A Human‐Specific De Novo Gene Promotes Cortical Expansion and Folding

Abstract

Newly originated de novo genes have been linked to the formation and function of the human brain. However, how a specific gene originates from ancestral noncoding DNAs and becomes involved in the preexisting network for functional outcomes remains elusive. Here, a human‐specific de novo gene, SP0535, is identified that is preferentially expressed in the ventricular zone of the human fetal brain and plays an important role in cortical development and function. In human embryonic stem cell‐derived cortical organoids, knockout of SP0535 compromises their growth and neurogenesis. In SP0535 transgenic (TG) mice, expression of SP0535 induces fetal cortex expansion and sulci and gyri‐like structure formation. The progenitors and neurons in the SP0535 TG mouse cortex tend to proliferate and differentiate in ways that are unique to humans. SP0535 TG adult mice also exhibit improved cognitive ability and working memory. Mechanistically, SP0535 interacts with the membrane protein Na+/K+ ATPase subunit alpha‐1 (ATP1A1) and releases Src from the ATP1A1‐Src complex, allowing increased level of Src phosphorylation that promotes cell proliferation. Thus, SP0535 is the first proven human‐specific de novo gene that promotes cortical expansion and folding, and can function through incorporating into an existing conserved molecular network.

One million years of solitude: the rapid evolution of de novo protein structure and complex

“…However, the possibility of origination and functionalization de novo genes was long dismissed (Jacob 1977; Mayr 1982). Nevertheless, recent studies have provided substantial evidence for de novo gene origination and function (An, et al 2023; Cai, et al 2008; Chen, et al 2023b; Heames, et al 2020; Qi, et al 2023; Suenaga, et al 2014; Zhang, et al 2019; Zhuang and Cheng 2021).…”

“…In contrast, de novo genes evolve through non-duplication mechanisms and have been shown to play diverse roles in biological functions. Their contributions have been highlighted in multiple systems, including DNA repair in yeast (Cai, et al 2008), providing a novel antifreeze function in Arctic fish (Zhuang and Cheng 2021), diversification of rice morphology (Chen, et al 2023b), cortical expansion in humans (An, et al 2023; Qi, et al 2023), and even oncogenesis in human cancers (Suenaga, et al 2014). The emergence and functional diversity of de novo genes introduce a novel dimension to our understanding of genome evolution and functional innovation, expanding our knowledge beyond traditional gene duplication models (Broeils, et al 2023; Carvunis, et al 2012; Knowles and McLysaght 2009; Vakirlis, et al 2022; Zhang, et al 2019; Zhao, et al 2014).…”

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

“…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).…”

ERK signaling expands mammalian cortical radial glial cells and extends the neurogenic period

“…This two-germinal-zone system in the human developing cortex ensures that the onset of tRG gliogenesis normally occurs in the VZ, as glial cells have multiple indispensable functions in the developing cortex 98 , while oRGs in the OSVZ continue to produce neurons 6,25 , which significantly increases the length of the neurogenic period, a process that is critical for producing the largest number of cortical PyNs in mammalian kingdom 2,7,36 . Furthermore, human-specific genes with preferential expression in cortical progenitors have also been implicated in cortical expansion and folding 18,[99][100][101][102][103][104][105][106] .…”