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Human-specific protein isoforms produced by novel splice sites in the human genome after the human-chimpanzee divergence.

ABSTRACT: BACKGROUND: Evolution of splice sites is a well-known phenomenon that results in transcript diversity during human evolution. Many novel splice sites are derived from repetitive elements and may not contribute to protein products. Here, we analyzed annotated human protein-coding exons and identified human-specific splice sites that arose after the human-chimpanzee divergence. RESULTS: We analyzed multiple alignments of the annotated human protein-coding exons and their respective orthologous mammalian genome sequences to identify 85 novel splice sites (50 splice acceptors and 35 donors) in the human genome. The novel protein-coding exons, which are expressed either constitutively or alternatively, produce novel protein isoforms by insertion, deletion, or frameshift. We found three cases in which the human-specific isoform conferred novel molecular function in the human cells: the human-specific IMUP protein isoform induces apoptosis of the trophoblast and is implicated in pre-eclampsia; the intronization of a part of SMOX gene exon produces inactive spermine oxidase; the human-specific NUB1 isoform shows reduced interaction with ubiquitin-like proteins, possibly affecting ubiquitin pathways. CONCLUSIONS: Although the generation of novel protein isoforms does not equate to adaptive evolution, we propose that these cases are useful candidates for a molecular functional study to identify proteomic changes that might bring about novel phenotypes during human evolution.

SUBMITTER: Kim DS

PROVIDER: S-EPMC3538075 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Human-specific protein isoforms produced by novel splice sites in the human genome after the human-chimpanzee divergence.

Kim Dong Seon DS Hahn Yoonsoo Y

BMC bioinformatics 20121113

<h4>Background</h4>Evolution of splice sites is a well-known phenomenon that results in transcript diversity during human evolution. Many novel splice sites are derived from repetitive elements and may not contribute to protein products. Here, we analyzed annotated human protein-coding exons and identified human-specific splice sites that arose after the human-chimpanzee divergence.<h4>Results</h4>We analyzed multiple alignments of the annotated human protein-coding exons and their respective or ...[more]

PMID: 23148531

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Project description:Low nucleotide divergence between human and chimpanzee does not sufficiently explain the species-specific morphological, physiological and behavioral traits. As gene duplication is a major prerequisite for the emergence of new genes and novel biological processes, comparative studies of human and chimpanzee duplicated genes may assist in understanding the mechanisms behind primate evolution. We addressed the divergence between human and chimpanzee duplicated genomic regions by using Luteinizing Hormone Beta (LHB)/Chorionic Gonadotropin Beta (CGB) gene cluster as a model. The placental CGB genes that are essential for implantation have evolved from an ancestral pituitary LHB gene by duplications in the primate lineage.We shotgun sequenced and compared the human (45,165 bp) and chimpanzee (39,876 bp) LHB/CGB regions and hereby present evidence for structural variation resulting in discordant number of CGB genes (6 in human, 5 in chimpanzee). The scenario of species-specific parallel duplications was supported (i) as the most parsimonious solution requiring the least rearrangement events to explain the interspecies structural differences; (ii) by the phylogenetic trees constructed with fragments of intergenic regions; (iii) by the sequence similarity calculations. Across the orthologous regions of LHB/CGB cluster, substitutions and indels contributed approximately equally to the interspecies divergence and the distribution of nucleotide identity was correlated with the regional repeat content. Intraspecies gene conversion may have shaped the LHB/CGB gene cluster. The substitution divergence (1.8-2.59%) exceeded two-three fold the estimates for single-copy loci and the fraction of transversional mutations was increased compared to the unique sequences (43% versus approximately 30%). Despite the high sequence identity among LHB/CGB genes, there are signs of functional differentiation among the gene copies. Estimates for dn/ds rate ratio suggested a purifying selection on LHB and CGB8, and a positive evolution of CGB1.If generalized, our data suggests that in addition to species-specific deletions and duplications, parallel duplication events may have contributed to genetic differences separating humans from their closest relatives. Compared to unique genomic segments, duplicated regions are characterized by high divergence promoted by intraspecies gene conversion and species-specific chromosomal rearrangements, including the alterations in gene copy number.

Project description:Abstract The mRNA identification and associated splice variants affecting meat marbling in Nellore cattle could contribute to a better understanding of the genetic architecture of this complex trait. Longissimus thoracis samples from the 20 most extreme bulls (out of 80 bulls set) for marbling [high (n=10) and low (n=10) groups] trait were used to perform transcriptomic analysis using RNA-Sequencing. The CLC Genomics Workbench software was used to align the fragments of each sample to the bovine reference genome (ARS-UCD1.2) and to perform differential expressed transcript analysis (DE). An average of 37,000 transcripts and 14 mRNA DE (P ≤ 0.001; FC > 2) were detected in the muscle transcriptome. Among them, three transcripts were up-regulated (COL4A2-202, GHRH-201 and ENSBTAT00000070459.1) and 11 down-regulated (HBB-201, HBA-201, RPL14-202, CATHL1-201, CATHL4-201, MAPKAPK2-204, PCBD1-201, RPL30-203, NEURL1-202, PGLYRP1-201 and ENSBTAT00000038384.2) in high marbling group in relation to low group. Structural variants, including Single Nucleotide Variant (SNV), insertion or deletion were also found in the mRNA DE (4 in high and 6 in low marbling groups), causing possible splice site disruption. For high marbling group, in the COL4A2-202 transcript, three SNVs [one guanine (G) located on chromosome 12 at 85,104,867 bp, two cytosine (C), at the positions: 85,119,139 and 85,145,937 bp] were found. From these, one is a non-synonyms mutation [SNV (G) 85,145,937bp], causing an amino acid change (ENSBTAP00000005916.5: p.Glu1088Asp) in Collagen alpha-2(IV) chain protein (COL4A2). Interestingly, animals with low marbling presented also deletions (85,100,930 pb) in this same gene, causing an amino acid change (ENSBTAP00000005916.5:p.Pro113fs)in the COL4A2 protein. Functional enrichment analysis, using the DE mRNAs list, identified significant metabolic pathways (FDR < 0.05), such as O2/CO2 exchange in erythrocytes, tyrosine biosynthesis and phenylalanine degradation. The results suggest potential key regulatory genes associated with marbling, an economically important trait for the beef industry and for the consumer. Funding FAPESP (#2009/16118-5, #11/21241-0, #2017/02470-3, #2017/10630–2, #2018/ 20026–8, #2018/11154-2) and CAPES (#001).

Dataset Information

Human-specific protein isoforms produced by novel splice sites in the human genome after the human-chimpanzee divergence.

Publications

Human-specific protein isoforms produced by novel splice sites in the human genome after the human-chimpanzee divergence.

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