Human Molecular Genetics Advance Access originally published online on April 27, 2006
Human Molecular Genetics 2006 15(11):1870-1875; doi:10.1093/hmg/ddl109
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Origination and evolution of a human-specific transmembrane protein gene, c1orf37-dup
1Key Laboratory of Bioresources Conservation and Utilization and Human Genetics Center of Yunnan University, Kunming 650091, PR China, 2CAS-Max Planck Junior Research Group and Key Laboratory of Cellular and Molecular Evolution, Kunming Institute of Zoology and 3Kunming Primate Research Center, Chinese Academy of Sciences, Kunming 650223, PR China and 4Graduate School of Chinese Academy Sciences, Beijing 100039, PR China
* To whom the correspondence should be addressed at: Kunming Institute of Zoology, No. 32 E. Jiao Chang Road, Kunming, Yunnan 650223, PR China. Tel: +86 8715192979; Fax: +86 8715193137; Email: wwang{at}mail.kiz.ac.cn or Yunnan University, No. 2 N. Cuihui Road, Kunming, Yunnan 650091, PR China. Tel and Fax: +86 8715034636; Email: cjxiao2005{at}yahoo.com.cn
Received January 26, 2006; Accepted April 14, 2006
GenBank (http://www.ncbi.nlm.nih.gov/Genbank) accession nos
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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A transmembrane protein gene, c1orf37-dup, was identified as a young gene specific to humans. It was derived from the conserved c1orf37 gene through retroposition after the divergence of human and chimpanzee. This gene has evolved rapidly driven by positive Darwinian selection as evident from a significantly high ratio of non-synonymous substitution rate to synonymous substitution rate (Ka/Ks=2.08) between the new c1orf37-dup and the parental c1orf37 genes. Population genetics analysis disclosed a very low level of polymorphism in the c1orf37-dup gene and its neighboring regions, thus providing support for the occurrence of a recent selective sweep. The GFP experiments revealed that it encodes a transmembrane protein associated with cell membranes. Non-random distribution of amino acid changes indicates the C1ORF37-DUP protein may have evolved diverged functions in the presumably functionally important N-terminal region in the cytoplasm and the extracellular loop. These lines of evidence support that the functional adaptation of c1orf37-dup has occurred in humans. Unlike its ubiquitously expressed parental gene, c1orf37-dup expresses selectively in several human tissues including brain. It is suggested that c1orf37-dup encodes a novel transmembrane protein in humans which potentially endows new properties to cell surface interactions.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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New genes with novel functions may have significantly contributed to the evolution of new phenotypes specific to species. The birth of a new gene comprises duplication, initial mutation events yielding a particular gene structure and subsequent evolutionary procedure, in which it is fixed in the species and improved for novel functions (1
). Among the several molecular mechanisms that have been observed in the creation of new gene structures (2), retroposition, usually recruiting a new regulatory sequence to survive, contributes tremendous structural and functional novelties to extant genomes (3). Moreover, positive-Darwinian selection, the important evolutionary driving force, helps newly created genes to become established in the population by increasing the frequency of advantageous mutations (4,5), which has often been observed in gene origination cases (2,6,7).
The novel genes created in the human genome are of special interest because of the unique evolutionary status of human beings and our unique phenotypic traits, such as bipedalism and higher cognitive abilities (8,9). Despite the phenotypic diversities, the genetic divergence between human and chimpanzee at the level of DNA sequence is 1.23% (10–12); therefore, it has been proposed that there may be few novel genes associated with human-specific traits (9). Besides the differences found in gene expression regulation between humans and other primates (9,13,14), human unique genes are nevertheless an important source to be investigated to understand the genetic basis of the human-specific traits. On the basis of the observation of segmental duplications in human, Bailey et al. (15) estimated that human and chimpanzee genomes may differ by 150–350 transcripts. Brosius (3) predicted about 110 gene differences between humans and chimpanzees assuming the 6 million year divergence time. Marques et al. (16) estimated that about one retrogene per million years has emerged on the lineage leading to humans. More recently from the comparison of the human and chimpanzee genomes, the Chimpanzee Sequencing and Analysis Consortium (12) estimated about 200 human-specific retroposed gene copies though the functionality of them remains to be investigated.
In this study, we report the comprehensive characterization of a human-specific gene, c1orf37-dup. It was identified in this study to be created through retroposition from the parental intron-containing gene c1orf37 (the open reading frame 37 on Chromosome 1, CA037_HUMAN, ENSG00000163444). Evolutionary and functional analyses reveal that c1orf37-dup has been undergoing rapid functional adaptation driven by strong positive Darwinian selection in humans and encodes a transmembrane protein which may bring new properties to cell surface interactions in human cells.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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Identification of the human-specific c1orf37-dup gene
In an effort to identify fast evolving human genes, a duplicated copy of the c1orf37 gene, designated as c1orf37-dup (ENSG00000169883, XP_370848.1), was identified on Chromosome 3q25.1 (151,183,864–151,182,148). It contains the hallmarks of retroposed sequences: the lack of introns, a remnant of the poly(A) tail at the 3' end and 14 bp direct repeats at the both ends (17
). It retained the full reading frame (1128 bp) from c1orf37 without any insertion and deletion (indel) and is predicted to encode a 376-amino acid peptide. Genomic DNA amplification by PCR (see Materials and Methods) with the chimpanzee DNAs and subsequent sequencing disclosed that c1orf37-dup is absent from the corresponding genomic location in chimpanzees (Fig. 1). Further investigation in orangutan which shares a common ancestor with the human, chimpanzee and gorilla lineage revealed that orangutan is also devoid of c1orf37-dup, reflecting the ancestral state of this genomic locus. These observations demonstrate that c1orf37-dup is a gene uniquely created in humans after the divergence of humans and chimpanzees. It is not among the previously reported human-specific retrosequences in Chimpanzee Sequencing and Analysis Consortium (12).
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Fast evolution of the c1orf37-dup gene
Compared with the parental transcript, c1orf37-dup has nine nucleotide changes: two in the 5'-UTR, one in the 3'-UTR and six in the coding region. Our population study shows that they are fixed in human populations. All the six coding region substitutions are non-synonymous and result in amino acid changes.
With the Ka/Ks test, a simple and useful measurement of functional constraint on a protein-coding gene (18), we found c1orf37-dup has an excess of non-synonymous substitution rate. The Ka/Ks test measures the ratio of non-synonymous substitution rate (Ka) to synonymous substitution rate (Ks) for a pair of sequences. The ratio is about one for a pseudogene derived from its parental gene because it evolves neutrally. Functional genes have a lower Ka due to the constraint on amino acid changes (i.e. purifying selection), which results in Ka/Ks<1. When a novel function emerges in a gene with strong positive selection involved, Ka/Ks>1 is observed. The Ka/Ks between the c1orf37-dup gene and c1orf37 transcript is 2.08 (0.0073/0.0035, P<0.02, Z-test for normal distribution), significantly higher than that of neutrally evolving sequences, suggesting the rapid evolution of c1orf37-dup driven by positive selection. In contrast, the parental c1orf37 gene itself is a much conserved gene. Its homologues are found from Drosophila to human. In mammals, the Ka/Ks of the coding region across species is very low, e.g. it is 0 between human and chimpanzee, 0.065 between human and mouse, 0.090 between human and rat and 0.072 between mouse and rat, which are comparable to the average Ka/Ks (0.093) for housekeeping genes between human and mouse (19). Furthermore, c1orf37 has maintained a single-copy status in a broad range of species, indicating its crucial function and that its copy number is maintained precisely during evolution (7). Consequently, the Ka/Ks between c1orf37 and c1orf37-dup in humans is 27 times the average Ka/Ks in c1orf37 between human and rodents, reflecting its unusually fast evolution in the short period, since the divergence of human and chimpanzee.
Low level of polymorphism and selective sweep affecting the neighboring regions
Rapid adaptive fixation of a new gene is expected to be reflected by the nucleotide polymorphism pattern in populations, as while selection helps to fix the advantageous mutations, it displaces linked nucleotide polymorphisms in the process (5). For this purpose, we studied nucleotide variation features in the c1orf37-dup gene and the regions in its neighborhood. When we obtained sequences of the coding region from 61 individuals (122 chromosomes) from different continents, only one polymorphic site, a non-synonymous ATG (Met) to GTG (Val) at the 193rd amino acid, was observed. The nucleotide diversity 
is 1.6x10–4 and the frequency of the derived (non-ancestral) GTG codon is high (54%). To obtain more informative sites of nucleotide variation for analyses, we extended sequencing to 280 bp upstream and 139 bp downstream to c1orf37-dup of total 2121 bp in length. The data revealed three more polymorphisms: two singletons locate, respectively, in the 5' flanking region and the 3'-UTR, and a 1 bp deletion (C) in the 5'-UTR that is linked with the 193GTG. A total of four segregation sites constructing four haplotypes were identified in this fragment despite a large number of samples investigated. A low level of polymorphism (=3.5x10–4) compared with the average of the human genome (8.3x10–4) (20) suggests that the evolution of c1orf37-dup has been shaped by a recent selective sweep.
If the selective sweep has been sufficiently recent and strong, its effect can be detected not only in the selected gene but also in the surrounding region (5). We labeled the above 2121 bp fragment harboring c1orf37-dup as region A and selected four neighboring regions (about 1 kb each) dispersed in 13.5 kb assigned as B, C, D and E which do not contain any annotated functional gene for sequencing (Fig. 2). We compared the observed and the expected numbers of variation in the regions following Wang et al. (21) given the expected nucleotide diversity 8.3x10–4 from the average of the human genome (see Methods and Materials), and the probability values (P) are shown in Figure 2. The number of the observed polymorphic sites is significantly lower than the expected (P=0.041) in regions C–D–A, whereas it resumes to match the expected values in regions B and E (P=0.188 and 0.185, respectively). The levels of DNA variation show a trough across this genomic segment, supporting that a strong selective sweep has occurred recently at the c1orf37-dup locus in human populations.
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Cell localization and functionality of c1orf37-dup
The rapid evolution of c1orf37-dup instigates more interests on its functional role in cells. Although the extreme conservation of the C1ORF37 protein (peptide ID NP_612400 [GenBank] .2) has indicated that it is an important protein in organisms, its function is yet unknown; neither is any homology to other genes or functional domains recognized. A structural analysis with TMpred (see Materials and Methods) showed that the C1ORF37 protein contains two predicted transmembrane regions at the amino acids 150–170 (score 835) and 302–321 (score 2224), suggesting a topology of two termini inside the membrane and a loop on the other side. The transient GFP–C1ORF37 fusion protein expression revealed that GFP signal is largely localized at plasma membranes (Fig. 3A and B). As the transmembrane span (150–170) has a strong preference of the orientation from inside to outside and the span (302–312) amino acid has an orientation preference from outside to inside as indicated in the TMpred analysis, the C1ORF37 protein is possibly a Nin–Cin integral protein with an extracellular loop localized on plasma membranes. In the predicted topology, although remaining open for experimental evidence, the cytoplasmic N-terminal region (150 amino acids) contains two low-complexity strings presumably with important functions (from Ensemble). The extracellular hairpin contains 131 amino acids harboring seven cysteines with the potential to form cystine bonds. On the basis of the information, we speculate that the extracellular hairpin may interact with signals from the environment and the N-terminal region is the reactive region responding to the signals. The GFP–C1ORF37–DUP protein maintains the same localization at plasma membranes (Fig. 3C). Comparing to the C1ORF37 protein, we found that the distribution of the amino acid changes in the C1ORF37–DUP protein is not random over the peptide. Among the six replacements, five replacements N44D, P47T, Q64R, C91A and S106N locate in a span of 66 amino acids in the N-terminal region, and the other replacement R197A is in the extracellular loop close to the 193M/V polymorphic site (Fig. 3D). In a pseudogene, non-synonymous substitutions more likely distribute randomly (22
), whereas in a new gene, the changes are expected to evolve in the part of peptide where novel functions may emerge. Therefore, it is implied that novel functions might have evolved in the N-terminal region and the extracellular loop of the C1ORF37–DUP protein.
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Tissue-specific expression
In a retroposition event, the original regulatory elements are generally not co-transferred with the transcript. When mRNA-derived retroposed sequences insert into a promoterless region, they usually degenerate to non-functional pseudogenes (23
,24). However, occasionally retroposition leads to active genes when new retrosequences are supported by resident promoter elements or new promoters evolve fortuitously, which often exhibit a different expression pattern from that of the original founder genes (25). Hence, we investigated the c1orf37-dup's transcription capability and its expression pattern in human tissues. Using c1orf37-dup-specific primers (Table 1), its expression was first detected in brain, which bears the most significant changes between human and other primates (Fig. 4). Next, the expression of c1orf37-dup was revealed by PCR with human cDNA panels in lung, pancreas, thymus, intestine and blood, but it was undetectable in heart, placenta, liver, muscle, kidney, spleen, prostate, testis, ovary or colon (Fig. 4). These results demonstrate that c1orf37-dup is an active gene in transcription and it selectively expresses in several tissues in human. In contrast, the parental c1orf37 expresses ubiquitously in different tissues based on NCBI's Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) and Serial Analysis of Gene Expression map (http://www.ncbi.nlm.nih.gov/SAGE/). These findings indicate that c1orf37-dup has acquired transcription regulatory components and become a new gene variant of the parental c1orf37 gene. Its expression in brain may have important implications relevant to human evolution.
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Overall, our study identifies and characterizes a human-specific gene c1orf37-dup. The rapid evolution driven by positive selection suggests its unusual functional adaptation in humans. As cell membrane proteins are engaged in the information exchanges between cell–cell and cell–environment, the novel functions of the C1ORF37–DUP protein may endow cells in several human tissues including brain to acquire unique properties in communication or interaction, which do not exist in the ancestral species. Future studies on the functions of the c1orf37 and c1orf37-dup genes will help us to disclose how this new gene creation event is related to human-specific traits formation.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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DNA samples
Sixty-one human genomic DNA samples from different populations in Asia, Africa and Europe were used in this study. The samples were obtained from the following collections: the Kunming Cell Bank of the Chinese Academy of Sciences, Human Genetics Center of Yunnan University, Kunming Blood Center and Shanghai National Genome Center in China. Genomic DNAs from three chimpanzees (Pan troglodytes) and one orangutan (Pongo abelii) were isolated from the cell lines from the Kunming Cell Bank of the Chinese Academy of Sciences with PUREGENE DNA Isolation Kit (Gentra Systems). Human sample manipulation was approved by Yunnan University and Kunming Institute of Zoology.
Genomic DNA PCR and sequencing
Primers 18 and 19 (Table 1) located in the flanking regions of c1orf37-dup were used to amplify the fragment containing this gene with 61 humans (122 chromosomes), three chimpanzees and one orangutan. PCR reactions were assembled quickly and carried out with Takara's ExTaq System at a condition of 95°C 3min, 35 cycles of 94°C 30 s, 54°C 30 s and 72°C 2 min, followed by 72°C 10 min with a hot start. PCR products were purified with Qiagen PCR Purification Kit and subject to sequencing. The internal sequencing primers are listed in Table 1.
Four neighboring genomic regions B, C, D and E were PCR amplified with a sample size of 7, 10, 7 and 7 individuals (14, 20, 14 and 14 chromosomes), respectively, and sequenced with their upper and lower primers (Table 1). The PCR condition was 95°C 3 min, 35 cycles of 94°C 30 s, 58°C 30 s and 72°C 1 min, followed by 72°C 7 min with Takara's ExTaq System.
Evolutionary analyses of sequence variation
DNA sequencing reads were assembled, trimmed and aligned with Sequencher 4.0.5 and by manual verification. Synonymous and non-synonymous changes, synonymous and non-synonymous substitution rates and DNA polymorphism (nucleotide diversity ) were calculated using Dnasp 3.51 (26).
Statistical comparison between observed (s) and expected values of variation followed Wang et al. (21). In brief, under the assumption of neutrality, a probability distribution of polymorphism for an expected variation =4Nµ was calculated following the recursion equation (27).
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of the human genome 8.3x10–4 (20) and the chromosome number n=15 were used in the calculation. n=15 was based on 14 chromosomes we sequenced and one chromosome from Entrez sequence.
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Plasmid construction, GFP expression and protein structure prediction
The pEGFP-c1orf37 and pEGFP-c1orf37-dup plasmids were constructed to make GFP tagged proteins for cellular localization investigation. The coding regions of c1orf37 and c1orf37-dup were PCR amplified with the cloning primers (Table 1). The PCR products were digested with BglII and SalI and ligated to pEGFP-C1 vector (Clontech), respectively. Ligations were carried out with T4 ligase (Fermentas) following its protocol. E. Coli DH
5 competent cells were transformed and positive clones were amplified in 3ml overnight cultures. Plasmid DNAs were isolated with Qiagen Miniprep Kit.
HEK293 cells were maintained with DMEM supplemented by 10% new born calf serum and 1% L-glutamine at 37°C with 5% CO2. The pEGFP-c1orf37, pEGFP-c1orf37-dup and vector pEGFP-C1 were transiently expressed in HEK293 cells. Cell spreading and transfection procedures followed the manufacturer's manual of LipofectamineTM 2000 (Invitrogen) in a 24-well plate. Twenty four hours after the transfection, cells were fixed as suggested by the manual and observed with fluorescent microscopy.
TMpred (http://www.ch.embnet.org/software/TMPRED_form.html) was used to predict protein transmembrane region. Scores over 500 were considered significant.
Expression survey with human tissue cDNAs
The expression of c1orf37-dup was investigated by PCR with Human cDNA panels from BD Biosciences, which contained cDNAs from heart, whole brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and blood. Owing to the high degree of sequence similarity between c1orf37 and c1orf37-dup, primers inner-U-D and inner-L-D (Table 1) were designed to amplify exclusively the c1orf37-dup cDNA. The c1orf37 and c1orf37-dup have few nucleotide differences in cDNA sequences. On the basis of these differences, the position of the primers was chosen so that the 3'-ending nucleotide of each primer matches to c1orf37-dup but not c1orf37. In addition, the third nucleotide at the 3' of each primer was mutated, which resulted in a pair of primers for c1orf37-dup with an affordable quantitative loss in PCR product but primers with the least possibility to pick up c1orf37 cDNA because of two 3' mismatching nucleotides. PCRs were performed with Expand High Fidelity PCR System (Roche) under a strict condition at 95°C 10 min, 40 cycles of 94°C 30 s and 68°C 1 min and followed by 68°C 10 min. Resulting PCR fragments were cloned with TOPO TA Cloning Kit for Sequencing (Invitrogen) according to its manual and sequenced to confirm their c1orf37-dup cDNA identity. Sequencing was carried out with the BigDye3.0 protocol using an ABI3100 autosequencer.
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ACKNOWLEDGEMENTS |
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We thank M. Long for constructive discussions, J.J. Emerson for initial computational analysis of the new gene candidates, W. Xiao, K. Kristiansen, K. Thornton and Wang lab members for helpful comments, X. Fan for sequencing and members in the Kunming Cell Bank of the Chinese Academy of Sciences for help in cell culture. We are grateful to F. Yang and F. Wilson for the critical reading of the manuscript. This project was supported by the Key Project KSCX2-SW-121 from Chinese Academy of Sciences to W.W. and B.S., the Science and Technology Key Project 2005NG08 from Yunnan Province and the Western Chinese Region Development Key Project 2004BA901A07 to C.X. and the grant 30560063 from National Science Foundation of China to H.Y.
Conflict of Interest statement. The authors have no conflicts of interest to declare.
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FOOTNOTES |
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The c1orf37-dup gene and its flanking region (region A in Fig. 4B): DQ186292–DQ186413. The neighboring region D: DQ186414–DQ186427, region C: DQ186428–DQ186447, region B: DQ186448–DQ186461 and region E: DQ186462–DQ186475. 
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