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PubMed2000

Molecular evolution of the growth hormone-releasing hormone/pituitary adenylate cyclase-activating polypeptide gene family. Functional implication in the regulation of growth hormone secretion.

Growth hormone-releasing hormone (GHRH) and pituitary adenylate cyclase-activating polypeptide (PACAP) belong to the same superfamily of regulatory neuropeptides and have both been characterized on the basis of their hypophysiotropic activities. This review describes the molecular evolution of the GHRH/PACAP gene family from urochordates to mammals and presents the hypothesis that the respective roles of GHRH and PACAP in the control of GH secretion are totally inverted in phylogenetically distant groups of vertebrates. In mammals, GHRH and PACAP originate from distinct precursors whereas, in all submammalian taxa investigated so far, including birds, amphibians and fish, a single precursor encompasses a GHRH-like peptide and PACAP. In mammals, GHRH-containing neurons are confined to the infundibular and dorsomedial nuclei of the hypothalamus while PACAP-producing neurons are widely distributed in hypothalamic and extrahypothalamic areas. In fish, both GHRH- and PACAP-immunoreactive neurons are restricted to the diencephalon and directly innervate the adenohypophysis. In mammals and birds, GHRH plays a predominant role in the control of GH secretion. In amphibians, both GHRH and PACAP are potent stimulators of GH release. In fish, PACAP strongly activates GH release whereas GHRH has little or no effect on GH secretion. The GHRH/PACAP family of peptides thus provides a unique model in which to investigate the structural and functional facets of evolution.

Amino Acid Sequence↗

PubMed2005

The evolution of noncoding DNA: how much junk, how much func?

Comparative sequence analysis on a genomic scale has opened the door for the systematic analysis of cis-acting regulatory DNA. It is now possible to begin to answer basic questions such as, how much meaningful noncoding sequence is in the genome? How strong is natural selection on functional noncoding sequences in different species? Two recent articles have capitalized on the comparative genomic approach in an attempt to answer these questions with surprising results.

DNA, Intergenic↗

PubMed1999

Evolutionary change in the functional specificity of genes.

Species throughout the animal kingdom share not only housekeeping but also many key regulatory genes. Nonetheless, species differ from one another developmentally and thus, also morphologically. One of the general aims of comparative developmental genetics is to understand how similar molecules can generate the known diversity of biological form. Here, we argue that gene function can change in different ways during the evolution of developmental processes. Genes can be recruited to serve completely new functions in a new regulatory linkage (co-option), they can change their molecular specificity while remaining in the original (homologous) developmental program and can, at the same time, retain other functions. We describe evidence for such evolutionary patterns based on the comparison of loss-of-function mutations of homologous genes of the two free-living nematodes Caenorhabditis elegans and Pristionchus pacificus. Ultimately, it is the interplay of conservation and change of the specificity of genes and genetic networks that generates developmental novelty over evolutionary time.

Animals↗

PubMed2006

Parallel genetic origins of pelvic reduction in vertebrates.

Despite longstanding interest in parallel evolution, little is known about the genes that control similar traits in different lineages of vertebrates. Pelvic reduction in stickleback fish (family Gasterosteidae) provides a striking example of parallel evolution in a genetically tractable system. Previous studies suggest that cis-acting regulatory changes at the Pitx1 locus control pelvic reduction in a population of threespine sticklebacks (Gasterosteus aculeatus). In this study, progeny from intergeneric crosses between pelvic-reduced threespine and ninespine (Pungitius pungitius) sticklebacks also showed severe pelvic reduction, implicating a similar genetic origin for this trait in both genera. Comparative sequencing studies in complete and pelvic-reduced Pungitius revealed no differences in the Pitx1 coding sequences, but Pitx1 expression was absent from the prospective pelvic region of larvae from pelvic-reduced parents. A much more phylogenetically distant example of pelvic reduction, loss of hindlimbs in manatees, shows a similar left-right size bias that is a morphological signature of Pitx1-mediated pelvic reduction in both sticklebacks and mice. These multiple lines of evidence suggest that changes in Pitx1 may represent a key mechanism of morphological evolution in multiple populations, species, and genera of sticklebacks, as well as in distantly related vertebrate lineages.

Amino Acid Sequence↗

PubMed2004

Mouse-centric comparative transcriptomics of protein coding and non-coding RNAs.

The largest transcriptome reported so far comprises 60,770 mouse full-length cDNA clones, and is an effective reference data set for comparative transcriptomics. The number of mouse cDNAs identified greatly exceeds the number of genes predicted from the sequenced human and mouse genomes. This is largely because of extensive alternative splicing and the presence of many non-coding RNAs (ncRNAs), which are difficult to predict from genomic sequences. Notably, ncRNAs are a major component of the transcriptomes of higher organisms, and many sense-antisense pairs have been identified. The ncRNAs function in a range of regulatory mechanisms for gene expression and other biological processes. They might also have contributed to the increased functional diversification of genomes during evolution. In this review, we discuss aspects of the transcriptome of various organisms in relation to the mouse data, in order to shed light on the regulatory mechanisms and physiological significance of these abundant RNAs.

Alternative Splicing↗

PubMed2005

Comparative promoter region analysis powered by CORG.

BACKGROUND: Promoters are key players in gene regulation. They receive signals from various sources (e.g. cell surface receptors) and control the level of transcription initiation, which largely determines gene expression. In vertebrates, transcription start sites and surrounding regulatory elements are often poorly defined. To support promoter analysis, we present CORG http://corg.molgen.mpg.de, a framework for studying upstream regions including untranslated exons (5' UTR). DESCRIPTION: The automated annotation of promoter regions integrates information of two kinds. First, statistically significant cross-species conservation within upstream regions of orthologous genes is detected. Pairwise as well as multiple sequence comparisons are computed. Second, binding site descriptions (position-weight matrices) are employed to predict conserved regulatory elements with a novel approach. Assembled EST sequences and verified transcription start sites are incorporated to distinguish exonic from other sequences. As of now, we have included 5 species in our analysis pipeline (man, mouse, rat, fugu and zebrafish). We characterized promoter regions of 16,127 groups of orthologous genes. All data are presented in an intuitive way via our web site. Users are free to export data for single genes or access larger data sets via our DAS server http://tomcat.molgen.mpg.de:8080/das. The benefits of our framework are exemplarily shown in the context of phylogenetic profiling of transcription factor binding sites and detection of microRNAs close to transcription start sites of our gene set. CONCLUSION: The CORG platform is a versatile tool to support analyses of gene regulation in vertebrate promoter regions. Applications for CORG cover a broad range from studying evolution of DNA binding sites and promoter constitution to the discovery of new regulatory sequence elements (e.g. microRNAs and binding sites).

5' Untranslated Regions↗

PubMed2001

Functional conservation of the promoter regions of vertebrate tyrosinase genes.

Tyrosinase is the key enzyme for synthesizing melanin pigments, which primarily determine mammalian skin coloration. Considering the important roles of pigments in the evolution and the adaptation of vertebrates, phylogenetic changes in the coding and flanking regulatory sequences of the tyrosinase gene are particularly intriguing. We have now cloned cDNA encoding tyrosinase from Japanese quail and snapping turtle. These nonmammalian cDNA are highly homologous to those of the mouse and human tyrosinases, whereas the 5' flanking sequences are far less conserved except for a few short sequence motifs. Nevertheless, we demonstrate that the 5' flanking sequences from the quail or turtle tyrosinase genes are capable of directing the expression of a fused mouse tyrosinase cDNA when introduced into cultured mouse albino melanocytes. This experimental method, which reveals the functional conservation of regulatory sequences in one cell type (the melanocyte), may be utilized to evaluate phylogenetic differences in mechanisms controlling specific gene expression in many other types of cells. We also provide evidence that the 5' flanking sequences from these nonmammalian genes are functional in vivo by producing transgenic mice. Phylogenetic changes of vertebrate tyrosinase promoters and the possible involvement of conserved sequence motifs in melanocyte-specific expression of tyrosinase are discussed.

5' Flanking Region↗

PubMed2006

Trophoblast and hypoblast in the monotreme, marsupial and eutherian mammal: evolution and origins.

The pregastrula stage mammalian conceptus consists of both embryonic and non-embryonic components. The latter forms the bulk of the tissues, provides nutrition for the developing embryo and also contributes developmental signals that influence events within the embryo itself. Understanding the origins and relationships between the embryonic and extraembryonic cell lineages is thus central to understanding development in mammals. Despite the apparent gross differences in early developmental strategy and form, the conceptuses of eutherian, marsupial and monotreme mammals show some remarkable similarities in the lineage allocation to trophoblast and hypoblast and in the emergent properties of the two cell types. We suggest that the gross differences can be explained by two relatively small evolutionary timing changes affecting cell adhesion patterns and the polarisation of developmentally significant information. These changes result in the conversion of a unilaminar blastocyst to a morula form composed of blastomeres with increased regulatory capacity.

Animals↗

PubMed2006

Rx-Cre, a tool for inactivation of gene expression in the developing retina.

Rx is a homeobox-containing gene that is critical for vertebrate eye development. Its expression domain delineates a field of cells from which the retina and the ventral hypothalamus develop. The 5' upstream regulatory sequences of the medaka fish Rx gene are functionally conserved during evolution to a degree that they direct gene expression into the Rx-expressing field of cells in mice. Using these sequences, we made a Cre line that can be used for inactivation of gene expression in the developing retina.

Alleles↗

PubMed2001

Similar myogenic functions for myogenin and MRF4 but not MyoD in differentiated murine embryonic stem cells.

The emergence of four genes encoding myogenic bHLH transcription factors in the stem vertebrate is a unique feature of vertebrate evolution that led to the acquisition of new target genes and novel regulatory circuits for skeletal muscle formation. One unresolved question is the extent to which each factor has evolved specialized functions for regulating muscle gene transcription. We have developed a system using differentiated myogenin (-/-) embryonic stem (ES) cells to determine whether other myogenic factors can replace myogenin's function in muscle differentiation. Previously, we showed that constitutively expressed myogenin restores myofiber formation in differentiated myogenin (-/-) ES cells, but constitutively expressed MyoD does not. Here, we confirm the distinction between myogenin and MyoD using another expression vector and show that constitutively expressed MRF4 leads to myofiber formation in myogenin's absence. Our analysis reveals a correlation between the levels of myogenin plus MRF4 and the extent of myofiber formation, suggesting a synergy between these factors. The results indicate that unlike MyoD, MRF4 plays a role similar to myogenin in skeletal muscle differentiation.

Animals↗

PubMed1990

Regulation of the segmentation gene fushi tarazu has been functionally conserved in Drosophila.

An evolutionary approach was applied to identify elements involved in the regulation of the segmentation gene fushi tarazu (ftz) by comparing the Drosophila melanogaster ftz gene with its Drosophila hydei homologue. The overall organization of the ftz gene is very similar in both species. Surprisingly, ftz proved to be inverted in the ANT-C of D. hydei with respect to D. melanogaster. Strong homologies extend over the entire 6 kb of the ftz upstream region with the best match in the 'upstream element'. We identified several highly conserved boxes embedded in unrelated sequences that correspond extremely well to two germ layer specific enhancers in the upstream element. Transformation experiments revealed that D. hydei ftz gene products can restore D. melanogaster ftz function and, furthermore, that trans-acting factors from D. melanogaster recognize and control D. hydei ftz regulatory elements. These findings indicate a conservation of the entire regulatory network among segmentation genes for several millions of years during the evolution of Drosophila.

Animals↗

PubMed1994

Baculovirus p35 prevents developmentally programmed cell death and rescues a ced-9 mutant in the nematode Caenorhabditis elegans.

Programmed cell death, or apoptosis, occurs throughout the course of normal development in most animals and can also be elicited by a number of stimuli such as growth factor deprivation and viral infection. Certain morphological and biochemical characteristics of programmed cell death are similar among different tissues and species. During development of the nematode Caenorhabditis elegans, a single genetic pathway promotes the death of selected cells in a lineally fixed pattern. This pathway appears to be conserved among animal species. The baculovirus p35-encoding gene (p35) is an inhibitor of virus-induced apoptosis in insect cells. Here we demonstrate that expression of p35 in C. elegans prevents death of cells normally programmed to die. This suppression of developmentally programmed cell death results in appearance of extra surviving cells. Expression of p35 can rescue the embryonic lethality of a mutation in ced-9, an endogenous gene homologous to the mammalian apoptotic suppressor bcl-2, whose absence leads to ectopic cell deaths. These results support the hypothesis that viral infection can activate the same cell death pathway as is used during normal development and suggest that baculovirus p35 may act downstream or independently of ced-9 in this pathway.

Animals↗

PubMed1993

SSV1-encoded site-specific recombination system in Sulfolobus shibatae.

We present evidence for the existence of a conservative site-specific recombination system in Archaea by demonstrating integrative recombination of Sulfolobus shibatae virus SSV1 DNA with the host chromosome, catalysed by the SSV1-encoded integrase in vitro. The putative int gene of SSV1 was expressed in Escherichia coli yielding a protein of about 39 kDa. This protein alone efficiently recombined linear DNA substrates containing chromosomal (attA) and viral (attP) attachment sites; recombination with either negatively or positively supercoiled SSV1 DNA was less efficient. Intermolecular attA x attA and attP x attP recombination was also promoted by the SSV integrase. The invariant 44 bp "common attachment core" present in all att sites contained sufficient information to allow recombination, whilst the flanking sequences effected the efficiency. These features clearly distinguish the SSV1--encoded site--specific recombination system from others and make it suitable for the study of regulatory mechanisms of SSV1 genome--host chromosome interaction and investigations of the evolution of the recombination machinery.

Bacteriophages↗

PubMed2006

Protein interaction networks in plants.

Protein-protein interactions are fundamental to virtually every aspect of cellular functions. With the development of high-throughput technologies of both the yeast two-hybrid system and tandem mass spectrometry, genome-wide protein-linkage mapping has become a major objective in post-genomic research. While at least partial "interactome" networks of several model organisms are already available, in the plant field, progress in this respect is slow. However, even with comprehensive protein interaction data still missing, substantial recent advance in the graph-theoretical functional interpretation of complex network architectures might pave the way for novel approaches in plant research. This article reviews current progress and discussions in network biology. Emphasis is put on the question of what can be learned about protein functions and cellular processes by studying the topology of complex protein interaction networks and the evolutionary mechanisms underlying their development. Particularly the intermediate and local levels of network organization--the modules, motifs and cliques--are increasingly recognized as the operational units of biological functions. As demonstrated by some recent results from systematic analyses of plant protein families, protein interaction networks promise to be a valuable tool for a molecular understanding of functional specificities and for identifying novel regulatory components and pathways.

Biological Evolution↗

PubMed1985

An elasmobranchian somatostatin: primary structure and tissue distribution in Torpedo marmorata.

Extracts of brain, stomach, pancreas, and intestine from Torpedo marmorata, an elasmobranchian cartilaginous fish, contained somatostatin-like immunoreactivity. Gel filtration studies demonstrated that material with the elution volume of somatostatin-14 was the only component detected in all tissue extracts. This result contrasts with the situation in mammals where prosomatostatin is processed to multiple molecular forms in a tissue-specific manner. Somatostatin from pancreas and gut was purified to homogeneity and amino acid sequence analysis indicated that T. marmorata somatostatin from both tissues has the same structure as somatostatin-14 isolated from the higher vertebrates. Further examination of other lower vertebrate species is required in order to test the hypothesis that the ability to regulate the production of multiple forms of a regulatory peptide from a single precursor molecule developed only relatively late in evolution.

Amino Acid Sequence↗

PubMed1993

Reconstitution of wild type viral DNA in simian cells transfected with early and late SV40 defective genomes.

The DNAs of polyomaviruses ordinarily exist as a single circular molecule of approximately 5000 base pairs. Variants of SV40, BKV and JCV have been described which contain two complementing defective DNA molecules. These defectives, which form a bipartite genome structure, contain either the viral early region or the late region. The defectives have the unique property of being able to tolerate variable sized reiterations of regulatory and terminus region sequences, and portions of the coding region. They can also exchange coding region sequences with other polyomaviruses. It has been suggested that the bipartite genome structure might be a stage in the evolution of polyomaviruses which can uniquely sustain genome and sequence diversity. However, it is not known if the regulatory and terminus region sequences are highly mutable. Also, it is not known if the bipartite genome structure is reversible and what the conditions might be which would favor restoration of the monomolecular genome structure. We addressed the first question by sequencing the reiterated regulatory and terminus regions of E- and L-SV40 DNAs. This revealed a large number of mutations in the regulatory regions of the defective genomes, including deletions, insertions, rearrangements and base substitutions. We also detected insertions and base substitutions in the T-antigen gene. We addressed the second question by introducing into permissive simian cells, E- and L-SV40 genomes which had been engineered to contain only a single regulatory region. Analysis of viral DNA from transfected cells demonstrated recombined genomes containing a wild type monomolecular DNA structure. However, the complete defectives, containing reiterated regulatory regions, could often compete away the wild type genomes. The recombinant monomolecular genomes were isolated, cloned and found to be infectious. All of the DNA alterations identified in one of the regulatory regions of E-SV40 DNA were present in the recombinant monomolecular genomes. These and other findings indicate that the bipartite genome state can sustain many mutations which wtSV40 cannot directly sustain. However, the mutations can later be introduced into the wild type genomes when the E- and L-SV40 DNAs recombine to generate a new monomolecular genome structure.

Animals↗

PubMed1988

Sequence of the 3386 3' nucleotides of the genome of the AVO1 strain rabies virus: structural similarities in the protein regions involved in transcription.

DNA fragments complementary to the genome of an avirulent strain (AVO1) of the rabies virus were cloned and sequenced. The sequence of the 3386 nucleotides from the 3' end covers the genes encoding the leader RNA, the nucleoprotein N, the phosphoprotein M1 and the matrix protein M2, as well as the intergenic regions. Comparison of the AVO1 sequence with those of other rabies strains reveals a very high conservation at both the nucleotide and the amino acid levels. The non-protein coding regions of the genome (leader gene, untranslated regions flanking mRNAs, untranscribed intergenic regions) are discussed in terms of their possible involvement in the rabies virus biology. Comparison of the rabies genome with those of other unsegmented negative strand RNA viruses (rhabdoviruses and paramyxoviruses) indicates that the start and stop transcription signals, located at the border of each gene encoding a protein, and the regions of the phosphoprotein and matrix proteins that could be implicated in the transcription process, retain a similar overall structure. Thus, it appears that during evolution, these virus genomes have diverged while keeping the protein structures and regulatory sequence important in transcription. These results prompt us to propose that the major distinctive feature of the rabies transcription may arise from the highly variable intergenic regions where the attenuation of transcription is assumed to take place.

Base Sequence↗

PubMed2026

Comparative genomics and full-length transcriptome profiling of wing morphs in Tetrix grossus (Orthoptera: Tetrigidae).

Wing polymorphism represents a paradigmatic dispersal-reproduction trade-off, yet its molecular basis remains uncharacterised in the phylogenetically distant pygmy grasshoppers (Tetrigidae). Here we integrate comparative genomics across ten orthopteran species with full-length transcriptomics of long-winged (FL) and short-winged (FS) Tetrix grossus. OrthoFinder recovered 118 orthogroups specific to T. grossus. Against a backdrop of pronounced gene-family contraction (36 expansions versus 222 contractions; net -186, mirrored at the ancestral Tetrix node, +37/-140), we identified an ancestral, Tetrix-specific expansion of hormone-regulation (12 genes; fold enrichment 7.93) and lipid/carbohydrate-metabolic families organised into syntenic clusters, alongside 513 positively selected genes enriched for integrin-mediated cell adhesion (6 genes), a process relevant to epithelial and appendage morphogenesis. Full-length transcriptomics of one long-winged (FL) and one short-winged (FS) adult female detected 7530 (FL) and 7515 (FS) expressed genes, with 794 FL- and 776 FS-restricted transcriptome-derived SNP-associated genes. The FL morph was enriched for an EGFR/Ras-Rho developmental-patterning axis and neuromuscular flight genes, whereas the FS morph was enriched for insulin/peptide-hormone response and growth-regulatory loci. Overall, we present genomic resources and testable hypotheses concerning the evolution and regulation of wing morphs in Tetrigidae rather than a validated genetic architecture of wing-morph determination.

Animals↗