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.
Highlights
Many mechanisms for the origination of new genes are known, such as tandem gene duplication, retrotransposition, exon shuffling and gene fusion [1,2,3,4,5]
The functional protein-coding features of the FLJ33706 gene are supported by population genetics, transcriptome profiling, Western-blot and immunohistochemistry assays
Data suggest that FLJ33706 may be involved in nicotine addiction and Alzheimer’s disease
Summary
Many mechanisms for the origination of new genes are known, such as tandem gene duplication, retrotransposition, exon shuffling and gene fusion [1,2,3,4,5]. More recently Knowles and McLysaght identified in silico three human-specific de novo genes supported by peptides from high-throughput mass spectrum data [11]. These studies, tremendously interesting, are lacking in two aspects. There is no solid protein evidence so far for any of the de novo genes identified— high-throughput mass spectrum data alone as protein evidence can have limitations, as commented by Siepel [12]. None of these genes has been linked to human specific phenotype. Could any de novo genes be associated with human unique biology, especially to brain functions?
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