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PubMed1981

Tumourigenesis: the subterfuge of selection.

Variation of rearrangement of regulatory genes is responsible for cellular malignant change. These types of chromosomal variations also produce heterochrony or paedomorphic evolution at the organismal level. Analogously, neoplasia represents a cellular 'macroevolutionary' event, and a tumour can be said to be an evolved population of cells. To understand this cellular evolution to malignancy, it may be necessary to go beyond a 'clonal selection' (adaptationist) explanation of neoplastic alteration. In the pericellular environment 'natural selection' consists of the organizational restraints of surrounding cells as well as the host's immunological surveillance and non-specific monocyte-macrophage systems. Indirect evidence suggests that success for the neoplasm depends not upon 'clonal selection', but solely upon a genetic methodology-the function of which is to elude selection. The author has coined the term 'cellular heterochrony' to illustrate analogic similarities in the molecular modes of speciation between anaplastic cancer cells and the heterochronic evolution of organisms. By reverting to juvenile (embryonic) repertoire of cellular behaviour a tumour secures its own tenure or niche by usurping the host's armamentarium of selection forces, employing many of the same or similar methods by which implanting and invading tissues of the mammalian embryo forestall maternal detection and rejection. A number of ways by which the tumour blocks, subverts or evades selection are discussed.

Biological Evolution↗
PubMed2002

Characterization and evolution of the mitochondrial DNA control region in hornbills (Bucerotiformes).

We determined the mitochondrial DNA control region sequences of six Bucerotiformes. Hornbills have the typical avian gene order and their control region is similar to other avian control regions in that it is partitioned into three domains: two variable domains that flank a central conserved domain. Two characteristics of the hornbill control region sequence differ from that of other birds. First, domain I is AT rich as opposed to AC rich, and second, the control region is approximately 500 bp longer than that of other birds. Both these deviations from typical avian control region sequence are explainable on the basis of repeat motifs in domain I of the hornbill control region. The repeat motifs probably originated from a duplication of CSB-1 as has been determined in chicken, quail, and snowgoose. Furthermore, the hornbill repeat motifs probably arose before the divergence of hornbills from each other but after the divergence of hornbills from other avian taxa. The mitochondrial control region of hornbills is suitable for both phylogenetic and population studies, with domains I and II probably more suited to population and phylogenetic analyses, respectively.

Animals↗
PubMed1997

A highly conserved apoptotic suppressor gene is located near the chicken T-cell receptor alpha chain constant region.

A cosmid clone containing the chicken T-cell receptor alpha chain constant region (TCRAC) was sequenced. The cosmid contains the TCRAC gene, six putative joining gene segments (TCRAJ), and surprisingly, a chicken homologue for the human apoptotic suppressor gene, defender against cell death (DAD1). The DAD1 gene is 6.3 kilobases downstream of the TCRAC gene and has an inverted transcription orientation with respect to the TCRAC gene. The cDNA for the chicken DAD1 gene is 597 base pairs in length and encodes a highly conserved hydrophobic protein. The proximal location of DAD1 to the TCRAC locus has also been confirmed in both humans and mouse. The location of the DAD1 gene suggests that DAD1 may play an important role in T-cell related apoptotic activities.

Amino Acid Sequence↗
PubMed1981

Mechanism of action of an orally active PGE1-analogue in pregnant guinea-pigs.

At the 43rd day of pregnancy 6 Experimental guinea-pigs were treated orally with the PGE1-analogue, CP 48,630 (Pfizer), while 6 animals served as vehicle Controls. An average dose of 1.5 mg CP 48,630 compromized the conceptus and provoked abortion in 6.6 +/- 1.4 hours in all 6 Experimental guinea-pigs. The vehicle Controls, with all pregnancies continuing intact, had high P-levels in peripheral and uterine vein plasma, ovaries, placenta and uterine tissue and low PGF-levels in the uterine vein plasma. In contrast, in the Experimental animals the P-levels were significantly reduced and the PGF-levels elevated. Thus, the "PG-Impact" rapidly tipped the regulatory balance of pregnancy, compromized the conceptus (all fetuses were dead and the placentae discolored), and provoked the evolution of uterine activity culminating in abortion.

Abortion, Induced↗
PubMed2006

Tribbles: a family of kinase-like proteins with potent signalling regulatory function.

The recent identification of tribbles as regulators of signal processing systems and physiological processes, including development, together with their potential involvement in diabetes and cancer, has generated considerable interest in these proteins. Tribbles have been reported to regulate activation of a number of intracellular signalling pathways with roles extending from mitosis and cell activation to apoptosis and modulation of gene expression. The current review summarises our current understanding of interactions between tribbles and various other proteins. Since our understanding on the molecular basis of tribbles function is far from complete, we also describe a bioinformatic analysis of various segments of tribbles proteins, which has revealed a number of highly conserved peptide motifs with potentially important functional roles.

Amino Acid Motifs↗
PubMed2006

Gonadotropin-releasing hormone signaling in behavioral plasticity.

Sex and reproduction sculpt brain and behavior throughout life and evolution. In vertebrates, gonadotropin-releasing hormone (GnRH) is essential to these processes. Recent advances have uncovered novel regulatory mechanisms in GnRH signaling, such as the initiation of sexual maturation by kisspeptins. Yet despite our increasing molecular knowledge, we know very little about environmental influences on GnRH signaling and reproductive behavior. Alternative model systems have been crucial for understanding the plasticity of GnRH effects within an organismal context. For instance, GnRH signaling is under the control of seasonal cues in songbirds, whereas social signals regulate GnRH in cichlid fishes, with crucial consequences for reproduction and behavior. Analyzing cellular signaling cascades within an organismic context is essential for an integrative understanding of GnRH function.

Animals↗
PubMed2005

Promoter activity of sea lamprey proopiocortin and proopiomelanotropin genes in AtT-20/D16v cells.

Adrenocorticotropic hormone (ACTH) and melanophore-stimulating hormone (MSH) are produced in the pars distalis and pars intermedia, respectively, throughout vertebrates. These hormones together with beta-endorphin are encoded on a single gene proopiomelanocortin (POMC) in gnathostomes, but in the sea lamprey, an agnathan, ACTH and MSH are encoded on two separate genes, proopiocortin (POC) and proopiomelanotropin (POM), respectively. Moreover, the nucleotide sequences of 5'-flanking regions of the POC and POM genes are significantly different from each other. To investigate the potential promoter activities of the POC and POM genes, we constructed promoter reporter plasmids by fusing the 5' flanking sequences (nucleotides -1151 to +31 and -2510 to +51, respectively) to a firefly luciferase gene. Transient transfection studies in AtT-20/D16v cells, which derived from a mouse pituitary tumor cell line, revealed that the 5'-flanking sequence of the POC gene did not exhibit promoter activity, whereas that of the POM gene showed the activity at high levels nearly equivalent to SV40 promoter. Analysis of a series of the 5'-deleted reporter for the POM gene in the AtT-20/D16v cells demonstrated that the 422 bp 5'-flanking sequence was sufficient for promoter activity, while the sequence from -853 to -574 may contain negatively acting regulatory elements. Because the POC and POM genes are supposed to have differentiated from a common ancestor, during evolution, the POC gene may lack essential element(s) for expression in the AtT-20/D16v cells.

Adrenocorticotropic Hormone↗
PubMed2004

Evidence for turnover of functional noncoding DNA in mammalian genome evolution.

The vast majority of the mammalian genome does not code for proteins, and a fundamental question in genomics is: What proportion of the noncoding mammalian genome is functional? Most attempts to address this issue use sequence comparisons between highly diverged mammals such as human and mouse to identify conservation due to negative selection. But such comparisons will underestimate the true proportion of functional noncoding DNA if there is turnover, if patterns of negative selection change over time. Here we test whether the inferred level of negative selection differs between different pairwise species comparisons. Using a multiple alignment of more than a megabase of contiguous sequence from eight mammalian species, we find a strong negative relationship between inferred levels of negative selection and pairwise divergence using 21 pairwise comparisons. This result suggests that there is a high rate of turnover of functional noncoding elements in the mammalian genome, so measures of functional constraint based on human-mouse comparisons may seriously underestimate the true value.

Animals↗
PubMed2003

Sensitization associated with stressors and cytokine treatments.

Like stressors, interleukin-1beta and tumor necrosis factor-alpha (TNF-alpha) increase hypothalamic-pituitary-adrenal (HPA) activity and monoamine turnover at hypothalamic and extrahypothalamic sites. These effects can be re-elicited more readily upon reintroduction of these challenges (sensitization), depending on their time of re-exposure and the particular system being assessed. Following TNF-alpha administration, the co-expression of corticotropin releasing hormone (CRH) and arginine vasopressin increased within the median eminence, peaking 7-14 days after treatment, and was associated with an early corticosterone sensitization. However, the re-elicitation of sickness symptoms and corticosterone release was most pronounced at lengthy re-exposure intervals (28 days), possibly reflecting histamine release from mast cells. In addition, the cytokine engendered the sensitization of norepinephrine and serotonin utilization, and CRH immunoreactivity at mesocorticolimbic sites, but these effects were most prominent at brief re-exposure intervals (1-7 days). Cytokines may independently prime multiple regulatory systems, and by virtue of the neurochemical changes imparted, have both immediate and proactive influences on the evolution of psychopathology.

Animals↗
PubMed1993

Bacterial chromosome origins of replication.

Bacteria regulate chromosomal replication from one specific origin. We compare the regulatory requirements, DNA structures, and biochemical properties of the prototypic Escherichia coli origin with those of evolutionarily distant Bacillus subtilis and Caulobacter crescentus origins. The ubiquitous DnaA protein is a major regulator of all three bacterial origins. Unique features of these origins, however, may reflect specific regulatory requirements placed on them.

Bacteria↗
PubMed1999

Characterization of in vivo developmental chromosome fragmentation intermediates in E. crassus.

Ligation-mediated PCR was used to characterize intermediates in the fragmentation/de novo telomere addition process that occurs during sexual reproduction in the ciliate E. crassus. Fragmentation generates ends with 6-base, 3' overhangs that have 5'-phosphate and 3'-hydroxyl groups. These intermediates are detected only during the period of chromosome fragmentation. Fragmentation always occurs at a precise distance from a conserved sequence, the E-Cbs, indicating that it is a key cis-acting element in the process. The results also serve to identify the natural substrate for de novo telomere addition and indicate that telomerase recognizes, and compensates for, partial telomeric repeats at the ends of fragmentation intermediates. Similarities of the Euplotes fragmentation/telomere addition process to the movement of some non-long terminal repeat retrotransposons are discussed.

Animals↗
PubMed2005

Contributions of GABAA receptor subtype selectivity to abuse liability and dependence potential of pharmacological treatments for anxiety and sleep disorders.

When benzodiazepines (BZs) supplanted barbiturates as a favored, safer treatment for anxiety and sleep disorders in the 1960s, the abuse liability and dependence potential of these drugs were little understood. Widespread recognition of the difficulty of stopping use of chronically taken BZs emerged through the popular press in the late 1970s, which resulted in reluctance to prescribe these otherwise clinically useful compounds. Evolution of the understanding of the biochemical basis for BZ effects in the 1980s and 1990s, coupled with regulatory emphasis on collection of data used in legal scheduling decisions, made possible a targeted search for drugs that would provide effective treatment for anxiety disorders in the absence of abuse liability or dependence potential. Compounds that have selective efficacy at subtypes of the gamma-aminobutyric acid type A receptor, are active in preclinical anxiolytic screens, but negative in preclinical studies of behavior relevant to evaluation of abuse liability appear to be one promising means for achieving this end.

Anxiety Disorders↗
PubMed2000

Analysis of expressed sequence tags indicates 35,000 human genes.

The number of protein-coding genes in an organism provides a useful first measure of its molecular complexity. Single-celled prokaryotes and eukaryotes typically have a few thousand genes; for example, Escherichia coli has 4,300 and Saccharomyces cerevisiae has 6,000. Evolution of multicellularity appears to have been accompanied by a several-fold increase in gene number, the invertebrates Caenorhabditis elegans and Drosophila melanogaster having 19,000 and 13,600 genes, respectively. Here we estimate the number of human genes by comparing a set of human expressed sequence tag (EST) contigs with human chromosome 22 and with a non-redundant set of mRNA sequences. The two comparisons give mutually consistent estimates of approximately 35,000 genes, substantially lower than most previous estimates. Evolution of the increased physiological complexity of vertebrates may therefore have depended more on the combinatorial diversification of regulatory networks or alternative splicing than on a substantial increase in gene number.

Alternative Splicing↗
PubMed2025

Exploring the genetics of social behaviour in C. calcarata.

Studies investigating social evolution often focus on species that are obligately eusocial, where presumably all of the adaptive genetic changes associated with sociality have already been completed. To fully understand eusociality, we must study species with facultative social behaviour. The small carpenter bee Ceratina calcarata is an ideal model for studying the genetics and molecular biology of eusocial evolution as it can exhibit both subsocial behaviour with parental care and social behaviour facilitated by the altruistic dwarf eldest daughter. Here, we sequenced the genomes of subsocial and social C. calcarata to identify mutations and genes associated with social behaviour and used these data to test several hypotheses related to the evolution of eusociality. Many single nucleotide polymorphisms that had high levels of genetic differentiation (Fst) between social and subsocial C. calcarata were in or near genes or regions important for regulating gene expression. These results are consistent with the Genetic Toolkit Hypothesis of eusocial evolution. Our findings suggest that the low behavioural complexity observed in C. calcarata may involve modulation of existing regulatory genes and gene networks to generate phenotypes associated with social behaviour.

Animals↗
PubMed2000

Hox cluster genomics in the horn shark, Heterodontus francisci.

Reconstructing the evolutionary history of Hox cluster origins will lead to insights into the developmental and evolutionary significance of Hox gene clusters in vertebrate phylogeny and to their role in the origins of various vertebrate body plans. We have isolated two Hox clusters from the horn shark, Heterodontus francisci. These have been sequenced and compared with one another and with other chordate Hox clusters. The results show that one of the horn shark clusters (HoxM) is orthologous to the mammalian HoxA cluster and shows a structural similarity to the amphioxus cluster, whereas the other shark cluster (HoxN) is orthologous to the mammalian HoxD cluster based on cluster organization and a comparison with noncoding and Hox gene-coding sequences. The persistence of an identifiable HoxA cluster over an 800-million-year divergence time demonstrates that the Hox gene clusters are highly integrated and structured genetic entities. The data presented herein identify many noncoding sequence motifs conserved over 800 million years that may function as genetic control motifs essential to the developmental process.

Animals↗
PubMed1987

Mutations that inactivate a yeast transcriptional regulatory protein cluster in an evolutionarily conserved DNA binding domain.

The protein encoded by the GAL4 gene of the yeast Saccharomyces cerevisiae binds to DNA upstream of several genes and activates transcription. To try to understand these processes, we have undertaken a genetic analysis of GAL4. Here we report that nearly all missense mutations in GAL4, selected in vivo to lack function of the protein, cluster in the small region of the gene that encodes the DNA binding domain. About half of these mutations alters a cysteine-rich region of the protein highly homologous to several eukaryotic DNA binding proteins; the other half alters some of the 20 amino acids adjacent to the cysteine-rich region. Nearly all of the missense mutations that alter the DNA binding domain abolish the DNA binding activity of GAL4 protein measured in vitro. In contrast, nearly all of the mutations that alter the 3' 95% of the gene that encodes the transcription activation function are nonsense or frameshift mutations. These results support the idea that the conserved cysteine-rich sequence motif is directly involved in binding of several eukaryotic transcriptional regulatory proteins to DNA.

Amino Acid Sequence↗
PubMed1995

Sequence similarity analysis of Escherichia coli proteins: functional and evolutionary implications.

A computer analysis of 2328 protein sequences comprising about 60% of the Escherichia coli gene products was performed using methods for database screening with individual sequences and alignment blocks. A high fraction of E. coli proteins--86%--shows significant sequence similarity to other proteins in current databases; about 70% show conservation at least at the level of distantly related bacteria, and about 40% contain ancient conserved regions (ACRs) shared with eukaryotic or Archaeal proteins. For > 90% of the E. coli proteins, either functional information or sequence similarity, or both, are available. Forty-six percent of the E. coli proteins belong to 299 clusters of paralogs (intraspecies homologs) defined on the basis of pairwise similarity. Another 10% could be included in 70 superclusters using motif detection methods. The majority of the clusters contain only two to four members. In contrast, nearly 25% of all E. coli proteins belong to the four largest superclusters--namely, permeases, ATPases and GTPases with the conserved "Walker-type" motif, helix-turn-helix regulatory proteins, and NAD(FAD)-binding proteins. We conclude that bacterial protein sequences generally are highly conserved in evolution, with about 50% of all ACR-containing protein families represented among the E. coli gene products. With the current sequence databases and methods of their screening, computer analysis yields useful information on the functions and evolutionary relationships of the vast majority of genes in a bacterial genome. Sequence similarity with E. coli proteins allows the prediction of functions for a number of important eukaryotic genes, including several whose products are implicated in human diseases.

Algorithms↗