Sequences and consequences Brenner, Sydney
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
01/2010, Letnik:
365, Številka:
1537
Journal Article
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The conversion of data into knowledge constitutes a great challenge for future biological research. The new science of Systems Biology claims to be able to solve the problem but I contend that this ...approach will fail because deducing models of function from the behaviour of a complex system is an inverse problem that is impossible to solve. In addition, one cannot easily escape into high-level holistic approaches, since the essence of all biological systems is that they are encoded as molecular descriptions in their genes and since genes are molecules and exert their functions through other molecules, the molecular explanation must constitute the core of understanding biological systems. We then solve the forward problem of computing the behaviour of the system from its components and their interactions. I propose that the correct level of abstraction is the cell and provide an outline of Cellmap, a design for a system to organize biological information.
Coleoid cephalopods (octopus, squid and cuttlefish) are active, resourceful predators with a rich behavioural repertoire. They have the largest nervous systems among the invertebrates and present ...other striking morphological innovations including camera-like eyes, prehensile arms, a highly derived early embryogenesis and a remarkably sophisticated adaptive colouration system. To investigate the molecular bases of cephalopod brain and body innovations, we sequenced the genome and multiple transcriptomes of the California two-spot octopus, Octopus bimaculoides. We found no evidence for hypothesized whole-genome duplications in the octopus lineage. The core developmental and neuronal gene repertoire of the octopus is broadly similar to that found across invertebrate bilaterians, except for massive expansions in two gene families previously thought to be uniquely enlarged in vertebrates: the protocadherins, which regulate neuronal development, and the C2H2 superfamily of zinc-finger transcription factors. Extensive messenger RNA editing generates transcript and protein diversity in genes involved in neural excitability, as previously described, as well as in genes participating in a broad range of other cellular functions. We identified hundreds of cephalopod-specific genes, many of which showed elevated expression levels in such specialized structures as the skin, the suckers and the nervous system. Finally, we found evidence for large-scale genomic rearrangements that are closely associated with transposable element expansions. Our analysis suggests that substantial expansion of a handful of gene families, along with extensive remodelling of genome linkage and repetitive content, played a critical role in the evolution of cephalopod morphological innovations, including their large and complex nervous systems.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Heterogametic sex chromosomes have evolved independently in various lineages of vertebrates. Such sex chromosome pairs often contain nonrecombining regions, with one of the chromosomes harboring a ...master sex-determining (SD) gene. It is hypothesized that these sex chromosomes evolved from a pair of autosomes that diverged after acquiring the SD gene. By linkage and association mapping of the SD locus in fugu (Takifugu rubripes), we show that a SNP (C/G) in the anti-Müllerian hormone receptor type II (Amhr2) gene is the only polymorphism associated with phenotypic sex. This SNP changes an amino acid (His/Asp384) in the kinase domain. While females are homozygous (His/His384), males are heterozygous. Sex in fugu is most likely determined by a combination of the two alleles of Amhr2. Consistent with this model, the medaka hotei mutant carrying a substitution in the kinase domain of Amhr2 causes a female phenotype. The association of the Amhr2 SNP with phenotypic sex is conserved in two other species of Takifugu but not in Tetraodon. The fugu SD locus shows no sign of recombination suppression between X and Y chromosomes. Thus, fugu sex chromosomes represent an unusual example of proto-sex chromosomes. Such undifferentiated X-Y chromosomes may be more common in vertebrates than previously thought.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cyclostomes, comprising jawless vertebrates such as lampreys and hagfishes, are the sister group of living jawed vertebrates (gnathostomes) and hence an important group for understanding the origin ...and diversity of vertebrates. In vertebrates and other metazoans, Hox genes determine cell fate along the anteroposterior axis of embryos and are implicated in driving morphological diversity. Invertebrates contain a single Hox cluster (either intact or fragmented), whereas elephant shark, coelacanth, and tetrapods contain four Hox clusters owing to two rounds of whole-genome duplication (“1R” and “2R”) during early vertebrate evolution. By contrast, most teleost fishes contain up to eight Hox clusters because of an additional “teleost-specific” genome duplication event. By sequencing bacterial artificial chromosome (BAC) clones and the whole genome, here we provide evidence for at least six Hox clusters in the Japanese lamprey (Lethenteron japonicum). This suggests that the lamprey lineage has experienced an additional genome duplication after 1R and 2R. The relative age of lamprey and human paralogs supports this hypothesis. Compared with gnathostome Hox clusters, lamprey Hox clusters are unusually large. Several conserved noncoding elements (CNEs) were predicted in the Hox clusters of lamprey, elephant shark, and human. Transgenic zebrafish assay indicated the potential of CNEs to function as enhancers. Interestingly, CNEs in individual lamprey Hox clusters are frequently conserved in multiple Hox clusters in elephant shark and human, implying a many-to-many orthology relationship between lamprey and gnathostome Hox clusters. Such a relationship suggests that the first two rounds of genome duplication may have occurred independently in the lamprey and gnathostome lineages.
Understanding how RNA binding proteins control the splicing code is fundamental to human biology and disease. Here, we present a comprehensive study to elucidate how heterogeneous nuclear ...ribonucleoparticle (hnRNP) proteins, among the most abundant RNA binding proteins, coordinate to regulate alternative pre-mRNA splicing (AS) in human cells. Using splicing-sensitive microarrays, crosslinking and immunoprecipitation coupled with high-throughput sequencing (CLIP-seq), and cDNA sequencing, we find that more than half of all AS events are regulated by multiple hnRNP proteins and that some combinations of hnRNP proteins exhibit significant synergy, whereas others act antagonistically. Our analyses reveal position-dependent RNA splicing maps, in vivo consensus binding sites, a surprising level of cross- and autoregulation among hnRNP proteins, and the coordinated regulation by hnRNP proteins of dozens of other RNA binding proteins and genes associated with cancer. Our findings define an unprecedented degree of complexity and compensatory relationships among hnRNP proteins and their splicing targets that likely confer robustness to cells.
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► Thousands of binding sites and splicing events identified for major hnRNP proteins ► HnRNP proteins act cooperatively, regulating cassette exons in similar directions ► HnRNP proteins cross- and autoregulate ► HnRNP proteins regulate other RNA binding proteins and cancer related genes
Heterogeneous nuclear ribonucleoparticle (hnRNP) proteins are among the most abundant RNA binding proteins (RBPs) and regulate cellular RNA levels. Through the integration of several genomic approaches, Huelga, Yeo, and colleagues have identified thousands of binding sites, splicing events, and regulated genes for major hnRNP proteins A1, A2/B1, F, H1, M, and U. HnRNP proteins cross- and autoregulate each other and a whole network of RBPs. These findings define an unprecedented degree of complexity and compensatory relationships among hnRNP proteins.
We demonstrate the use of fluorescent molecular rotors as probes for detecting biomolecular interactions, specifically peptide–protein interactions. Molecular rotors undergo twisted intramolecular ...charge transfer upon irradiation, relax via the nonradiative torsional relaxation pathway, and have been typically used as viscosity probes. Their utility as a tool for detecting specific biomolecular interactions has not been explored. Using the well characterized p53–Mdm2 interaction as a model system, we designed a 9-(2-carboxy-2-cyanovinyl) julolidine-based p53 peptide reporter, JP1-R, which fluoresces conditionally only upon Mdm2 binding. The reporter was used in a rapid, homogeneous assay to screen a fragment library for antagonists of the p53–Mdm2 interaction, and several inhibitors were identified. Subsequent validation of these hits using established secondary assays suggests increased sensitivity afforded by JP1-R. The fluorescence of molecular rotors contingent upon target binding makes them a versatile tool for detecting specific biomolecular interactions.
Traditional methods for selecting aptamers require multiple rounds of selection and optimization in order to identify aptamers that bind with high affinity to their targets. Here we describe an assay ...that requires only one round of positive selection followed by high-throughput DNA sequencing and informatic analysis in order to select high-affinity aptamers. The assay is flexible, requires less hands on time, and can be used by laboratories with minimal expertise in aptamer biology to quickly select high-affinity aptamers to a target of interest. This assay has been utilized to successfully identify aptamers that bind to thrombin with dissociation constants in the nanomolar range.
Vasopressin and oxytocin are mammalian neurohypophysial hormones with distinct functions. Vasopressin is involved mainly in osmoregulation and oxytocin is involved primarily in parturition and ...lactation. Jawed vertebrates contain at least one homolog each of vasopressin and oxytocin, whereas only a vasopressin-family hormone, vasotocin, has been identified in jawless vertebrates. The genes encoding vasopressin and oxytocin are closely linked tail-to-tail in eutherian mammals whereas their homologs in chicken, Xenopus and coelacanth (vasotocin and mesotocin) are linked tail-to-head. In contrast, their pufferfish homologs, vasotocin and isotocin, are located on the same strand of DNA with isotocin located upstream of vasotocin and separated by five genes. These differences in the arrangement of the two genes in different bony vertebrate lineages raise questions about their origin and ancestral arrangement. To trace the origin of these genes, we have sequenced BAC clones from the neurohypophysial gene loci in a cartilaginous fish, the elephant shark (Callorhinchus milii), and in a jawless vertebrate, the Japanese lamprey (Lethenteron japonicum). We have also analyzed the neurohypophysial hormone gene locus in an invertebrate chordate, the amphioxus (Branchiostoma floridae).
The elephant shark neurohypophysial hormone genes encode vasotocin and oxytocin, and are linked tail-to-head like their homologs in coelacanth and non-eutherian tetrapods. Besides the hypothalamus, the two genes are also expressed in the ovary. In addition, the vasotocin gene is expressed in the kidney, rectal gland and intestine. These expression profiles indicate a paracrine role for the two hormones. The lamprey locus contains a single neurohypophysial hormone gene, the vasotocin. The synteny of genes in the lamprey locus is conserved in elephant shark, coelacanth and tetrapods but disrupted in teleost fishes. The amphioxus locus encodes a single neurohypophysial hormone, designated as Ile4vasotocin.
The vasopressin- and oxytocin-family of neurohypophysial hormones evolved in a common ancestor of jawed vertebrates through tandem duplication of the ancestral vasotocin gene. The duplicated genes were linked tail-to-head like their homologs in elephant shark, coelacanth and non-eutherian tetrapods. In contrast to the conserved linkage of the neurohypophysial genes in these vertebrates, the neurohypophysial hormone gene locus has experienced extensive rearrangements in the teleost lineage.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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