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PubMed2001

Nucleotide substitutions and the evolution of duplicate genes.

This paper describes software created to search for and analyze pairs of duplicate genes within a genome. The process is based on a program that uses aligned amino acid sequences to generate a corresponding alignment of the underlying nucleotide sequences and perform a codon by codon comparison of the nucleotides. Observed numbers of nucleotide substitutions can be used to make inferences about the ages of gene duplication events and the effects of natural selection acting on duplicate genes.

Animals↗

PubMed2006

Multiple mechanisms promote the retained expression of gene duplicates in the tetraploid frog Xenopus laevis.

Gene duplication provides a window of opportunity for biological variants to persist under the protection of a co-expressed copy with similar or redundant function. Duplication catalyzes innovation (neofunctionalization), subfunction degeneration (subfunctionalization), and genetic buffering (redundancy), and the genetic survival of each paralog is triggered by mechanisms that add, compromise, or do not alter protein function. We tested the applicability of three types of mechanisms for promoting the retained expression of duplicated genes in 290 expressed paralogs of the tetraploid clawed frog, Xenopus laevis. Tests were based on explicit expectations concerning the ka/ks ratio, and the number and location of nonsynonymous substitutions after duplication. Functional constraints on the majority of paralogs are not significantly different from a singleton ortholog. However, we recover strong support that some of them have an asymmetric rate of nonsynonymous substitution: 6% match predictions of the neofunctionalization hypothesis in that (1) each paralog accumulated nonsynonymous substitutions at a significantly different rate and (2) the one that evolves faster has a higher ka/ks ratio than the other paralog and than a singleton ortholog. Fewer paralogs (3%) exhibit a complementary pattern of substitution at the protein level that is predicted by enhancement or degradation of different functional domains, and the remaining 13% have a higher average ka/ks ratio in both paralogs that is consistent with altered functional constraints, diversifying selection, or activity-reducing mutations after duplication. We estimate that these paralogs have been retained since they originated by genome duplication between 21 and 41 million years ago. Multiple mechanisms operate to promote the retained expression of duplicates in the same genome, in genes in the same functional class, over the same period of time following duplication, and sometimes in the same pair of paralogs. None of these paralogs are superfluous; degradation or enhancement of different protein subfunctions and neofunctionalization are plausible hypotheses for the retained expression of some of them. Evolution of most X. laevis paralogs, however, is consistent with retained expression via mechanisms that do not radically alter functional constraints, such as selection to preserve post-duplication stoichiometry or temporal, quantitative, or spatial subfunctionalization.

Amino Acid Substitution↗

PubMed1995

Benzene induces gene-duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans.

Occupational exposure to benzene is known to cause leukemia, but the mechanism remains unclear. Unlike most other carcinogens, benzene and its metabolites are weakly or nonmutagenic in most simple gene mutation assays. Benzene and its metabolites do, however, produce chromosomal damage in a variety of systems. Here, we have used the glycophorin A (GPA) gene loss mutation assay to evaluate the nature of DNA damage produced by benzene in 24 workers heavily exposed to benzene and 23 matched control individuals in Shanghai, China. The GPA assay identifies stem cell or precursor erythroid cell mutations expressed in peripheral erythrocytes of MN-heterozygous subjects, distinguishing the NN and N phi mutant variants. A significant increase in the NN GPA variant cell frequency (Vf) was found in benzene-exposed workers as compared with unexposed control individuals (mean +/- SEM, 13.9 +/- 1.7 per million cells vs. 7.4 +/- 1.1 per million cells in control individuals; P = 0.0002). In contrast, no significant difference existed between the two groups for the N phi Vf (9.1 +/- 0.9 vs. 8.8 +/- 1.8 per million cells; P = 0.21). Further, lifetime cumulative occupational exposure to benzene was associated with the NN Vf (P = 0.005) but not with the N phi Vf (P = 0.31), suggesting that NN mutations occur in longer-lived bone marrow stem cells. NN variants result from loss of the GPA M allele and duplication of the N allele, presumably through recombination mechanisms, whereas NO variants arise from gene inactivation, presumably due to point mutations and deletions. Thus, these results suggest that benzene produces gene-duplicating mutations but does not produce gene-inactivating mutations at the GPA locus in bone marrow cells of humans exposed to high benzene levels. This finding is consistent with data on the genetic toxicology of benzene and its metabolites and adds further weight to the hypothesis that chromosome damage and mitotic recombination are important in benzene-induced leukemia.

Adolescent↗

PubMed2002

Asymmetric functional divergence of duplicate genes in yeast.

Most duplicate genes are eliminated from a genome shortly after duplication, but those that remain are an important source of biochemical diversity. Here, I present evidence from genome-scale protein-protein interaction data, microarray expression data, and large-scale gene knockout data that this diversification is often asymmetrical: one duplicate usually shows significantly more molecular or genetic interactions than the other. I propose a model that can explain this divergence pattern if asymmetrically diverging duplicate gene pairs show increased robustness to deleterious mutations.

Environment↗

PubMed2003

Frequent segmental sequence exchanges and rapid gene duplication characterize the MHC class I genes in lemurs.

Major histocompatibility complex (MHC) class I genes have complicated and profound evolutionary histories. To reconstruct and better understand their histories, partial class I genes (exon 2-intron 2-exon 3) were sequenced in a sampling of prosimians (Strepsirhini, Primates). In total, we detected 117 different sequences from 36 Malagasy prosimians (lemurs) and 1 non-Malagasy prosimian (galago) representing 4 families, 7 genera, and 13 species. Unlike the MHC class II genes ( MHC-DRB), MHC class I genes show a generally genus-specific mode of evolution in lemurs. Additionally, no prosimian class I loci were found to be orthologous to HLA genes, even at highly conserved loci (such as HLA-E, HLA-F). Phylogenetic analysis indicates that nucleotide diversity among loci was very small and the persistence time of the polymorphisms was short, suggesting that the origin of the lemur MHC class I genes detected in this study was relatively recent. The evolutionary mode of these genes is similar to that of classic HLA genes, HLA-A, HLA-B, and HLA-C, in terms of their recent origin and rarity of pseudogenes, and differs from them with respect to the degree of gene duplications. From the viewpoint of MHC genes evolution, some interlocus sequence exchanges were apparently observed in the lemur lineage upon phylogenetic and amino acid motif analyses. This is also in contrast to the evolutionary mode of HLA genes, where intralocus exchanges have certainly occurred but few interlocus exchanges have taken place. Consequently, the gene conversion model for explaining the generation of the MHC diversity among different loci can be thought to play more important roles in the evolution of lemur MHC class I genes than in that of HLA genes.

Animals↗

PubMed1984

Evolution of aspartyl proteases by gene duplication: the mouse renin gene is organized in two homologous clusters of four exons.

Overlapping recombinant clones that appear to encompass the entire renin gene, named Ren 1, have been isolated from a library of BALB/c mouse genomic DNA fragments. Based on restriction endonuclease mapping and DNA sequence analysis, Ren 1 spans 9.6 kb and contains nine exons interrupted by eight intervening sequences of highly variable size. The first exon, encoding the signal peptide of preprorenin, is separated from the eight following exons by a 3-kb intron. These eight exons are organized into two clusters of four separated by a 2-kb intron. DNA stretches encoding the aspartyl residues, which are part of the active site of renin, are located at homologous positions in both clusters. Our results show that aspartyl protease genes have arisen by duplication and fusion of an ancestral gene containing five exons. The estimated date of the duplication event of the mouse renin genes Ren 1 and Ren 2 is discussed.

Amino Acid Sequence↗

PubMed2006

Functional analysis of gene duplications in Saccharomyces cerevisiae.

Gene duplication can occur on two scales: whole-genome duplications (WGD) and smaller-scale duplications (SSD) involving individual genes or genomic segments. Duplication may result in functionally redundant genes or diverge in function through neofunctionalization or subfunctionalization. The effect of duplication scale on functional evolution has not yet been explored, probably due to the lack of global knowledge of protein function and different times of duplication events. To address this question, we used integrated Bayesian analysis of diverse functional genomic data to accurately evaluate the extent of functional similarity and divergence between paralogs on a global scale. We found that paralogs resulting from the whole-genome duplication are more likely to share interaction partners and biological functions than smaller-scale duplicates, independent of sequence similarity. In addition, WGD paralogs show lower frequency of essential genes and higher synthetic lethality rate, but instead diverge more in expression pattern and upstream regulatory region. Thus, our analysis demonstrates that WGD paralogs generally have similar compensatory functions but diverging expression patterns, suggesting a potential of distinct evolutionary scenarios for paralogs that arose through different duplication mechanisms. Furthermore, by identifying these functional disparities between the two types of duplicates, we reconcile previous disputes on the relationship between sequence divergence and expression divergence or essentiality.

Bayes Theorem↗

PubMed2003

Genomic and phylogenetic analysis of the S100A7 (Psoriasin) gene duplications within the region of the S100 gene cluster on human chromosome 1q21.

The human S100 gene family encodes the EF-hand superfamily of calcium-binding proteins, with at least 14 family members clustered relatively closely together on chromosome 1q21. We have analyzed the most recently available genomic sequence of the human S100 gene cluster for evidence of tandem gene duplications during primate evolutionary history. The sequences obtained from both GenBank and GoldenPath were analyzed in detail using various comparative sequence analysis tools. We found that of the S100A genes clustered relatively closely together within a genomic region of 260 kb, only the S100A7 (psoriasin) gene region showed evidence of recent duplications. The S100A7 gene duplicated region is composed of three distinct genomic regions, 33, 11, and 31 kb, respectively, that together harbor at least five identifiable S100A7-like genes. Regions 1 and 3 are in opposite orientation to each other, but each region carries two S100A7-like genes separated by an 11-kb intergenic region (region 2) that has only one S100A7-like gene, providing limited sequence resemblance to regions 1 and 3. The duplicated genomic regions 1 and 3 share a number of different retroelements including five Alu subfamily members that serve as molecular clocks. The shared (paralogous) Alu S insertions suggest that regions 1 and 3 were probably duplicated during or after the phase of AluS amplification some 30-40 mya. We used PCR to amplify an indel within intron 1 of the S100A7a and S100A7c genes that gave the same two expected product sizes using 40 human DNA samples and 1 chimpanzee sample, therefore confirming the presence of the region 1 and 3 duplication in these species. Comparative genomic analysis of the other S100 gene members shows no similarity between intergenic regions, suggesting that they diverged long before the emergence of the primates. This view was supported by the phylogenetic analysis of different human S100 proteins including the human S100A7 protein members. The S100A7 protein, also known as psoriasin, has important functions as a mediator and regulator in skin differentiation and disease (psoriasis), in breast cancer, and as a chemotactic factor for inflammatory cells. This is the first report of five copies of the S100A7 gene in the human genome, which may impact on our understanding of the possible dose effects of these genes in inflammation and normal skin development and pathogenesis.

Amino Acid Sequence↗

PubMed2004

Very low gene duplication rate in the yeast genome.

The gene duplication rate in the yeast genome is estimated without assuming the molecular clock model to be approximately 0.01 to 0.06 per gene per billion years; this rate is two orders of magnitude lower than a previous estimate based on the molecular clock model. This difference is explained by extensive concerted evolution via gene conversion between duplicated genes, which violates the assumption of the molecular clock in the analyses of duplicated genes. The average length of the period of concerted evolution and the gene conversion rate are estimated to be approximately 25 million years and approximately 28 times the mutation rate, respectively.

Evolution, Molecular↗

PubMed1998

Duplicate genes and the root of angiosperms, with an example using phytochrome sequences.

The root of the angiosperm tree has not yet been established. Major morphological and molecular differences between angiosperms and other seed plants have introduced ambiguities and possibly spurious results. Because it is unlikely that extant species more closely related to angiosperms will be discovered, and because relevant fossils will almost certainly not yield molecular data, the use of duplicate genes for rooting purposes may provide the best hope of a solution. Simultaneous analysis of the genes resulting from a gene duplication event along the branch subtending angiosperms would yield an unrooted network, wherein two congruent gene trees should be connected by a single branch. In these circumstances the best rooted species tree is the one that corresponds to the two gene trees when the network is rooted along the connecting branch. In general, this approach can be viewed as choosing among rooted species trees by minimizing hypothesized events such as gene duplication, gene loss, lineage sorting, and lateral transfer. Of those gene families that are potentially relevant to the angiosperm problem, phytochrome genes warrant special attention. Phylogenetic analysis of a sample of complete phytochrome (PHY) sequences implies that an initial duplication event preceded (or occurred early within) the radiation of seed plants and that each of the two resulting copies duplicated again. In one of these cases, leading to the PHYA and PHYC lineages, duplication appears to have occurred before the diversification of angiosperms. Duplicate gene trees are congruent in these broad analyses, but the sample of sequences is too limited to provide much insight into the rooting question. Preliminary analyses of partial PHYA and PHYC sequences from several presumably basal angiosperm lineages are promising, but more data are needed to critically evaluate the power of these genes to resolve the angiosperm radiation.

Genes, Plant↗

PubMed2000

Expression of sox11 gene duplicates in zebrafish suggests the reciprocal loss of ancestral gene expression patterns in development.

To investigate the role of sox genes in vertebrate development, we have isolated sox11 from zebrafish (Danio rerio). Two distinct classes of sox11-related cDNAs were identified, sox11a and sox11b. The predicted protein sequences shared 75% identity. In a gene phylogeny, both sox11a and sox11b cluster with human, mouse, chick, and Xenopus Sox11, indicating that zebrafish, like Xenopus, has two orthologues of tetrapod Sox11. The work reported here investigates the evolutionary origin of these two gene duplicates and the consequences of their duplication for development. The sox11a and sox11b genes map to linkage groups 17 and 20, respectively, together with other loci whose orthologues are syntenic with human SOX11, suggesting that during the fish lineage, a large chromosome region sharing conserved syntenies with mammals has become duplicated. Studies in mouse and chick have shown that Sox11 is expressed in the central nervous system during development. Expression patterns of zebrafish sox11a and sox11b confirm that they are expressed in the developing nervous system, including the forebrain, midbrain, hindbrain, eyes, and ears from an early stage. Other sites of expression include the fin buds and somites. The two sox genes, sox11a and sox11b, are expressed in both overlapping and distinct sites. Their expression patterns suggest that sox11a and sox11b may share the developmental domains of the single Sox11 gene present in mouse and chick. For example, zebrafish sox11a is expressed in the anterior somites, and zebrafish sox11b is expressed in the posterior somites, but the single Sox11 gene of mouse is expressed in all the somites. Thus, the zebrafish duplicate genes appear to have reciprocally lost expression domains present in the sox11 gene of the last common ancestor of tetrapods and zebrafish. This splitting of the roles of Sox11 between two paralogues suggests that regulatory elements governing the expression of the sox11 gene in the common ancestor of zebrafish and tetrapods may have been reciprocally mutated in the zebrafish gene duplicates. This is consistent with duplicate gene evolution via a duplication-degeneration-complementation process.

Amino Acid Sequence↗

PubMed2003

The fates of zebrafish Hox gene duplicates.

In his 1970 book, Susumu Ohno stressed the importance of gene duplication in the evolution of the vertebrate genome and body plan. He elaborated the idea that duplication events provide novel genetic material on which evolution may act. Data are accumulating to show that extensive duplication events, perhaps incorporating the duplication of entire genomes, occurred in the lineage leading to teleost fishes. These duplications may have been pivotal in the explosive radiation of this highly successful vertebrate group. Thus, the teleosts provide us with an ideal opportunity to investigate the fates and functions of duplicated genes. A convenient system for these studies is the zebrafish, Danio rerio, which has become a popular genetic and embryological model.

Animals↗

PubMed2001

Two C or not two C: recurrent disruption of Zn-ribbons, gene duplication, lineage-specific gene loss, and horizontal gene transfer in evolution of bacterial ribosomal proteins.

BACKGROUND: Ribosomal proteins are encoded in all genomes of cellular life forms and are, generally, well conserved during evolution. In prokaryotes, the genes for most ribosomal proteins are clustered in several highly conserved operons, which ensures efficient co-regulation of their expression. Duplications of ribosomal-protein genes are infrequent, and given their coordinated expression and functioning, it is generally assumed that ribosomal-protein genes are unlikely to undergo horizontal transfer. However, with the accumulation of numerous complete genome sequences of prokaryotes, several paralogous pairs of ribosomal protein genes have been identified. Here we analyze all such cases and attempt to reconstruct the evolutionary history of these ribosomal proteins. RESULTS: Complete bacterial genomes were searched for duplications of ribosomal proteins. Ribosomal proteins L36, L33, L31, S14 are each duplicated in several bacterial genomes and ribosomal proteins L11, L28, L7/L12, S1, S15, S18 are so far duplicated in only one genome each. Sequence analysis of the four ribosomal proteins, for which paralogs were detected in several genomes, two of the ribosomal proteins duplicated in one genome (L28 and S18), and the ribosomal protein L32 showed that each of them comes in two distinct versions. One form contains a predicted metal-binding Zn-ribbon that consists of four conserved cysteines (in some cases replaced by histidines), whereas, in the second form, these metal-chelating residues are completely or partially replaced. Typically, genomes containing paralogous genes for these ribosomal proteins encode both versions, designated C+ and C-, respectively. Analysis of phylogenetic trees for these seven ribosomal proteins, combined with comparison of genomic contexts for the respective genes, indicates that in most, if not all cases, their evolution involved a duplication of the ancestral C+ form early in bacterial evolution, with subsequent alternative loss of the C+ and C- forms in different lineages. Additionally, evidence was obtained for a role of horizontal gene transfer in the evolution of these ribosomal proteins, with multiple cases of gene displacement 'in situ', that is, without a change of the gene order in the recipient genome. CONCLUSIONS: A more complex picture of evolution of bacterial ribosomal proteins than previously suspected is emerging from these results, with major contributions of lineage-specific gene loss and horizontal gene transfer. The recurrent theme of emergence and disruption of Zn-ribbons in bacterial ribosomal proteins awaits a functional interpretation.

Bacterial Proteins↗

PubMed2005

The evolutionary dynamics of plant duplicate genes.

Given the prevalence of duplicate genes and genomes in plant species, the study of their evolutionary dynamics has been a focus of study in plant evolutionary genetics over the past two decades. The past few years have been a particularly exciting time because recent theoretical and experimental investigations have led to a rethinking of the classic paradigm of duplicate gene evolution. By combining recent advances in genomic analysis with a new conceptual framework, researchers are determining the contributions of single-gene and whole-genome duplications to the diversification of plant species. This research provides insights into the roles that gene and genome duplications play in plant evolution.

Evolution, Molecular↗

PubMed2000

Organizations and gene duplications of the human and mouse MHC complement gene clusters.

The MHC complement gene cluster (MCGC) in most people contains thirteen structural genes, pseudogenes and gene segments. Novel genes RD, SKI2W, DOM3Z and RP1 are organized as two head-to-head gene pairs between complement gene Bf and the first locus of C4. Southern blot analysis shows that single-copy genes for DOM3Z are detectable in primates and other mammals. Sequence analyses revealed that the exon- intron structures of human and mouse DOM3Z genes are identical. Both human and mouse DOM3Z transcripts exhibit splice variants at the 5' regions, although the open reading frames remain identical. Cloning and characterization of the mouse RP1 cDNA revealed a reading frame for 254 amino acids with a bipartite nuclear localization signal close to the amino terminus. The mouse RP1 gene consists of 7 exons and spans 12.9 kb. Located in intron 4 of mouse RP1 is an endogenous retrovirus that probably confers the androgen-responsive expression of the Slp protein in certain male mice. The availability of the complete human and mouse MCGC genomic and cDNA sequences allows further deliberate analyses of gene duplications and evolution. The intergenic region between mouse SLP and C4 genes is more than six times larger than the corresponding region in humans. It contains the functional gene steroid CYP21A, long stretches of repetitive DNA elements, and three partially duplicated gene segments TNXA, SKI2W2 and RP2. The modular duplications of human and mouse RP-C4-CYP21-TNX (RCCX) are sharply different as SKI2W2 is absent in the human MCGC, and TNXA and RP2 are smaller in size but higher in sequence conservation in humans.

Amino Acid Sequence↗

PubMed2005

Expression divergence between duplicate genes.

A general picture of the role of expression divergence in the evolution of duplicate genes is emerging, thanks to the availability of completely sequenced genomes and functional genomic data, such as microarray data. It is now clear that expression divergence, regulatory-motif divergence and coding-sequence divergence all increase with the age of duplicate genes, although their exact interrelationships remain to be determined. It is also clear that gene duplication increases expression diversity and enables tissue or developmental specialization to evolve. However, the relative roles of subfunctionalization and neofunctionalization in the retention of duplicate genes remain to be clarified, especially for higher eukaryotes. In addition, the relationship between gene duplication and evolution of transcriptional regulatory networks is largely unexplored.

Evolution, Molecular↗

PubMed2006

A novel approach for characterizing expression levels of genes duplicated by polyploidy.

Studying gene expression in polyploids is complicated by genomewide gene duplication and the problem of distinguishing transcript pools derived from each of the two homeologous genomes such as the A- and D-genomes of allotetraploid Gossypium. Short oligonucleotide probes designed to specifically target several hundred homeologous gene pairs of Gossypium were printed on custom NimbleGen microarrays. These results demonstrate that relative expression levels of homeologous genes may be measured by microarrays and that deviation from equal expression levels of homeologous loci may be common in the allotetraploid nucleus of Gossypium.

Base Sequence↗

PubMed2001

Pattern and timing of gene duplication in animal genomes.

Duplication of genes, giving rise to multigene families, has been a characteristic feature of the evolution of eukaryotic genomes. In the case of vertebrates, it has been proposed that an increase in gene number resulted from two rounds of duplication of the entire genome by polyploidization (the 2R hypothesis). In the most extensive test to date of this hypothesis, we compared gene numbers in homologous families and conducted phylogenetic analyses of gene families with two to eight members in the complete genomes of Caenorhabditis elegans and Drosophila melanogaster and the available portion of the human genome. Although the human genome showed a higher proportion of recent gene duplications than the other animal genomes, the proportion of duplications after the deuterostome-protostome split was constant across families, with no peak of such duplications in four-member families, contrary to the expectation of the 2R hypothesis. A substantial majority (70.9%) of human four-member families and four-member clusters in larger families showed topologies inconsistent with two rounds of polyploidization in vertebrates.

Animals↗