A Human-Specific De Novo Protein-Coding Gene Associated with Human Brain Functions

Abstract

To understand whether any human-specific new genes may be associated with human brain functions, we computationally screened the genetic vulnerable factors identified through Genome-Wide Association Studies and linkage analyses of nicotine addiction and found one human-specific de novo protein-coding gene, FLJ33706 (alternative gene symbol C20orf203). Cross-species analysis revealed interesting evolutionary paths of how this gene had originated from noncoding DNA sequences: insertion of repeat elements especially Alu contributed to the formation of the first coding exon and six standard splice junctions on the branch leading to humans and chimpanzees, and two subsequent substitutions in the human lineage escaped two stop codons and created an open reading frame of 194 amino acids. We experimentally verified FLJ33706's mRNA and protein expression in the brain. Real-Time PCR in multiple tissues demonstrated that FLJ33706 was most abundantly expressed in brain. Human polymorphism data suggested that FLJ33706 encodes a protein under purifying selection. A specifically designed antibody detected its protein expression across human cortex, cerebellum and midbrain. Immunohistochemistry study in normal human brain cortex revealed the localization of FLJ33706 protein in neurons. Elevated expressions of FLJ33706 were detected in Alzheimer's brain samples, suggesting the role of this novel gene in human-specific pathogenesis of Alzheimer's disease. FLJ33706 provided the strongest evidence so far that human-specific de novo genes can have protein-coding potential and differential protein expression, and be involved in human brain functions.

Transposable element insertions have strongly affected human evolution

“…12-16). The effect of Alu insertions on specific genes has been studied (16)(17)(18)(19). Further studies have been made of the effect of TEs on the human genome and its expression (20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

Evolution of New Functions De Novo and from Preexisting Genes

“…Evolutionary divergence characteristics are commonly used as a filter to distinguish de novo gene candidates from neutrally evolving genomic regions. De novo gene emergence have been reported from many organisms such as insects (Begun et al 2007;Reinhardt et al 2013), yeast (Cai et al 2008;Li et al 2010b), Hydra (Khalturin et al 2008), primates (Johnson et al 2001;Knowles and McLysaght 2009;Toll-Riera et al 2009;Li et al 2010a;Wu et al 2011;Xie et al 2012), mouse (Murphy and McLysaght 2012;Neme and Tautz 2013), Plasmodium (Yang and Huang 2011), and plants (Donoghue et al 2011).…”

Evolution of genetic and genomic features unique to the human lineage

“…In addition, a number of HLS changes linked to human specific cognitive abilities are also associated with severity of Alzheimer’s disease and dementias 51,108 . For example, FLJ33706 115 , a novel human gene highly expressed in the cortex, cerebellum and midbrain, has been reported to show increased expression in Alzheimers brain specimens. The Asp (abnormal spindle) homolog, microcephaly ( ASPM ) gene, a microcephaly disease gene 57,58 , reportedly underwent accelerated evolution in the human lineage, although the certainty of this is contested in recent literature 123 .…”