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PubMed1995

Molecular genetics of the glycophorin gene family, the antigens for MNSs blood groups: multiple gene rearrangements and modulation of splice site usage result in extensive diversification.

The purpose of the review is to describe a system of human erythrocyte membrane glycoproteins exhibiting extensive diversity. Glycophorins A and B (GPA and GPB) are the antigens of the MNSs blood groups; thus individuals bearing variant glycophorins can be readily identified by serological typing. Examination of the wide array of variants of these antigens showed that they include many forms, possibly made evident by lack of constraints due to the apparent dispensability of the parent molecules. This article reviews the molecular genetics of 25 variants of the glycophorin gene family, whose common denominator is that they arise from unequal gene recombinations or gene conversions coupled to splice-site mutations. Most rearrangements occurred within a 2-kb region mainly within GPA and GPB of the gene family and only rarely within the third member, GPE. The key feature is the shuffling of sequences within two specific exons (one of which is silent), homologous in the two parent genes. This has resulted in expression of a mosaic of sequences within this region, leading to polymorphism. The common pattern of recombinations coupled to pre-mRNA splicing was the predominant mechanism of the origin of glycophorin diversity. Thus far this mechanism appears to be unique among human gene families. It could have occurred by chance rearrangements among closely linked genes and been driven by a biological advantage, not as yet identified. This remains to be established. Nevertheless, gene rearrangements observed here are akin to those reported for the major histocompatibility complex (MHC). In the glycophorin family the small size of the region within which gene interactions have occurred and the participation of essentially only two alleles makes this relatively simpler system more focused and easier to dissect and describe molecularly.

Chromosome Mapping↗
PubMed1988

Chicken immunoglobulin gamma-heavy chains: limited VH gene repertoire, combinatorial diversification by D gene segments and evolution of the heavy chain locus.

cDNA clones encoding the variable and constant regions of chicken immunoglobulin (Ig) gamma-chains were obtained from spleen cDNA libraries. Southern blots of kidney DNA show that the variable region sequences of eight cDNA clones reveal the same set of bands corresponding to approximately 30 cross-hybridizing VH genes of one subgroup. Since the VH clones were randomly selected, it is likely that the bulk of chicken H-chains are encoded by a single VH subgroup. Nucleotide sequence determinations of two cDNA clones reveal VH, D, JH and the constant region. The VH segments are closely related to each other (83% homology) as expected for VH or the same subgroup. The JHs are 15 residues long and differ by one amino acid. The Ds differ markedly in sequence (20% homology) and size (10 and 20 residues). These findings strongly indicate multiple (at least two) D genes which by a combinatorial joining mechanism diversify the H-chains, a mechanism which is not operative in the chicken L-chain locus. The most notable among the chicken Igs is the so-called 7S IgG because its H-chain differs in many important aspects from any mammalian IgG. The sequence of the C gamma cDNA reported here resolves this issue. The chicken C gamma is 426 residues long with four CH domains (unlike mammalian C gamma which has three CH domains) and it shows 25% homology to the chicken C mu. The chicken C gamma is most related to the mammalian C epsilon in length, the presence of four CH domains and the distribution of cysteines in the CH1 and CH2 domains. We propose that the unique chicken C gamma is the ancestor of the mammalian C epsilon and C gamma subclasses, and discuss the evolution of the H-chain locus from that of chicken with presumably three genes (mu, gamma, alpha) to the mammalian loci with 8-10 H-chain genes.

Amino Acid Sequence↗
PubMed1991

Quantitative variations in gene expression: possible role in cellular diversification and tumor progression.

Changes in the quantitative expression of certain genes or in the amounts of their products can quickly stimulate progression to the metastatic phenotype. This has been done experimentally by transferring dominantly acting oncogenes such as c-H-rasEJ into susceptible cells or more recently by interfering with metastasis suppressor genes. In vivo such rapid qualitative changes in dominantly acting oncogenes or suppressor genes occur only rarely, and progression to highly metastatic phenotypes is thought to occur through a process involving the slow stepwise progression of a subpopulation of neoplastic cells to more malignant states. Such slow changes can be reversible and need not involve known dominantly acting oncogenes or metastatic suppressor genes, consistent with clinical and experimental observations on naturally occurring, highly advanced metastatic tumors. An important element in the natural progression of tumors to more malignant states may be their ability to circumvent host environmental controls that regulate growth and cellular diversity. They also evolve into heterogeneous cellular phenotypes, a process that appears to mainly involve quantitative changes in gene expression but can be rapidly stimulated in cell culture by the introduction of a dominantly acting oncogene or inhibited by the introduction of a suppressor gene. The oncogenes and suppressor genes that affect malignancy may control important steps in the quantitative regulation of sets of genes that are ultimately responsible for the cellular alterations seen in adhesion receptors, cell motility responses, cell-cell communication components, degradative enzymes and their inhibitors, growth factor receptors, components that aid in escape from host surveillance mechanisms and others that are important in malignancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Shh-Bmp2 signaling module and the evolutionary origin and diversification of feathers.

To examine the role of development in the origin of evolutionary novelties, we investigated the developmental mechanisms involved in the formation of a complex morphological novelty-branched feathers. We demonstrate that the anterior-posterior expression polarity of Sonic hedgehog (Shh) and Bone morphogenetic protein 2 (Bmp2) in the primordia of feathers, avian scales, and alligator scales is conserved and phylogenetically primitive to archosaurian integumentary appendages. In feather development, derived patterns of Shh-Bmp2 signaling are associated with the development of evolutionarily novel feather structures. Longitudinal Shh-Bmp2 expression domains in the marginal plate epithelium between barb ridges provide a prepattern of the barbs and rachis. Thus, control of Shh-Bmp2 signaling is a fundamental component of the mechanism determining feather form (i.e., plumulaceous vs. pennaceous structure). We show that Shh signaling is necessary for the formation and proper differentiation of a barb ridge and that it is mediated by Bmp signaling. BMP signaling is necessary and sufficient to negatively regulate Shh expression within forming feather germs and this epistatic relationship is conserved in scale morphogenesis. Ectopic SHH and BMP2 signaling leads to opposing effects on proliferation and differentiation within the feather germ, suggesting that the integrative signaling between Shh and Bmp2 is a means to regulate controlled growth and differentiation of forming skin appendages. We conclude that Shh and Bmp signaling is necessary for the formation of barb ridges in feathers and that Shh and Bmp2 signaling constitutes a functionally conserved developmental signaling module in archosaur epidermal appendage development. We propose a model in which branched feather form evolved by repeated, evolutionary re-utilization of a Shh-Bmp2 signaling module in new developmental contexts. Feather animation Quicktime movies can be viewed at http://fallon.anatomy.wisc.edu/feather.html.

Alligators and Crocodiles↗
PubMed2001

A molecular phylogenetic study of ecological diversification in the Australian lizard genus Ctenophorus.

We present phylogenetic analyses of the lizard genus Ctenophorus using 1,639 aligned positions of mitochondrial DNA sequences containing 799 parsimony-informative characters for samples of 22 species of Ctenophorus and 12 additional Australian agamid genera. Sequences from three protein-coding genes (ND1, ND2, and COI) and eight intervening tRNA genes are examined using both parsimony and maximum-likelihood analyses. Species of Ctenophorus form a monophyletic group with Rankinia adelaidensis, which we suggest placing in Ctenophorus. Ecological differentiation among species of Ctenophorus is most evident in the kinds of habitats used for shelter. Phylogenetic analyses suggest that the ancestral condition is to use burrows for shelter, and that habits of sheltering in rocks and shrubs/hummock grasses represent separately derived conditions. Ctenophorus appears to have undergone extensive cladogenesis approximately 10-12 million years ago, with all three major ecological modes being established at that time.

Adaptation, Physiological↗
PubMed2006

Rapid diversification of measles virus genotypes circulating in Morocco during 2004-2005 epidemics.

Measles virus strains circulating in six different regions in Morocco during 2004-2005 were analysed. They were genotyped using two different methods: the recently developed method based on real-time PCR amplification and melting curve analyses, and the conventional method based on nucleic acid sequencing and phylogenetic analysis of 456 nucleotides of the 3'-region of the nucleoprotein (N) gene sequence. Five genotypes (A, B3.2, C2, D7 and D8) were shown to be circulating during this period. Previous studies on measles virus genotypes in Morocco (1998-2003) showed that only the genotype C2 was present and was considered to be endemic. Sequence comparison of the 2004-2005 viruses with other measles strains suggests that measles strains belonging to genotype B3.2 were probably imported from West Africa, whereas those belonging to genotypes D7 and D8 were imported from Europe. These studies which identify the route of importation of measles are important for developing strategies for measles elimination in Morocco.

Disease Outbreaks↗
PubMed2005

Diversification of CDK11 transcripts during chicken testis development and regression.

CDK11 (cyclin-dependent kinase 11, formerly known as PITSLRE) is a serine/threonine kinase that associates with the cyclin L2 regulatory partner. CDK11 catalytic activity has been associated with apoptosis, transcription, and RNA processing. Here, we identify novel chicken testis CDK11 transcripts that differ in their 5'UTR, 3'UTR, splicing of the exon 6, and polyadenylation. We have also characterized the differential expression of CDK11 in somatic tissues, during testis development and upon testicular regression by diethylstilbestrol (DES) treatment. The heterogeneity of CDK11 transcripts presented in this study suggests new possibilities for post-transcriptional regulation.

Animals↗
PubMed1998

Diversification of gap junction proteins (connexins) in the central nervous system and the concept of functional compartments.

This review describes recent progress in the identification of the molecular composition of gap junction proteins (connexins) in brain tissue. First, a general overview of gap junction function and the composition of the hemichannels (connexons) is given. Then the question of diversity of gap junction channels in the nervous system is addressed and its functional implications are discussed. Based on recent findings of gap junction mediated cell-to-cell communication we attempt to refine the concept of functionally coupled compartments in the brain. This conceptual introduction passes on to a detailed description of the coupling efficiency in glial and neuronal compartments with emphasis on innovative perspectives that allow a better understanding of gap junction function in the brain.

Animals↗
PubMed1993

Lineage diversification of the neural crest: in vitro investigations.

This review addresses the contribution of in vitro investigations to our understanding of neural crest development. Cell culture has been used to study the environmental control of cell lineage decisions in the neural crest and to define the developmental potentials of specific populations of neural crest and neural crest-derived cells. We consider the roles of environmental signals in the context of the development of several different neural crest-derived lineages. We also discuss evidence for influences of local cell-cell interactions and substrate molecules on neural crest development. Data bearing on the issues of neural crest cell multipotency, self-renewal, and lineage commitment are reviewed.

Animals↗
PubMed1996

The inhibition of differentiation caused by TGFbeta in fetal myoblasts is dependent upon selective expression of PKCtheta: a possible molecular basis for myoblast diversification during limb histogenesis.

Embryonic and fetal skeletal myoblasts are responsible for the formation of primary and secondary fibers in mammals, but the mechanism which diversifies their fate is unknown. In vitro, embryonic myoblasts are resistant to the differentiation inhibitory effects of transforming growth factor beta and phorbol esters. Thus, differential expression of specific molecules involved in the transduction of extracellular signals may contribute to the different phenotypes. We report here that protein kinase C theta, but none of the other known protein kinase C isoforms, is selectively expressed in fetal and postnatal muscle cells (at both the myoblast and myotube stage) in vitro and in vivo. By contrast, embryonic myoblasts and myotubes do not express protein kinase C theta in vitro or in vivo. This difference is causally related to a differential response to transforming growth factor beta, since overexpression of protein kinase C theta, but not of protein kinase C alpha or zeta, in embryonic myoblasts makes these cells sensitive to transforming growth factor beta. These data demonstrate for the first time that a protein kinase C isoform is a key component of the signal transduction cascade which follows exposure of myoblasts to transforming growth factor beta. They also suggest a specific role for protein kinase C theta in determining the fate of different myoblasts during muscle histogenesis.

Amino Acid Sequence↗
PubMed1999

Regulation of E- and P-cadherin expression correlated with melanocyte migration and diversification.

Melanocytes (Mc) and their progenitors melanoblasts (Mb) are derived from the neural crest and migrate along the dorsolateral pathway to colonize the dermis, the epidermis, and finally the hair matrix. To examine the involvement of cadherins in the migration of Mc lineage cells, we combined flow cytometric analysis of dissociated live cells with immunohistochemical staining of tissue sections to quantify the level of cadherin expression on the surface of Mb/Mc. At 11.5 days postcoitum, Mb are in the dermis and are E-cadherin(-)P-cadherin(-) (E-cad(-)P-cad(-)). During the next 48 h, a 200-fold increase of E-cadherin expression is induced on the surface of Mb prior to their entry into the epidermis, thereby forming a homogeneous E-cad(high)P-cad(-/low) population. The cadherin expression pattern then diversifies, giving rise to three populations, an E-cad(-)P-cad(-) dermal population, E-cad(high)P-cad(low) epidermal population, and E-cad(-)P-cad(med-high) follicular population. In all three populations, the patterns of expression are region-specific, being identical with those of surrounding cells such as keratinocytes and fibroblasts, and are preserved before and after pigmentation. While most of the epidermal Mb/Mc disappear after the neonatal stage in normal mice, forced expression of steel factor in the epidermis of transgenic mice promotes survival of epidermal Mb/Mc, maintaining epidermal-type cadherin expression pattern (E-cad(high)P-cad(low)) throughout the postnatal life. These findings indicate the involvement of extrinsic cues in coordinating the cadherin expression pattern of Mb/Mc and suggest a role for E- and P-cadherins in guiding Mc progenitors to their final destinations.

Animals↗
PubMed1995

Concerted evolution of the tandemly repeated genes encoding primate U2 small nuclear RNA (the RNU2 locus) does not prevent rapid diversification of the (CT)n.(GA)n microsatellite embedded within the U2 repeat unit.

The RNU2 locus encoding human U2 small nuclear RNA (snRNA) is organized as a nearly perfect tandem array containing 5 to 22 copies of a 5.8-kb repeat unit. Just downstream of the U2 snRNA gene in each 5.8-kb repeat unit lies a large (CT)n.(GA)n dinucleotide repeat (n approximately equal to 70). This form of genomic organization, in which one repeat is embedded within another, provides an unusual opportunity to study the balance of forces maintaining the homogeneity of both kinds of repeats. Using a combination of field inversion gel electrophoresis and polymerase chain reaction, we have been able to study the CT microsatellites within individual U2 tandem arrays. We find that the CT microsatellites within an RNU2 allele exhibit significant length polymorphism, despite the remarkable homogeneity of the surrounding U2 repeat units. Length polymorphism is due primarily to loss or gain of CT dinucleotide repeats, but other types of deletions, insertions, and substitutions are also frequent. Polymorphism is greatly reduced in regions where pure (CT)n tracts are interrupted by occasional G residues, suggesting that irregularities stabilize both the length and the sequence of the dinucleotide repeat. We further show that the RNU2 loci of other catarrhine primates (gorilla, chimpanzee, orangutan, and baboon) contain orthologous CT microsatellites; these also exhibit length polymorphism, but are highly divergent from each other. Thus, although the CT microsatellite is evolving far more rapidly than the rest of the U2 repeat unit, it has persisted through multiple speciation events spanning > 35 Myr. The persistence of the CT microsatellite, despite polymorphism and rapid evolution, suggests that it might play a functional role in concerted evolution of the RNU2 loci, perhaps as an initiation site for recombination and/or gene conversion.

Animals↗
PubMed1994

Development and diversification of the Last Universal Ancestor.

The majority of evolutionary steps in the development of basic cellular processes took place in the time interval after the "First Cell" arose until the time of the "Last Universal Ancestor". During this period, life evolved in a monophyletic way in which no stable diversity arose; i.e. although side branches developed, only one survived because of simple "survival of the fittest". The myriad of enzymes and processes developed in this time interval can be grouped in eight qualitatively different categories. In many cases, the evolution of a particular gene was dependent on the concomitant improvement of the cellular machinery generally, including developments in other categories. Eventually several individuals arose (the immediate descendants of the Last Universal Ancestor) that made stable diversity possible because they developed alternative non-competing strategies. These diverse strategies subsequently led to eubacteria, archaebacteria, and eukaryotes (and viruses, plasmids, etc). This paper considers the evolutionary developments in this monophyletic epoch. It depends on three assertions: first, that there is no trivial spontaneous mechanism for the introduction of polynucleotides into a living cell and thus transfer of genes from organism to organism did not occur; second, that the number of accessible habitats and niches was very limited; and third, that the major factor that led to stable diversity was three nearly simultaneous developments. Two were radically different and independent solutions of the problem of overcoming cellular osmotic stress and the third was the development of methanogenesis. Sufficient osmotic pressure could create a high turgor pressure and destructive tension in the wall. However, osmotic stress only became a problem with development of improved metabolism, which resulted in greater success in the accumulation of cellular macromolecules and soluble constituents. One solution preventing osmotic rupture of the cell was the development of mechano-proteins and associated elements of the cytoskeleton by the predecessors of future eukaryotes. The second solution was the development of the murein sacculus (i.e. a covalently closed, cross-linked fabric made of peptidoglycan) by the predecessors of future eubacteria. The former allowed larger cells with flexible cell membranes to evolve and the latter to the development of a strong elastic "exoskeleton" providing ability to survive in extreme environments. Each of these diverse strategies allow both cell types to resist turgor pressure and led to independent non-competing organisms. Interwoven with these developments was the concomitant development of methanogenesis (the third change needed to generate three Kingdoms), which provided the first truly large-scale generation of metabolic energy.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

The simultaneous diversification of South American echimyid rodents (Hystricognathi) based on complete cytochrome b sequences.

Variation in the complete nucleotide sequence of the mitochondrial cytochrome b gene was examined for 32 individuals representing 12 supraspecific taxa of South American rodents of the family Echimyidae (Hystricognathi). Representative genera of four other New World hystricognath families, the Old World porcupine Hystrix, and the myomorph murid rodents Rattus and Mus were used as outgroups in phylogenetic reconstructions. Monopoly of the family Echimyidae is strongly supported, a result fully consistent with existing morphological and paleontological data relative to the taxa examined. However, relationships among most supraspecific taxa within the family are poorly resolved. Poor resolution appears not to result from lack of data, but to a rapid, nearly simultaneous divergence of most Recent taxa. Generic groupings that are moderately to strongly supported include the tree rats of the Brazilian Atlantic Forest (Nelomys) and Amazonia (Echimys, Makalata) and the Amazonian arboreal spiny rats Mesomys and Lonchothrix. However, the two subgenera of the terrestrial spiny rats, Proechimys, do not form a monophyletic unit, and elevation of the Atlantic Forest Trinomys to generic status is supported. The genus Hoplomys is closely related to Proechimys (sensu stricto), a finding supported by other molecular data.

Animals↗