Series Of Duplication Events Research Articles

Constraints on the expansion of paralogous protein families.

Duplication and divergence is a major mechanism by which new proteins and functions emerge in biology. Consequently, most organisms, in all domains of life, have genomes that encode large paralogous families of proteins. For recently duplicated pathways to acquire different, independent functions, the two paralogs must acquire mutations that effectively insulate them from one another. For instance, paralogous signaling proteins must acquire mutations that endow them with different interaction specificities such that they can participate in different signaling pathways without disruptive cross-talk. Although duplicated genes undoubtedly shape each other's evolution as they diverge and attain new functions, it is less clear how other paralogs impact or constrain gene duplication. Does the establishment of a new pathway by duplication and divergence require the system-wide optimization of all paralogs? The answer has profound implications for molecular evolution and our ability to engineer biological systems. Here, we discuss models, experiments, and approaches for tackling this question, and for understanding how new proteins and pathways are born.

Comparative genomics and evolutionary analysis of hydrophobins from three species of wood-degrading fungi

Hydrophobins are small, secreted proteins playing important roles at different stages of fungal life cycles. Their characteristic feature is the presence of eight highly conserved cysteine residues. Here we present an inventory and evolutionary analysis of hydrophobin genes from three wood-degrading basidiomycetes, Phlebia brevispora, Ganoderma sp. and Bjerkandera adusta. The genomes of the three analyzed species are characterized by the presence of high copy numbers of hydrophobin genes. Results of the phylogenetic analysis of the identified proteins revealed that many of them share a high degree of sequence similarity and probably originated from a series of duplication events. The presence of several clusters of adjacent copies of the hydrophobin gene in a particular location in the genome further supports the interpretation that gene duplication has played a role in the evolution of hydrophobins in the analyzed species.

Gains, Losses and Changes of Function after Gene Duplication: Study of the Metallothionein Family

Metallothioneins (MT) are small proteins involved in heavy metal detoxification and protection against oxidative stress and cancer. The mammalian MT family originated through a series of duplication events which generated four major genes (MT1 to MT4). MT1 and MT2 encode for ubiquitous proteins, while MT3 and MT4 evolved to accomplish specific roles in brain and epithelium, respectively. Herein, phylogenetic, transcriptional and polymorphic analyses are carried out to expose gains, losses and diversification of functions that characterize the evolutionary history of the MT family. The phylogenetic analyses show that all four major genes originated through a single duplication event prior to the radiation of mammals. Further expansion of the MT1 gene has occurred in the primate lineage reaching in humans a total of 13 paralogs, five of which are pseudogenes. In humans, the reading frame of all five MT1 pseudogenes is reconstructed by sequence homology with a functional duplicate revealing that loss of invariant cysteines is the most frequent event accounting for pseudogeneisation. Expression analyses based on EST counts and RT-PCR experiments show that, as for MT1 and MT2, human MT3 is also ubiquitously expressed while MT4 transcripts are present in brain, testes, esophagus and mainly in thymus. Polymorphic variation reveals two deleterious mutations (Cys30Tyr and Arg31Trp) in MT4 with frequencies reaching about 30% in African and Asian populations suggesting the gene is inactive in some individuals and physiological compensation for its loss must arise from a functional equivalent. Altogether our findings provide novel data on the evolution and diversification of MT gene duplicates, a valuable resource for understanding the vast set of biological processes in which these proteins are involved.

Evolution and functional divergence of the anoctamin family of membrane proteins

BackgroundThe anoctamin family of transmembrane proteins are found in all eukaryotes and consists of 10 members in vertebrates. Ano1 and ano2 were observed to have Ca2+ activated Cl- channel activity. Recent findings however have revealed that ano6, and ano7 can also produce chloride currents, although with different properties. In contrast, ano9 and ano10 suppress baseline Cl- conductance when co-expressed with ano1 thus suggesting that different anoctamins can interfere with each other. In order to elucidate intrinsic functional diversity, and underlying evolutionary mechanism among anoctamins, we performed comprehensive bioinformatics analysis of anoctamin gene family.ResultsOur results show that anoctamin protein paralogs evolved from several gene duplication events followed by functional divergence of vertebrate anoctamins. Most of the amino acid replacements responsible for the functional divergence were fixed by adaptive evolution and this seem to be a common pattern in anoctamin gene family evolution. Strong purifying selection and the loss of many gene duplication products indicate rigid structure-function relationships among anoctamins.ConclusionsOur study suggests that anoctamins have evolved by series of duplication events, and that they are constrained by purifying selection. In addition we identified a number of protein domains, and amino acid residues which contribute to predicted functional divergence. Hopefully, this work will facilitate future functional characterization of the anoctamin membrane protein family.

Characterization of Genes Encoding Poly(A) Polymerases in Plants: Evidence for Duplication and Functional Specialization

BackgroundPoly(A) polymerase is a key enzyme in the machinery that mediates mRNA 3′ end formation in eukaryotes. In plants, poly(A) polymerases are encoded by modest gene families. To better understand this multiplicity of genes, poly(A) polymerase-encoding genes from several other plants, as well as from Selaginella, Physcomitrella, and Chlamydomonas, were studied.Methodology/Principal FindingsUsing bioinformatics tools, poly(A) polymerase-encoding genes were identified in the genomes of eight species in the plant lineage. Whereas Chlamydomonas reinhardtii was found to possess a single poly(A) polymerase gene, other species possessed between two and six possible poly(A) polymerase genes. With the exception of four intron-lacking genes, all of the plant poly(A) polymerase genes (but not the C. reinhardtii gene) possessed almost identical intron positions within the poly(A) polymerase coding sequences, suggesting that all plant poly(A) polymerase genes derive from a single ancestral gene. The four Arabidopsis poly(A) polymerase genes were found to be essential, based on genetic analysis of T-DNA insertion mutants. GFP fusion proteins containing three of the four Arabidopsis poly(A) polymerases localized to the nucleus, while one such fusion protein was localized in the cytoplasm. The fact that this latter protein is largely pollen-specific suggests that it has important roles in male gametogenesis.Conclusions/SignificanceOur results indicate that poly(A) polymerase genes have expanded from a single ancestral gene by a series of duplication events during the evolution of higher plants, and that individual members have undergone sorts of functional specialization so as to render them essential for plant growth and development. Perhaps the most interesting of the plant poly(A) polymerases is a novel cytoplasmic poly(A) polymerase that is expressed in pollen in Arabidopsis; this is reminiscent of spermatocyte-specific cytoplasmic poly(A) polymerases in mammals.

Alpha-fetoprotein related gene ( ARG): A new member of the albumin gene family that is no longer functional in primates

The serum albumin gene family is comprised of albumin, alpha-fetoprotein, alpha-albumin ( afamin), and the more distantly related Vitamin D binding protein. These genes arose from a common ancestor through a series of duplication events, are expressed primarily in the liver and tightly linked in all species where this has been investigated. Here, we describe a fifth member of the albumin gene family that we have named Alpha-fetoprotein Related Gene ( ARG) since it exhibits greatest similarity to this family member. ARG is activated in the liver perinatally, but is expressed at very low levels. The ARG gene is present and intact in the mouse, rat, dog and horse genomes. In contrast, the ARG gene in human, chimpanzee, rhesus monkey, and marmoset contains a number of mutations common to all four species, indicating that this gene has been an inactive pseudogene in primates for at least 40 million years. Low expression and aberrant splicing of the ARG gene in the mouse liver suggests that ARG may have less functional significance than other members of the serum albumin gene family even in species where it is still intact.

Comparative genomic analysis of a mammalian β-defensin gene cluster

Comparative genomic analyses have yielded valuable insights into conserved and divergent aspects of gene function, regulation, and evolution. Herein, we describe the characterization of a mouse beta-defensin gene cluster locus on chromosome 2F6. In addition, we present the evolutionary analysis of this cluster and its human, rhesus, and rat orthologs. Expression analysis in mouse revealed the occurrence of defensin cluster transcripts in multiple tissues, with the highest abundance in the urogenital tract. Molecular evolutionary analysis suggests that this cluster originated by a series of duplication events, and by positive selection occurring even after the rodent-primate split. In addition, the constraints analysis showed higher positive selection in rodents than in primates, especially distal to the six-cysteine array. Positive selection in the evolution of these defensins may relate not only to the evolving enhancement of ancestral host defense but also to functional innovations in reproduction. The multiplicity of defensins and their preferential overexpression in the urogenital tract indicate that defensins function in the protection and maintenance of fertility.

Identification, characterization, and evolution of a primate β-defensin gene cluster

Defensins are members of a large diverse family of cationic antimicrobial peptides that share a signature pattern consisting of six conserved cysteine residues. Defensins have a wide variety of functions and their disruption has been implicated in various human diseases. Here we report the characterization of DEFB119-DEFB123, five genes in the human beta-defensin cluster locus on chromosome 20q11.1. The genomic structures of DEFB121 and DEFB122 were determined in silico. Sequences of the five macaque orthologs were obtained and expression patterns of the genes were analyzed in humans and macaque by semiquantitative reverse transcription polymerase chain reaction. Expression was restricted to the male reproductive tract. The genes in this cluster are differentially regulated by androgens. Evolutionary analyses suggest that this cluster originated by a series of duplication events and by positive selection. The evolutionary forces driving the proliferation and diversification of these defensins may be related to reproductive specialization and/or the host-parasite coevolutionary process.

Zinc finger gene clusters and tandem gene duplication.

Zinc finger genes in mammalian genomes are frequently found to occur in clusters with cluster members appearing in a tandem array on the chromosome. It has been suggested that in situ gene duplication events are primarily responsible for the evolution of such clusters. The problem of inferring the series of duplication events responsible for producing clustered families is different from the standard phylogeny problem. In this paper, we study this inference problem using a graph called duplication model that captures the series of duplication events while taking into account the observed order of the genes on the chromosome. We provide algorithms to reconstruct a duplication model for a given data set. We use our method to hypothesize the series of duplication events that may have produced the ZNF45 family that appears on human chromosome 19.

Genomic expansion across the albumin gene family on human chromosome 4q is directional.

The albumin gene family arose in a series of duplication events which gave rise to symmetry in its structure. The four genes are tandemly linked on human chromosome 4q in the order: 5'ALB-5'AFP-5'ALF-5'DBP-centromere, and their introns display a symmetrical and repetitive pattern that is shared by members of the gene family. These repetitive motifs provide an internal reference, allowing observations of evolutionary changes within a single line (human) of evolutionary descent. The four genes and three intergenic regions between them increase in size as they get closer to the centromere. An invasion by multiple repetitive DNA elements may account, in part, for this expansion.

IFI60/ISG60/IFIT4, a New Member of the Human IFI54/IFIT2 Family of Interferon-Stimulated Genes

We report the cloning and sequencing of a full-length cDNA encoding a new member of the human IFI54 (HGMW-approved symbol IFIT2) gene family, designated IFI60 (HGMW-approved symbol IFIT4). The upstream regulatory region of IFI60 shows conservation in structure with that of the IFI54 and IFI56 (HGMW-approved symbol IFIT1) genes, each containing two interferon-stimulated response elements upstream of a conserved TATA box. We have established a partial gene map of the IFI54 gene family by analysis of YAC library clones. All four members of the human family are clustered together at chromosome 10q23.3. It is proposed that the four members of the IFI54 gene family evolved by a series of duplication events from a common gene of origin.

Genetics HLA: the major human histocompatibility system.

The HLA system was first defined as a cell surface genetic polymorphism with the aim of using it for transplantation matching. The originally defined specificities of the system, usually identified by a microcytotoxicity assay on peripheral blood lymphocytes, are controlled by the alleles of three closely linked loci HLA-A, B and C. These loci are highly polymorphic with at least 19 A alleles, 26 B alleles and 5 C alleles defined. There is extensive cross reaction amongst the determinants controlled by each locus, though not usually between loci. Skin or kidney grafts exchanged between HLA-A, B and C identical sibs survive much longer than those between unmatched sibs showing that the HLA system is indeed a histocompatibility system. The mixed lymphocyte culture reaction has been shown to be controlled by a series of alleles at a fourth locus, closely linked to A, B and C, the HLA-D locus. Eight alleles have been identified at this locus by use of the mixed lymphocyte culture reaction as a typing procedure. The H-2 system, the mouse equivalent of HLA, has been shown to encompass genes controlling certain immune responses, in addition to those controlling cell surface determinants equivalent to those controlled by the HLA-A, B and C loci. Genes controlling the second and fourth components of complement and factor B of the alternative pathway have also been assigned to the HLA and H-2 regions. The evidence for the existence of immune response genes in man is mainly indirect and comes from a number of striking associations between HLA and certain diseases, a number of which have a presumptive or suspected auto-immune etiology. In the mouse, a series of antigens called Ia for immune associated, have been defined which have a tissue distribution restricted mainly to B lymphocytes and monocytes. This contrasts with the distribution of the HLA-A, B and C antigens and their mouse equivalents, which are present on virtually all tissues except, generally, red cells in man. A variety of approaches are being used to define the human homologues of the mouse Ia antigens. They depend on the use of an appropriate source of B lymphocytes either purified from the peripheral blood, from patients with chronic lymphocytic leukaemia or from B cell derived transformed cell lines. Cytotoxic assays by using blocking techniques or absorption with platelets, which do not have Ia antigens, can produce sera which will react with the human equivalent of Ia antigens, but not to HLA-A, B and C determinants. Using such sera several human Ia determinants have been defined. These have been shown to be associated closely with the HLA-D determinants identified by the mixed lymphocyte culture reaction and there is much evidence to suggest that the Ia and D determinants may in fact be one and the same. As in the case of the HLA-A, B and C determinants, there is extensive cross-reaction among these newly defined Ia antigens. A combination of family studies and somatic cell genetics has shown that the HLA region is located on chromosome 6. The gene for β 2 microglobulin, the polypeptide which is non-covalently bound to the product of the HLA-A, B and C loci, has, however, been shown by the use of human/mouse somatic cell hybrids to be located on chromosome 15. A series of such hybrids showing all possible combinations of presence and absence of chromosomes 6 and 15 and presence and absence of HLA-A and B specificities and β 2 microglobulin has been obtained. In these hybrids the expression of the HLA-A and B antigens has been shown to depend on their association with mouse β 2 microglobulin, in the absence of human β 2 microglobulin. Further investigation of co-expression of β 2 m and of HLA-A and B products has depended on studies of hybrids made with the Daudi cell line which lacks β 2 m and HLA-A, B or C specificities. Hybrids between Daudi and the HeLa derivative D98/AH-2 express determinants of the A and B loci which must be attributed to Daudi. Two of these determinants have also been found in hybrids made between Daudi and a mouse L cell derivative containing only one copy of Daudi’s chromosome 6. These results show that the HLA-A and B determinants of Daudi can be re-expressed in the presence of either human or mouse β 2 m and suggest that control of expression of HLA-A, B and C products is somehow dependant on β 2 microglobulin. The HLA system is a remarkable example of a complex gene cluster containing probably several hundreds at least, if not a few thousand, loci, and has probably arisen by a series of duplication events.