The coalescent with selection on copy number variants

We develop a coalescent-based simulation tool to generate patterns of single nucleotide polymorphisms (SNPs) in a wide region encompassing both the original and duplicated genes. Selection on the new duplicated copy and interlocus gene conversion between the two copies are incorporated. This simulation enables us to explore how selection on duplicated copies affects the pattern of SNPs. The fixation of an advantageous duplicated copy causes a strong reduction in polymorphism not only in the duplicated copy but also in its flanking regions, which is a typical signature of a selective sweep by positive selection. After fixation, polymorphism gradually increases by accumulating neutral mutations and eventually reaches the equilibrium value if there is no gene conversion. When gene conversion is active, the number of SNPs in the duplicated copy quickly increases by transferring SNPs from the original copy; therefore, the time when we can recognize the signature of selection is decreased. Because this effect of gene conversion is restricted only to the duplicated region, more power to detect selection is expected if a flanking region to the duplicated copy is used.     

Sequence-Dependent Gene Conversion: Can Duplicated Genes Diverge Fast Enough to Escape Conversion?

Conversion between duplicated genes limits their independent evolution. Models in which conversion frequencies decrease as genes diverge are examined to determine conditions under which genes can "escape" further conversion and hence escape from a gene family. A review of results from various recombination systems suggests two classes of sequence-dependence models: (1) the "k-hit" model in which conversion is completely inactivated by a few (k) mutational events, such as the insertion of a mobile element, and (2) more general models where conversion frequency gradually declines as genes diverge through the accumulation of point mutants. Exact analysis of the k-hit model is given and an approximate analysis of a more general sequence-dependent model is developed and verified by computer simulation. If mu is the per nucleotide mutation rate, then neutral duplicated genes diverging through point mutants are likely to escape conversion provided 2 mu/lambda much greater than 0.1, where lambda is the conversion rate between identical genes. If 2 mu/lambda much less than 0.1, the expected number of conversions before escape increases exponentially so that, for biological purposes, the genes never escape conversion. For single mutational events sufficient to block further conversions, occurring at rate nu per copy per generation, many conversions are expected if 2 nu/lambda much less than 1, while the genes essentially evolve independently if 2 nu/lambda much greater than 1. Implications of these results for both models of concerted evolution and the evolution of new gene functions via gene duplication are discussed.     

Preservation of a pseudogene by gene conversion and diversifying selection

Interlocus gene conversion is considered a crucial mechanism for generating novel combinations of polymorphisms in duplicated genes. The importance of gene conversion between duplicated genes has been recognized in the major histocompatibility complex and self-incompatibility genes, which are likely subject to diversifying selection. To theoretically understand the potential role of gene conversion in such situations, forward simulations are performed in various two-locus models. The results show that gene conversion could significantly increase the number of haplotypes when diversifying selection works on both loci. We find that the tract length of gene conversion is an important factor to determine the efficacy of gene conversion: shorter tract lengths can more effectively generate novel haplotypes given the gene conversion rate per site is the same. Similar results are also obtained when one of the duplicated genes is assumed to be a pseudogene. It is suggested that a duplicated gene, even after being silenced, will contribute to increasing the variability in the other locus through gene conversion. Consequently, the fixation probability and longevity of duplicated genes increase under the presence of gene conversion. On the basis of these findings, we propose a new scenario for the preservation of a duplicated gene: when the original donor gene is under diversifying selection, a duplicated copy can be preserved by gene conversion even after it is pseudogenized.     

Theories for analyzing polymorphism data in duplicated genes

A simple model for the evolutionary process of a pair of duplicated genes under concerted evolution is developed. The model considers mutation, recombination and gene conversion between two genes in a finite population. Based on diffusion theory, the expected amount of DNA variation within and between two genes are obtained. To investigate the pattern of DNA polymorphism, a coalescent tool to simulate patterns of polymorphism is developed. The theoretical results are well in agreement with polymorphism data in duplicated genes. The effect of selection on the pattern of polymorphism is also considered.     

Conserved functions of yeast genes support the duplication, degeneration and complementation model for gene duplication

Gene duplication is often cited as a potential mechanism for the evolution of new traits, but this hypothesis has not been thoroughly tested experimentally. A classical model of gene duplication states that after gene duplication one copy of the gene preserves the ancestral function, while the other copy is free to evolve a new function. In an alternative duplication, divergence, and complementation model, duplicated genes are preserved because each copy of the gene loses some, but not all, of its functions through degenerating mutations. This results in the degenerating mutations in one gene being complemented by the other and vice versa. These two models make very different predictions about the function of the preduplication orthologs in closely related species. These predictions have been tested here for several duplicated yeast genes that appeared to be the leading candidates to fit the classical model. Surprisingly, the results show that duplicated genes are maintained because each copy carries out a subset of the conserved functions that were already present in the preduplication gene. Therefore, the results are not consistent with the classical model, but instead fit the duplication, divergence, and complementation model.     

Selection for functional uniformity of tuf duplicates in gamma-proteobacteria

Having an extra copy of a gene is thought to provide some functional redundancy, which results in a higher rate of evolution in duplicated genes. In this article, we estimate the impact of gene duplication on the selection of tuf paralogs, and we find that in the absence of gene conversion, tuf paralogs have evolved significantly slower than when gene conversion has been a factor in their evolution. Thus, tuf gene copies evolve under a selective pressure that ensures their functional uniformity, and gene conversion reduces selection against amino acid substitutions that affect the function of the encoded protein, EF-Tu.     

Nucleotide variation of the duplicated amylase genes in Drosophila kikkawai

We examined levels and patterns of the nucleotide polymorphism of the Amylase genes with a head-to-head duplication in Drosophila kikkawai. The levels of variation in D. kikkawai were comparable to those in Drosophila melanogaster. Tajima's test, Fu and Li's test, HKA test, and MK test did not show significant departure from neutrality. We found an excess of replacement changes in the within-locus class, representing polymorphism in one of the duplicated genes, compared with the between-locus class, representing polymorphism shared between the duplicated genes. Most replacement changes in the within-locus class were singletons. These results suggest that most replacement changes are deleterious. A contrasting evolutionary pattern, involving concerted evolution in the coding regions but differential evolution in the 5'-flanking regions, was observed. However, unlike the duplicated Amy genes of D. melanogaster, the coding regions of the duplicated genes in D. kikkawai tended to diverge. Using Ohta's model of the small multigene family, we found that recombination (interchromosomal equal crossing-over) rate was one order higher than gene conversion (unequal crossing-over) rate, resulting in a considerable but incomplete homogenization of the duplicated coding regions. Linkage disequilibria were found in the intron as well as within and around the regulatory cis-element sequences of one of the duplicated genes (Amy1). The possible causes of these linkage disequilibria were discussed.     

Role of gene duplication in evolution

It is now known that many multigene and supergene families exist in eukaryote genomes: multigene families with uniform copy members like genes for ribosomal RNA, those with variable members like immunoglobulin genes, and supergene families such as those for various growth factor and hormone receptors. Many such examples indicate that gene duplication and subsequent differentiation are extremely important for organismal evolution. In particular, gene duplication could well have been the primary mechanism for the evolution of complexity in higher organisms. Population genetic models for the origin of gene families with diverse functions are presented, in which natural selection favors those genomes with more useful mutants in duplicated genes. Since any gene has a certain probability of degenerating by mutation, success versus failure in acquiring a new gene by duplication may be expressed as the ratio of probabilities of spreading of useful versus detrimental mutations in redundant gene copies. Also examined are the effects of gene duplication on evolution by compensatory advantageous mutations. Results of the analyses show that both natural selection and random drift are important for the origin of gene families. In addition, interaction between molecular mechanisms such as unequal crossing-over and gene conversion, and selection or drift is found to have a large effect on evolution by gene duplication.     

African trypanosome glucose transporter genes: organization and evolution of a multigene family

Trypanosoma brucei brucei (EATRO-164) contains a tandem array of six genes encoding a glucose transporter, THT1 (trypanosome hexose transporter), followed by five genes encoding a second isoform, THT2. Two distinct clusters containing THT1 and THT2 genes have been identified in the EATRO-164 clone and in most other African trypanosome clones analyzed. Analysis of progeny from crosses between clones of T. b. brucei displaying polymorphism in THT1 copy number per cluster suggests that the two clusters of THT genes are present on homologous chromosomes. In addition, analysis of 30 African trypanosome clones revealed a high degree of polymorphism in THT1 copy number per cluster. Sequence comparison of five THT1 and two and one-half THT2 unit repeats, present within a 20-kb region, provided information about the genesis and evolution of the THT multigene family. The most divergent regions between THT1 and THT2 unit repeats probably arose from insertion of DNA fragments into an ancestral THT region. Genes of each of the different families are almost identical, and there are large regions of identity shared between THT1 and THT2 members. A mosaic copy containing most of a THT1 gene with the 3' extremity of a THT2 gene is found within the cluster. These results suggest that THT1 and THT2 arose by modification (insertion, mutation, or conversion) of duplicated ancestral genes. Functional constraints and homologous recombination may be evoked to explain the maintenance of the conserved sequences of THT1 and THT2.      

The major shifts of human duplicated genes

Since many gene duplications in the human genome are ancient duplications going back to the origin of vertebrates, the question may be asked about the fate of such duplicated genes at the compositional genome transitions that occurred between cold- and warm-blooded vertebrates. Indeed, at that transition, about half of the (GC-poor) genes of cold-blooded vertebrates (the genes of the gene-dense "ancestral genome core") underwent a GC enrichment to become the genes of the "genome core" of warm-blooded vertebrates. Since the compositional distribution of the human duplicated genes investigated (1111 pairs) mimics the general distribution of human genes (about 50% GC(3)-poor and 50% GC(3)-rich genes, the border being at 60% GC(3)), we considered two possibilities, namely that the compositional transition affected either (i) about half of the copies on a random basis, or (ii) preferentially only one copy of the duplicated genes. The two possibilities could be distinguished if each copy is put into one of two subsets according to its GC(3) level. Indeed, in the first case, the two distributions would be similar, whereas in the second case, the two distributions would be different, one copy having maintained the ancestral GC-poor composition, and one copy having undergone the compositional change. Using this approach, we could show that, by far and large, one copy of the duplicated genes preferentially underwent the GC enrichment. This result implies that this copy, which had possibly acquired a different function and/or regulation, was preferentially translocated into the gene-dense compartment of the genome, the "ancestral genome core", namely the "gene space" which underwent the compositional transition at the emergence of warm-blooded vertebrates.     

Expression partitioning between genes duplicated by polyploidy under abiotic stress and during organ development

Allopolyploidy has been a prominent mode of speciation and a recurrent process during plant evolution and has contributed greatly to the large number of duplicated genes in plant genomes [1-4]. Polyploidy often leads to changes in genome organization and gene expression [5-9]. The expression of genes that are duplicated by polyploidy (termed homeologs) can be partitioned between the duplicates so that one copy is expressed and functions only in some organs and the other copy is expressed only in other organs, indicative of subfunctionalization [10]. To determine how homeologous-gene expression patterns change during organ development and in response to abiotic stress conditions, we have examined expression of the alcohol dehydrogenase gene AdhA in allopolyploid cotton (Gossypium hirsutum). Expression ratios of the two homeologs vary considerably during the development of organs from seedlings and fruits. Abiotic stress treatments, including cold, dark, and water submersion, altered homeologous-gene expression. Most notably, only one copy is expressed in hypocotyls during a water-submersion treatment, and only the other copy is expressed during cold stress. These results imply that subfunctionalization of genes duplicated by polyploidy has occurred in response to abiotic stress conditions. Partitioning of duplicate gene expression in response to environmental stress may lead to duplicate gene retention during subsequent evolution.     

The effect of gene conversion on the divergence between duplicated genes

Nonindependent evolution of duplicated genes is called concerted evolution. In this article, we study the evolutionary process of duplicated regions that involves concerted evolution. The model incorporates mutation and gene conversion: the former increases d, the divergence between two duplicated regions, while the latter decreases d. It is demonstrated that the process consists of three phases. Phase I is the time until d reaches its equilibrium value, d(0). In phase II d fluctuates around d(0), and d increases again in phase III. Our simulation results demonstrate that the length of concerted evolution (i.e., phase II) is highly variable, while the lengths of the other two phases are relatively constant. It is also demonstrated that the length of phase II approximately follows an exponential distribution with mean tau, which is a function of many parameters including gene conversion rate and the length of gene conversion tract. On the basis of these findings, we obtain the probability distribution of the level of divergence between a pair of duplicated regions as a function of time, mutation rate, and tau. Finally, we discuss potential problems in genomic data analysis of duplicated genes when it is based on the molecular clock but concerted evolution is common.     

Role of selection in fixation of gene duplications

New genes commonly appear through complete or partial duplications of pre-existing genes. Duplications of long DNA segments are constantly produced by rare mutations, may become fixed in a population by selection or random drift, and are subject to divergent evolution of the paralogous sequences after fixation, although gene conversion can impede this process. New data shed some light on each of these processes. Mutations which involve duplications can occur through at least two different mechanisms, backward strand slippage during DNA replication and unequal crossing-over. The background rate of duplication of a complete gene in humans is 10(-9)-10(-10) per generation, although many genes located within hot-spots of large-scale mutation are duplicated much more often. Many gene duplications affect fitness strongly, and are responsible, through gene dosage effects, for a number of genetic diseases. However, high levels of intrapopulation polymorphism caused by presence or absence of long, gene-containing DNA segments imply that some duplications are not under strong selection. The polymorphism to fixation ratios appear to be approximately the same for gene duplications and for presumably selectively neutral nucleotide substitutions, which, according to the McDonald-Kreitman test, is consistent with selective neutrality of duplications. However, this pattern can also be due to negative selection against most of segregating duplications and positive selection for at least some duplications which become fixed. Patterns in post-fixation evolution of duplicated genes do not easily reveal the causes of fixations. Many gene duplications which became fixed recently in a variety of organisms were positively selected because the increased expression of the corresponding genes was beneficial. The effects of gene dosage provide a unified framework for studying all phases of the life history of a gene duplication. Application of well-known methods of evolutionary genetics to accumulating data on new, polymorphic, and fixed duplication will enhance our understanding of the role of natural selection in the evolution by gene duplication.     

Duplication and Gene Conversion in the Drosophila melanogaster Genome

Using the genomic sequences of Drosophila melanogaster subgroup, the pattern of gene duplications was investigated with special attention to interlocus gene conversion. Our fine-scale analysis with careful visual inspections enabled accurate identification of a number of duplicated blocks (genomic regions). The orthologous parts of those duplicated blocks were also identified in the D. simulans and D. sechellia genomes, by which we were able to clearly classify the duplicated blocks into post- and pre-speciation blocks. We found 31 post-speciation duplicated genes, from which the rate of gene duplication (from one copy to two copies) is estimated to be 1.0×10⁻⁹ per single-copy gene per year. The role of interlocus gene conversion was observed in several respects in our data: (1) synonymous divergence between a duplicated pair is overall very low. Consequently, the gene duplication rate would be seriously overestimated by counting duplicated genes with low divergence; (2) the sizes of young duplicated blocks are generally large. We postulate that the degeneration of gene conversion around the edges could explain the shrinkage of “identifiable” duplicated regions; and (3) elevated paralogous divergence is observed around the edges in many duplicated blocks, supporting our gene conversion–degeneration model. Our analysis demonstrated that gene conversion between duplicated regions is a common and genome-wide phenomenon in the Drosophila genomes, and that its role should be especially significant in the early stages of duplicated genes. Based on a population genetic prediction, we applied a new genome-scan method to test for signatures of selection for neofunctionalization and found a strong signature in a pair of transporter genes.     

Evolutionary Dynamics of Recently Duplicated Genes: Selective Constraints on Diverging Paralogs in the <Emphasis Type="Italic">Drosophila pseudoobscura</Emphasis> Genome

Duplicated genes produce genetic variation that can influence the evolution of genomes and phenotypes. In most cases, for a duplicated gene to contribute to evolutionary novelty it must survive the early stages of divergence from its paralog without becoming a pseudogene. I examined the evolutionary dynamics of recently duplicated genes in the Drosophila pseudoobscura genome to understand the factors affecting these early stages of evolution. Paralogs located in closer proximity have higher sequence identity. This suggests that gene conversion occurs more often between duplications in close proximity or that there is more genetic independence between distant paralogs. Partially duplicated genes have a higher likelihood of pseudogenization than completely duplicated genes, but no single factor significantly contributes to the selective constraints on a completely duplicated gene. However, DNA-based duplications and duplications within chromosome arms tend to produce longer duplication tracts than retroposed and inter-arm duplications, and longer duplication tracts are more likely to contain a completely duplicated gene. Therefore, the relative position of paralogs and the mechanism of duplication indirectly affect whether a duplicated gene is retained or pseudogenized. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Gene duplication, the evolution of novel gene functions, and detecting functional divergence of duplicates in silico

Duplication of genes increases the amount of genetic material on which evolution can work and has been considered of major importance for the development of biological novelties or to explain important transitions that have occurred during biological evolution. Recently, much research has been devoted to the study of the evolutionary and functional divergence of duplicated genes. Since the majority of genes are part of gene families, there is considerable interest in predicting differences in function between duplicates and assessing the functional redundancy of genes within gene families. In this review, we discuss the strengths and limitations of both older and novel approaches to investigate the evolution of duplicated genes in silico.     

Rapid rates of lineage-specific gene duplication and deletion in the alpha-globin gene family

Phylogeny reconstructions of the globin gene families have revealed that paralogous genes within species are often more similar to one another than they are to their orthologous counterparts in closely related species. This pattern has been previously attributed to mechanisms of concerted evolution such as interparalog gene conversion that homogenize sequence variation between tandemly duplicated genes and therefore create the appearance of recent common ancestry. Here we report a comparative genomic analysis of the alpha-globin gene family in mammals that reveal a surprisingly high rate of lineage-specific gene duplication and deletion via unequal crossing-over. Results of our analysis reveal that patterns of sequence similarity between paralogous alpha-like globin genes from the same species are only partly explained by concerted evolution between preexisting gene duplicates. In a number of cases, sequence similarity between paralogous sequences from the same species is attributable to recent ancestry between the products of de novo gene duplications. As a result of this surprisingly rapid rate of gene gain and loss, many mammals possess alpha-like globin genes that have no orthologous counterparts in closely related species. The resultant variation in gene copy number among species may represent an important source of regulatory variation that affects physiologically important aspects of blood oxygen transport and aerobic energy metabolism.     

Genome evolution in polyploids

Polyploidy is a prominent process in plants and has been significant in the evolutionary history of vertebrates and other eukaryotes. In plants, interdisciplinary approaches combining phylogenetic and molecular genetic perspectives have enhanced our awareness of the myriad genetic interactions made possible by polyploidy. Here, processes and mechanisms of gene and genome evolution in polyploids are reviewed. Genes duplicated by polyploidy may retain their original or similar function, undergo diversification in protein function or regulation, or one copy may become silenced through mutational or epigenetic means. Duplicated genes also may interact through inter-locus recombination, gene conversion, or concerted evolution. Recent experiments have illuminated important processes in polyploids that operate above the organizational level of duplicated genes. These include inter-genomic chromosomal exchanges, saltational, non-Mendelian genomic evolution in nascent polyploids, inter-genomic invasion, and cytonuclear stabilization. Notwithstanding many recent insights, much remains to be learned about many aspects of polyploid evolution, including: the role of transposable elements in structural and regulatory gene evolution; processes and significance of epigenetic silencing; underlying controls of chromosome pairing; mechanisms and functional significance of rapid genome changes; cytonuclear accommodation; and coordination of regulatory factors contributed by two, sometimes divergent progenitor genomes. Continued application of molecular genetic approaches to questions of polyploid genome evolution holds promise for producing lasting insight into processes by which novel genotypes are generated and ultimately into how polyploidy facilitates evolution and adaptation.     

The evolution of mammalian chemokine genes

Chemokines play an important role in orchestrating cell recruitment and localization in both physiological and pathological conditions. More than 44 ligands have been identified in the human genome. A significantly different set of chemokines, however, is found in the mouse genome, suggesting a rapid evolution of the chemokine system in mammalian genomes. Thus, there are lineage and even individual-specific differences in chemokine genes in mammals. Differences in the expression and function between even recently duplicated genes are also evident. In this review, we discuss how evolutionary events such as gene duplication and gene conversion have shaped the diverse arrays of chemokines in mammalian genomes.