New words in human mutagenesis

<p>Abstract</p> <p>Background</p> <p>The substitution rates within different nucleotide contexts are subject to varying levels of bias. The most well known example of such bias is the excess of C to T (C > T) mutations in CpG (CG) dinucleotides. The molecular mechanisms underlying this bias are important factors in human genome evolution and cancer development. The discovery of other nucleotide contexts that have profound effects on substitution rates can improve our understanding of how mutations are acquired, and why mutation hotspots exist.</p> <p>Results</p> <p>We compared rates of inherited mutations in 1-4 bp nucleotide contexts using reconstructed ancestral states of human single nucleotide polymorphisms (SNPs) from intergenic regions. Chimp and orangutan genomic sequences were used as outgroups. We uncovered 3.5 and 3.3-fold excesses of T > C mutations in the second position of ATTG and ATAG words, respectively, and a 3.4-fold excess of A > C mutations in the first position of the ACAA word.</p> <p>Conclusions</p> <p>Although all the observed biases are less pronounced than the 5.1-fold excess of C > T mutations in CG dinucleotides, the three 4 bp mutation contexts mentioned above (and their complementary contexts) are well distinguished from all other mutation contexts. This provides a challenge to discover the underlying mechanisms responsible for the observed excesses of mutations.</p

Winnerless competition between sensory neurons generates chaos: A possible mechanism for molluscan hunting behavior

© 2002 American Institute of Physics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics.In the presence of prey, the marine mollusk Clione limacina exhibits search behavior, i.e., circular motions whose plane and radius change in a chaotic-like manner. We have formulated a dynamical model of the chaotic hunting behavior of Clione based on physiological in vivo and in vitroexperiments. The model includes a description of the action of the cerebral hunting interneuron on the receptor neurons of the gravity sensory organ, the statocyst. A network of six receptor model neurons with Lotka–Volterra-type dynamics and nonsymmetric inhibitory interactions has no simple static attractors that correspond to winner take all phenomena. Instead, the winnerless competition induced by the hunting neuron displays hyperchaos with two positive Lyapunov exponents. The origin of the chaos is related to the interaction of two clusters of receptor neurons that are described with two heteroclinic loops in phase space. We hypothesize that the chaotic activity of the receptor neurons can drive the complex behavior of Clione observed during hunting.Support for this work came from NIH Grant No. 2R01 NS38022- 05A1. P.V. acknowledges support from MCT BFI2000-0157. M.R. acknowledges support from U.S. Department of Energy Grant No. DE-FG03-96ER14592

Functional implications of calcium permeability of the channel formed by pannexin 1

Although human pannexins (PanX) are homologous to gap junction molecules, their physiological function in vertebrates remains poorly understood. Our results demonstrate that overexpression of PanX1 results in the formation of Ca2+-permeable gap junction channels between adjacent cells, thus, allowing direct intercellular Ca2+ diffusion and facilitating intercellular Ca2+ wave propagation. More intriguingly, our results strongly suggest that PanX1 may also form Ca2+-permeable channels in the endoplasmic reticulum (ER). These channels contribute to the ER Ca2+ leak and thereby affect the ER Ca2+ load. Because leakage remains the most enigmatic of those processes involved in intracellular calcium homeostasis, and the molecular nature of the leak channels is as yet unknown, the results of this work provide new insight into calcium signaling mechanisms. These results imply that for vertebrates, a new protein family, referred to as pannexins, may not simply duplicate the connexin function but may also provide additional pathways for intra- and intercellular calcium signaling and homeostasis

Dicyemida and Orthonectida: Two Stories of Body Plan Simplification

Two enigmatic groups of morphologically simple parasites of invertebrates, the Dicyemida (syn. Rhombozoa) and the Orthonectida, since the 19th century have been usually considered as two classes of the phylum Mesozoa. Early molecular evidence suggested their relationship within the Spiralia (=Lophotrochozoa), however, high rates of dicyemid and orthonectid sequence evolution led to contradicting phylogeny reconstructions. Genomic data for orthonectids revealed that they are highly simplified spiralians and possess a reduced set of genes involved in metazoan development and body patterning. Acquiring genomic data for dicyemids, however, remains a challenge due to complex genome rearrangements including chromatin diminution and generation of extrachromosomal circular DNAs, which are reported to occur during the development of somatic cells. We performed genomic sequencing of one species of Dicyema, and obtained transcriptomic data for two Dicyema spp. Homeodomain (homeobox) transcription factors, G-protein-coupled receptors, and many other protein families have undergone a massive reduction in dicyemids compared to other animals. There is also apparent reduction of the bilaterian gene complements encoding components of the neuromuscular systems. We constructed and analyzed a large dataset of predicted orthologous proteins from three species of Dicyema and a set of spiralian animals including the newly sequenced genome of the orthonectid Intoshia linei. Bayesian analyses recovered the orthonectid lineage within the Annelida. In contrast, dicyemids form a separate clade with weak affinity to the Rouphozoa (Platyhelminthes plus Gastrotricha) or (Entoprocta plus Cycliophora) suggesting that the historically proposed Mesozoa is a polyphyletic taxon. Thus, dramatic simplification of body plans in dicyemids and orthonectids, as well as their intricate life cycles that combine metagenesis and heterogony, evolved independently in these two lineages

Comparative Analysis of Context-Dependent Mutagenesis in Humans and Fruit Flies

In general, mutation frequencies are context-dependent: specific adjacent nucleotides may influence the probability to observe a specific type of mutation in a genome. Recently, several hypermutable motifs were identified in the human genome. Namely, there is an increased frequency of T>C mutations in the second position of the words ATTG and ATAG and an increased frequency of A>C mutations in the first position of the word ACAA. Previous studies have also shown that there is a remarkable difference between the mutagenesis of humans and drosophila. While C>T mutations are overrepresented in the CG context in humans (and other vertebrates), this mutation regularity is not observed in Drosophila melanogaster. Such differences in the observed regularities of mutagenesis between representatives of different taxa might reflect differences in the mechanisms involved in mutagenesis. We performed a systematical comparison of mutation regularities within 2–4 bp contexts in Homo sapiens and Drosophila melanogaster and found that the aforementioned contexts are not hypermutable in fruit flies. It seems that most mutation contexts affect mutation rates in a similar manner in H. sapiens and D. melanogaster; however, several important exceptions are noted and discussed

Comparative Analysis of Context-Dependent Mutagenesis Using Human and Mouse Models

Substitution rates strongly depend on their nucleotide context. One of the most studied examples is the excess of C > T mutations in the CG context in various groups of organisms, including vertebrates. Studies on the molecular mechanisms underlying this mutation regularity have provided insights into evolution, mutagenesis, and cancer development. Recently several other hypermutable motifs were identified in the human genome. There is an increased frequency of T > C mutations in the second position of the words ATTG and ATAG and an increased frequency of A > C mutations in the first position of the word ACAA. For a better understanding of evolution, it is of interest whether these mutation regularities are human specific or present in other vertebrates, as their presence might affect the validity of currently used substitution models and molecular clocks. A comprehensive analysis of mutagenesis in 4 bp mutation contexts requires a vast amount of mutation data. Such data may be derived from the comparisons of individual genomes or from single nucleotide polymorphism (SNP) databases. Using this approach, we performed a systematical comparison of mutation regularities within 2–4 bp contexts in Mus musculus and Homo sapiens and uncovered that even closely related organisms may have notable differences in context-dependent mutation regularities

Are there gap junctions without connexins or pannexins?

Abstract Background Gap junctions (GJ) are one of the most common forms of intercellular communication. GJs are assembled from proteins that form channels connecting the cytoplasm of adjacent cells. They are considered to be the main or the only type of intercellular channels and the universal feature of all multicellular animals. Two unrelated protein families are currently considered to be involved in this function, namely, connexins and pannexins (pannexins/innexins). Pannexins were hypothesized to be the universal GJ proteins of multicellular animals, distinct from connexins that are characteristic of chordates only. Here we have revised this supposition by applying growing high throughput sequencing data from diverse metazoan species. Results Pannexins were found in Chordates, Ctenophores, Cnidarians, and in the most major groups of bilateral protostomes. Yet some metazoans appear to have neither connexins nor pannexins in their genomes. We detected no connexins or pannexins/innexins homologues in representatives of all five classes of echinoderms and their closest relatives hemichordates with available genomic sequences. Despite this, our intracellular recordings demonstrate direct electrical coupling between blastomeres at the 2-cell embryo of the echinoderm (starfish Asterias rubens). In these experiments, carboxyfluorescein fluorescent dye did not diffuse between electrically coupled cells. This excludes the possibility that the observed electrical coupling is mediated by incomplete cytoplasm separation during cleavage. Conclusion Functional GJs are present in representatives of the clade that lack currently recognized GJ protein families. New undiscovered protein families utilized for intercellular channels are predicted. It is possible that the new type(s) of intercellular channels are present in parallel to pannexin and connexin gap junctions in animal groups, other than Echinodermata

Electrophysiology of the rhythmic defecation program in nematode Heterorhabditis megidis

Abstract The nervous system controls most rhythmic behaviors, with a remarkable exception. In Caenorhabditis elegans periodic defecation rhythm does not appear to involve the nervous system. Such oscillations are studied in detail with genetic and molecular biology tools. The small size of C. elegans cells impairs the use of standard electrophysiological methods. We studied a similar rhythmic pacemaker in the noticeably larger gut cells of Heterorhabditis megidis nematode. H. megidis defecation cycle is driven by a central pattern generator (CPG) associated with unusual all-or-none hyper-polarization “action potential”. The CPG cycle period depends on the membrane potential and CPG cycling also persisted in experiments where the membrane potential of gut cells was continuously clamped at steady voltage levels. The usual excitable tissue description does not include the endoderm or imply the generation of hyper-polarization spikes. The nematode gut cells activity calls for a reevaluation of the excitable cells definition