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PubMed2003

Molecular evolution and recombination in gender-associated mitochondrial DNAs of the Manila clam Tapes philippinarum.

Doubly uniparental inheritance (DUI) provides an intriguing system for addressing aspects of molecular evolution and intermolecular recombination of mitochondrial DNA. For this reason, a large sequence analysis has been performed on Tapes philippinarum (Bivalvia, Veneridae), which has mitochondrial DNA heteroplasmy that is consistent with a DUI. The sequences of a 9.2-kb region (containing 29 genes) from 9 individuals and the sequences of a single gene from another 44 individuals are analyzed. Comparisons suggest that the two sex-related mitochondrial genomes do not experience a neutral pattern of divergence and that selection may act with varying strength on different genes. This pattern of evolution may be related to the long, separate history of M and F genomes within their tissue-specific "arenas." Moreover, our data suggest that recombinants, although occurring in soma, may seldom be transmitted to progeny in T. philippinarum.

Animals↗
PubMed1998

Molecular evolution modeled as a fractal renewal point process in agreement with the dispersion of substitutions in mammalian genes.

A fractal renewal point process (FRPP) is used to model molecular evolution in agreement with the relationship between the variance and the mean numbers of nonsynonymous and synonymous substitutions in mammals. Like other episodic models such as the doubly stochastic Poisson process, this model accounts for the large variances observed in amino acid substitution rates, but unlike certain other episodic models, it also accounts for the increase in the index of dispersion with the mean number of substitutions in Ohta's (1995) data. We find that this correlation is significant for nonsynonymous substitutions at the 1% level and for synonymous substitutions at the 10% level, even after removing lineage effects and when using Bulmer's (1989) unbiased estimator of the index of dispersion. This model is simpler than most other overdispersed models of evolution in the sense that it is fully specified by a single interevent probability distribution. Interpretations in terms of chaotic dynamics and in terms of chance and selection are discussed.

Animals↗
PubMed2005

Molecular evolution of duplicated ray finned fish HoxA clusters: increased synonymous substitution rate and asymmetrical co-divergence of coding and non-coding sequences.

In this study the molecular evolution of duplicated HoxA genes in zebrafish and fugu has been investigated. All 18 duplicated HoxA genes studied have a higher non-synonymous substitution rate than the corresponding genes in either bichir or paddlefish, where these genes are not duplicated. The higher rate of evolution is not due solely to a higher non-synonymous-to-synonymous rate ratio but to an increase in both the non-synonymous as well as the synonymous substitution rate. The synonymous rate increase can be explained by a change in base composition, codon usage, or mutation rate. We found no changes in nucleotide composition or codon bias. Thus, we suggest that the HoxA genes may experience an increased mutation rate following cluster duplication. In the non-Hox nuclear gene RAG1 only an increase in non-synonymous substitutions could be detected, suggesting that the increased mutation rate is specific to duplicated Hox clusters and might be related to the structural instability of Hox clusters following duplication. The divergence among paralog genes tends to be asymmetric, with one paralog diverging faster than the other. In fugu, all b-paralogs diverge faster than the a-paralogs, while in zebrafish Hoxa-13a diverges faster. This asymmetry corresponds to the asymmetry in the divergence rate of conserved non-coding sequences, i.e., putative cis-regulatory elements. These results suggest that the 5' HoxA genes in the same cluster belong to a co-evolutionary unit in which genes have a tendency to diverge together.

Animals↗
PubMed2002

Growth and molecular evolution of vesicular stomatitis serotype New Jersey in cells derived from its natural insect-host: evidence for natural adaptation.

In this study we evaluated the growth and molecular evolution of a natural isolate of VSV-NJ (89GAS) from sand flies in cells derived from sand flies (LL5), mosquitoes (C6/36) or hamsters (BHK21). Two VSV-NJ natural isolates of mammalian origin were used for comparison. For each virus we measured: (i) ability to grow in one-step growth curve or after serial passage on each cell type; (ii) ability to induce persistent infection, and (iii) genetic stability of the glycoprotein gene (G) after serial passage in each cell type. Sand fly virus 89GAS grew to higher titers in insect cells compared with viruses of mammalian origin and showed increasing titers with each passage only in C6/36 cells. All viruses established productive persistent infections in both mosquito and sand fly cells but only LL5 cells yielded sustained high virus titers for periods of up to 81 days. Analyses of the consensus sequences of the G gene from each virus after 0, 10 or up to 25 passages in each cell line showed nucleotide substitution rates between 1.39 x l0(-4) and 6.95 x l0(-5). The majority of these changes were non-synonymous, suggesting positive selection. We did not detect increased nucleotide substitution rates on the G gene of 89GAS after passage in cell lines of mosquito or mammalian origin, nor in viruses of mammalian origin after passage in insect cells. This indicates that although VSV G is positively selected in vitro by the insect cell environment, this does not fully explain VSV natural adaptation. This is the first evidence of naturally occurring adaptation of VSV to cells derived from its natural host.

Adaptation, Physiological↗
PubMed2000

Molecular evolution of the murine tspy genes.

Molecular aspects of murine evolution were studied by sequencing, and subsequently comparing, introns of the Y-chromosomal tspy genes from Apodemus agrarius, A. sylvaticus, A. flavicollis, Mus platythrix (subgenus Pyromys), M. booduga (subgenus Leggada), and from species of the subgenus Mus, including M. cervicolor, M. macedonicus and M. spretus. Estimates of nucleotide substitution rates in these lineages were in perfect agreement with phylogenetic data previously published by She et al. (1990), Catzeflis et al. (1992; 1993), and Lyon et al. (1996). The only exception was provided by a comparatively late divergence of M. spretus and M. macedonicus. Our data also suggest that M. booduga diverged from the subgenus Mus about 3 Myr ago.

Animals↗
PubMed1998

Antibody scFv fragments without disulfide bonds made by molecular evolution.

We generated stable and functional cysteine-free antibody single-chain fragments (scFv) lacking the conserved disulfide bonds in both VH and VL. This was achieved by molecular evolution, starting from the scFv fragment of the levan binding antibody ABPC48, which is naturally missing one of the conserved cysteine residues, by using DNA shuffling and phage display. Several of the selected sequences were expressed and the resulting scFv proteins characterized by equilibrium urea denaturation. Three of the characterized proteins exhibit thermodynamic stability similar to the wild-type protein, and these cysteine-free mutant proteins can now be expressed in functional form in the Escherichia coli cytoplasm. We believe that such molecules are of great utility for use as intrabodies, can be produced by simpler expression strategies and may give further insight into the folding and stability of the immunoglobulin fold.

Amino Acid Sequence↗
PubMed1994

DNA shuffling by random fragmentation and reassembly: in vitro recombination for molecular evolution.

Computer simulations of the evolution of linear sequences have demonstrated the importance of recombination of blocks of sequence rather than point mutagenesis alone. Repeated cycles of point mutagenesis, recombination, and selection should allow in vitro molecular evolution of complex sequences, such as proteins. A method for the reassembly of genes from their random DNA fragments, resulting in in vitro recombination is reported. A 1-kb gene, after DNase I digestion and purification of 10- to 50-bp random fragments, was reassembled to its original size and function. Similarly, a 2.7-kb plasmid could be efficiently reassembled. Complete recombination was obtained between two markers separated by 75 bp; each marker was located on a separate gene. Oligonucleotides with 3' and 5' ends that are homologous to the gene can be added to the fragment mixture and incorporated into the reassembled gene. Thus, mixtures of synthetic oligonucleotides and PCR fragments can be mixed into a gene at defined positions based on homology. As an example, a library of chimeras of the human and murine genes for interleukin 1 beta has been prepared. Shuffling can also be used for the in vitro equivalent of some standard genetic manipulations, such as a backcross with parental DNA. The advantages of recombination over existing mutagenesis methods are likely to increase with the numbers of cycles of molecular evolution.

Base Sequence↗
PubMed2001

Applied molecular evolution of O6-benzylguanine-resistant DNA alkyltransferases in human hematopoietic cells.

Applied molecular evolution is a rapidly developing technology that can be used to create and identify novel enzymes that nature has not selected. An important application of this technology is the creation of highly drug-resistant enzymes for cancer gene therapy. Seventeen O(6)-alkylguanine-DNA alkyltransferase (AGT) mutants highly resistant to O(6)-benzylguanine (BG) were identified previously by screening 8 million variants, using genetic complementation in Escherichia coli. To examine the potential of these mutants for use in humans, the sublibrary of AGT clones was introduced to human hematopoietic cells and stringently selected for resistance to killing by the combination of BG and 1,3-bis(2-chloroethyl)-1-nitrosourea. This competitive analysis between the mutants in human cells revealed three AGT mutants that conferred remarkable resistance to the combination of BG and 1,3-bis(2-chloroethyl)-1-nitrosourea. Of these, one was recovered significantly more frequently than the others. Upon further analysis, this mutant displayed a level of BG resistance in human hematopoietic cells greater than that of any previously reported mutant.

Amino Acid Sequence↗
PubMed2002

Directed molecular evolution: bridging the gap between genomics leads and commercial products.

Agricultural crops, engineered to express transgenic traits, have been rapidly adopted by farmers since the initial commercialization of this technology in 1996. However, despite nearly 20 years of research in agricultural biotechnology, only two product categories have achieved commercial success: plants containing transgenes conferring tolerance to herbicides and plants containing insecticidal protein genes derived from Bacillus thuringensis. A number of transgenic concepts, while exhibiting promising phenotypes in laboratory experiments, have failed to generate commercially viable crops. Many of the leads produced by modern integrative approaches to understanding plant biology will need further optimization to deliver economically viable crops. Directed molecular evolution represents a powerful technology to optimize newly discovered leads towards product objectives. In this review, we show by example how directed molecular evolution can be used to develop enabling technologies for plant biologists; how genes can be optimized to generate improved input traits such as those conferring insect tolerance, disease control and herbicide tolerance; and how plant quality can be altered to improve yield, produce novel industrial feedstocks and improve nutritional qualities.

Agriculture↗
PubMed1994

A hypothesis: reciprocal information transfer between oligoribonucleotides and oligopeptides in prebiotic molecular evolution.

We wish to propose a mechanism for reciprocal information transfer in prebiotic molecular evolution, based on heterologous pairing complex formation between oligoribonucleotides and oligopeptides. In this proposed pairing complex, the bases of the oligoribonucleotide and the side chains of the oligopeptide may form three types of complementary Watson-Crick-type hydrogen bonds. The structural basis for the pairing is the close correspondence of the distances between the side chains in the two molecules. Both the inter-nucleotide spacing of the RNA and the inter-side-chain spacing of the peptide are approximately 3.4 A. The proposed pairing mode would allow both specific and nonspecific interactions required for reciprocal information transfer. Thus, it represents a simple and versatile coding system that could have had significant implications in prebiotic molecular selection and evolution. In addition, we propose several testable experimental approaches based on the pairing mode of oligoribonucleotides and oligopeptides to verify our hypothesis.

Amino Acid Sequence↗
PubMed2001

Molecular evolution of calmodulin-like domain protein kinases (CDPKs) in plants and protists.

Many genes for calmodulin-like domain protein kinases (CDPKs) have been identified in plants and Alveolate protists. To study the molecular evolution of the CDPK gene family, we performed a phylogenetic analysis of CDPK genomic sequences. Analysis of introns supports the phylogenetic analysis; CDPK genes with similar intron/exon structure are grouped together on the phylogenetic tree. Conserved introns support a monophyletic origin for plant CDPKs, CDPK-related kinases, and phosphoenolpyruvate carboxylase kinases. Plant CDPKs divide into two major branches. Plant CDPK genes on one branch share common intron positions with protist CDPK genes. The introns shared between protist and plant CDPKs presumably originated before the divergence of plants from Alveolates. Additionally, the calmodulin-like domains of protist CDPKs have intron positions in common with animal and fungal calmodulin genes. These results, together with the presence of a highly conserved phase zero intron located precisely at the beginning of the calmodulin-like domain, suggest that the ancestral CDPK gene could have originated from the fusion of protein kinase and calmodulin genes facilitated by recombination of ancient introns.

Amino Acid Sequence↗
PubMedDate not supplied

Molecular evolution of human immunodeficiency virus type 1 subtype A in Senegal: 1988-1997.

OBJECTIVE: Few studies have been able to track the genetic diversity of HIV-1 viruses in human populations over time. We analyzed the molecular evolution of subtype A over a 10-year period, in a cohort of female sex workers with a known time of infection. STUDY DESIGN/METHODS: We amplified and sequenced the C2-V3 region of the surface envelope glycoprotein from 73 HIV-1-infected women, infected between 1987-1997. RESULTS: Fifty-one patients were infected by subtype A viruses. The viruses demonstrated significant diversification (p < 0.001) with mean genetic distance increasing from 8.6% in 1989 to 15.9% in 1997. The slope of the fitted curve suggested a rate of diversification of 0.7% per year. The majority of subtype A viruses clustered with HIV-1 subtype A/G recombinant form (IbNG). CONCLUSION: The genetic diversity of HIV-1 subtype A infections doubled over the first 10 years of this high risk population's epidemic, suggesting that implementation of vaccines early in the epidemic may have a higher likelihood of success based on levels of genetic diversity. The A/G recombinant form (IbNG) has taken epidemic proportions in West Africa. This is of particular importance in understanding the epidemiology of HIV-1 subtypes in Africa and to further dissect the potential phenotypic and biological characteristics of these viruses.

Cohort Studies↗
PubMed1995

Molecular evolution of the mitochondrial 12S rRNA in Ungulata (mammalia).

The complete 12S rRNA gene has been sequenced in 4 Ungulata (hoofed eutherians) and 1 marsupial and compared to 38 available mammalian sequences in order to investigate the molecular evolution of the mitochondrial small-subunit ribosomal RNA molecule. Ungulata were represented by one artiodactyl (the collared peccary, Tayassu tajacu, suborder Suiformes), two perissodactyls (the Grevy's zebra, Equus grevyi, suborder Hippomorpha; the white rhinoceros, Ceratotherium simum, suborder Ceratomorpha), and one hyracoid (the tree hyrax, Dendrohyrax dorsalis). The fifth species was a marsupial, the eastern gray kangaroo (Macropus giganteus). Several transition/transversion biases characterized the pattern of changes between mammalian 12S rRNA molecules. A bias toward transitions was found among 12S rRNA sequences of Ungulata, illustrating the general bias exhibited by ribosomal and protein-encoding genes of the mitochondrial genome. The derivation of a mammalian 12S rRNA secondary structure model from the comparison of 43 eutherian and marsupial sequences evidenced a pronounced bias against transversions in stems. Moreover, transversional compensatory changes were rare events within double-stranded regions of the ribosomal RNA. Evolutionary characteristics of the 12S rRNA were compared with those of the nuclear 18S and 28S rRNAs. From a phylogenetic point of view, transitions, transversions and indels in stems as well as transversional and indels events in loops gave congruent results for comparisons within orders. Some compensatory changes in double-stranded regions and some indels in single-stranded regions also constituted diagnostic events. The 12S rRNA molecule confirmed the monophyly of infraorder Pecora and order Cetacea and demonstrated the monophyly of the suborder Ruminantia was not supported and the branching pattern between Cetacea and the artiodacytyl suborders Ruminantia and Suiformes was not established. The monophyly of the order Perissodactyla was evidenced, but the relationships between Artiodactyla, Cetacea, and Perissodactyla remained unresolved. Nevertheless, we found no support for a Perissodactyla + Hyracoidea clade, neither with distance approach, nor with parsimony reconstruction. The 12S rRNA was useful to solve intraordinal relationships among Ungulata, but it seemed to harbor too few informative positions to decipher the bushlike radiation of some Ungulata orders, an event which has most probably occurred in a short span of time between 55 and 70 MYA.

Animals↗
PubMed2001

Molecular evolution of GH in primates: characterisation of the GH genes from slow loris and marmoset defines an episode of rapid evolutionary change.

Pituitary growth hormone (GH), like several other protein hormones, shows an unusual episodic pattern of molecular evolution in which sustained bursts of rapid change are imposed on long periods of very slow evolution (near-stasis). A marked period of rapid change occurred in the evolution of GH in primates or a primate ancestor, and gave rise to the species specificity that is characteristic of human GH. We have defined more precisely the position of this burst by cloning and sequencing the GH genes for a prosimian, the slow loris (Nycticebus pygmaeus) and a New World monkey, marmoset (Callithrix jacchus). Slow loris GH is very similar in sequence to pig GH, demonstrating that the period of rapid change occurred during primate evolution, after the separation of lines leading to prosimians and higher primates. The putative marmoset GH is similar in sequence to human GH, demonstrating that the accelerated evolution occurred before divergence of New World monkeys and Old World monkeys/apes. The burst of change was confined largely to coding sequence for mature GH, and is not marked in other components of the gene sequence including signal peptide, 5' upstream region and introns. A number of factors support the idea that this episode of rapid change was due to positive adaptive selection. Thus (1) there is no apparent loss of function of GH in man compared with non-primates, (2) after the episode of rapid change the rate of evolution fell towards the slow basal level that is seen for most mammalian GHs, (3) the accelerated rate of substitution for the exons of the GH gene significantly exceeds that for introns, and (4) the amino acids contributing to the hydrophobic core of GH are strongly conserved when higher primate and other GH sequences are compared, and for coding sequences other than that coding for hydrophobic core residues the rate of substitution for non-synonymous sites (K(A)) is significantly greater than that for synonymous sites (K(S)). In slow loris, as in most non-primate mammals, there is no evidence for duplication of the GH gene, but in marmoset, as in rhesus monkey and man, the putative GH gene is one of a cluster of closely related genes.

Animals↗
PubMed2006

Hypoallergens for allergen-specific immunotherapy by directed molecular evolution of mite group 2 allergens.

Allergen-specific immunotherapy is the only treatment that provides long lasting relief of allergic symptoms. Currently, it is based on repeated administration of allergen extracts. To improve the safety and efficacy of allergen extract-based immunotherapy, application of hypoallergens, i.e. modified allergens with reduced IgE binding capacity but retained T-cell reactivity, has been proposed. It may, however, be difficult to predict how to modify an allergen to create a hypoallergen. Directed molecular evolution by DNA shuffling and screening provides a means by which to evolve proteins having novel or improved functional properties without knowledge of structure-function relationships of the target molecules. With the aim to generate hypoallergens we applied multigene DNA shuffling on three group 2 dust mite allergen genes, two isoforms of Lep d 2 and Gly d 2. DNA shuffling yielded a library of genes from which encoded shuffled allergens were expressed and screened. A positive selection was made for full-length, high-expressing clones, and screening for low binding to IgE from mite allergic patients was performed using an IgE bead-based binding assay. Nine selected shuffled allergens revealed 80-fold reduced to completely abolished IgE binding compared with the parental allergens in IgE binding competition experiments. Two hypoallergen candidates stimulated allergen-specific T-cell proliferation and cytokine production at comparable levels as the wild-type allergens in patient peripheral blood mononuclear cell cultures. The two candidates also induced blocking Lep d 2-specific IgG antibodies in immunized mice. We conclude that directed molecular evolution is a powerful approach to generate hypoallergens for potential use in allergen-specific immunotherapy.

Allergens↗
PubMed1998

The molecular evolution of sperm bindin in six species of sea urchins (Echinoida: Strongylocentrotidae).

The acrosomal protein bindin attaches sperm to eggs during sea urchin fertilization. Complementary to ongoing functional biochemical studies, I take a comparative approach to explore the molecular evolution of bindin in a group of closely related free-spawning echinoid species. Two alleles of the mature bindin gene were sequenced for each of six species in the sea urchin family Strongylocentrotidae. The nucleotide sequences diverged by at least 1% per Myr at both silent and replacement sites. Two short sections flanking the conserved block show an excess of nonsynonymous substitutions. Each is homologous to a region that had been identified as a target of selection in other sea urchin comparisons. A large proportion of the bindin-coding sequence consists of a highly variable repeat region. Bindin sequences, even including the large intron, could not resolve the branching order among five of the species.

Alleles↗
PubMed2000

Dating the common ancestor of SIVcpz and HIV-1 group M and the origin of HIV-1 subtypes using a new method to uncover clock-like molecular evolution.

Attempts to estimate the time of origin of human immunodeficiency virus (HIV)-1 by using phylogenetic analysis are seriously flawed because of the unequal evolutionary rates among different viral lineages. Here, we report a new method of molecular clock analysis, called Site Stripping for Clock Detection (SSCD), which allows selection of nucleotide sites evolving at an equal rate in different lineages. The method was validated on a dataset of patients all infected with hepatitis C virus in 1977 by the same donor, and it was able to date exactly the known origin of the infection. Using the same method, we calculated that the origin of HIV-1 group M radiation was in the 1930s. In addition, we show that the coalescence time of the simian ancestor of HIV-1 group M and its closest related cpz strains occurred around the end of the XVII century, a date that could be considered the upper limit to the time of simian-to-human transmission of HIV-1 group M. The results show also that SSCD is an easy-to-use method of general applicability in molecular evolution to calibrate clock-like phylogenetic trees.

Animals↗
PubMed2005

Structural features and molecular evolution of Bowman-Birk protease inhibitors and their potential application.

The Bowman-Birk inhibitors (BBIs) are well-studied serine protease inhibitors that are abundant in dicotyledonous and monocotyledonous plants. BBIs from dicots usually have a molecular weight of 8k and are double-headed with two reactive sites, whereas those from monocots can be divided into two classes, one approximately 8 kDa in size with one reactive site (another reactive site was lost) and the other approximately 16 kDa in size with two reactive sites. The reactive site is located at unique exposed surfaces formed by a disulfide-linked beta-sheet loop that is highly conserved, rigid and mostly composed of nine residues. The structural features and molecular evolution of inhibitors are described, focusing on the conserved disulfide bridges. The sunflower trypsin inhibitor-1 (SFTI-1), with 14 amino acid residues, is a recently discovered bicyclic inhibitor, and is the most small and potent naturally occurring Bowman-Birk inhibitor. Recently, BBIs have become a hot topic because of their potential applications. BBIs are now used for defense against pathogens and insects in transgenic plants, which has advantages over using toxic and polluting insecticides. BBIs could also be applied in the prevention of cancer, Dengue fever, and inflammatory and allergic disorders, because of their inhibitory activity with respect to the serine proteases that play a pivotal role in the development and pathogenesis of these diseases. The canonical nine-residue loop of BBIs/STFI-1 provides an ideal template for drug design of specific inhibitors to target their respective proteases.

Amino Acid Sequence↗