The birth of a human-specific neural gene by incomplete duplication and gene fusion

• Published in: Genome Biology Vol. 18; no. 1; p. 49
• Main Authors: Dougherty, Max L., Nuttle, Xander, Penn, Osnat, Nelson, Bradley J., Huddleston, John, Baker, Carl, Harshman, Lana, Duyzend, Michael H., Ventura, Mario, Antonacci, Francesca, Sandstrom, Richard, Dennis, Megan Y., Eichler, Evan E.
• Format: Journal Article
• Language: English
• Published: London BioMed Central 09.03.2017
• Subjects: Animal Genetics and Genomics; Autism; Bioinformatics; Biomedical and Life Sciences; Breakpoints; Chromosome 1; Chromosome 16; Chromosome Aberrations; Chromosome Breakpoints; Chromosome Disorders - genetics; Chromosomes; Chromosomes, Human, Pair 1; Copy number; diploidy; DNA Copy Number Variations; evolution; Evolution, Molecular; Evolutionary Biology; Exons; Gene Conversion; Gene Duplication; Gene Expression Profiling; Gene Fusion; Genes; Genetic Variation; Genetics, Population; Genomes; Genomics - methods; Homo; Human Genetics; Humans; Hydrocephalus; Life Sciences; loci; Microbial Genetics and Genomics; Microcephaly; Mutation; Neurons - metabolism; Open Reading Frames; Organ Specificity - genetics; patients; Phenotype; Phylogenetics; Plant Genetics and Genomics; Polymerase chain reaction; reverse transcriptase polymerase chain reaction; Reverse transcription; Selection, Genetic; sequence analysis; Splicing; tissues; transcription (genetics); Transcription, Genetic; Long-read sequencing; Evolution; Segmental duplication; 1q21 microdeletion/microduplication syndrome; Duplicate genes; Gene fusion
• ISSN: 1474-760X; 1474-7596; 1474-760X
• DOI: 10.1186/s13059-017-1163-9

Background Gene innovation by duplication is a fundamental evolutionary process but is difficult to study in humans due to the large size, high sequence identity, and mosaic nature of segmental duplication blocks. The human-specific gene hydrocephalus-inducing 2, HYDIN2 , was generated by a 364 kbp duplication of 79 internal exons of the large ciliary gene HYDIN from chromosome 16q22.2 to chromosome 1q21.1. Because the HYDIN2 locus lacks the ancestral promoter and seven terminal exons of the progenitor gene, we sought to characterize transcription at this locus by coupling reverse transcription polymerase chain reaction and long-read sequencing. Results 5' RACE indicates a transcription start site for HYDIN2 outside of the duplication and we observe fusion transcripts spanning both the 5' and 3' breakpoints. We observe extensive splicing diversity leading to the formation of altered open reading frames (ORFs) that appear to be under relaxed selection. We show that HYDIN2 adopted a new promoter that drives an altered pattern of expression, with highest levels in neural tissues. We estimate that the HYDIN duplication occurred ~3.2 million years ago and find that it is nearly fixed (99.9%) for diploid copy number in contemporary humans. Examination of 73 chromosome 1q21 rearrangement patients reveals that HYDIN2 is deleted or duplicated in most cases. Conclusions Together, these data support a model of rapid gene innovation by fusion of incomplete segmental duplications, altered tissue expression, and potential subfunctionalization or neofunctionalization of HYDIN2 early in the evolution of the Homo lineage.