et al, 2020; X. Zhao et al, 2016), CLLU1 in chronic lymphocytic leukemia (Buhl et al, 2006), PART‐1 in prostate cancer development (Lin et al, 2000), PBOV1 in breast cancer and glioma (Samusik et al, 2013), and GR6 in acute myeloid leukemia (Pekarsky et al, 1997).…”

Gene Birth in a Model of Non-genic Adaptation

“…Our understanding of the range of possible mechanisms of de novo gene birth comes from several well-known case studies. The proposed mechanisms are typically expressed as a series of sub-steps involving gains and losses of stable transcription, open reading frames [3], and sequences for nuclear export of RNA [14]. Case studies have also uncovered how certain genomic regions, such as introns [15], and certain tissues like the brains and testes of animals [3] favor the emergence of de novo genes.…”