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PubMed2003

Patterns of nucleotide polymorphism and divergence in the odorant-binding protein genes OS-E and OS-F: analysis in the melanogaster species subgroup of Drosophila.

The Olfactory Specific-E and -F genes (OS-E and OS-F) belong to the odorant-binding protein gene family, which includes the general odorant-binding proteins and the pheromone-binding proteins. In Drosophila melanogaster, these genes are arranged in tandem in a genomic region near the centromere of chromosome arm 3R. We examined the pattern of DNA sequence variation in an approximately 7-kb genomic region encompassing the two OS genes in four species of the melanogaster subgroup of Drosophila and in a population sample of D. melanogaster. We found that both the OS-E and the OS-F gene are present in all surveyed species. Nucleotide divergence estimates would support that the two genes are functional, although they diverge in their functional constraint. The pattern of nucleotide variation in D. melanogaster also differed between genes. Variation in the OS-E gene region exhibited an unusual and distinctive pattern: (i) a relatively high number of fixed amino acid replacements in the encoded protein and (ii) a peak of nucleotide polymorphism around the OS-E gene. These results are unlikely under the neutral model and suggest the action of natural selection in the evolution of the two odorant-binding protein genes.

Amino Acid Sequence↗
PubMed1993

Effects of water restriction on digestive function in two macropodid marsupials from divergent habitats and the feral goat.

The effects of water restriction on digestive function in the euro (Macropus robustus erubescens) found in the arid zone of inland Australia, the eastern wallaroo (M.r.robustus) from more mesic regions of eastern Australia, and the feral goat (Capra hircus) found throughout the range of M. robustus, were compared in order to examine some physiological adaptations required by herbivores for the exploitation of arid environments. Eight animals of each species were held in individual metabolism cages in temperature-moderated rooms and given a chopped hay diet ad libitum. Half the animals were restricted to 40 ml water.kg-0.80.day-1. This was 40%, 32% and 57% of voluntary drinking water intake in the euro, wallaroo and goat, respectively. All species responded to water restriction by reducing faecal, urinary and evaporative water losses in association with reductions in feed intake. All animals increased urine osmolality and electrolyte concentrations but not to maximal levels, while packed-cell volume and plasma osmolality and electrolyte concentrations were unaffected by water restriction. The euro displayed a suite of characteristics that separated it from the wallaroo in terms of physiological adaptation, including lower voluntary water intake, an increase in fibre digestibility and maintenance of nitrogen balance during water restriction, and lower faecal water efflux associated with a consistently lower faecal water content (54% versus 59% water in the wallaroo during water restriction, P < 0.05). The euro's colon was 37% longer (P < 0.01) than that of the wallaroo. The goat had the lowest faecal water efflux (P < 0.05) and the longest colon (P < 0.001). Water restriction did not affect water content in digesta, nor short-chain fatty acid concentrations or production rates in vitro. Total body water, as a proportion of body mass, was depressed (P < 0.05) in the macropodids, but not in the goat. The reduction in dietary nitrogen intake, which accompanied water restriction, was partially compensated by an increase in urea degradation in the gut from 68% to 76% of urea synthesis water-restricted macropodids. These responses to water restriction are discussed in relation to those reported in other macropodid and ruminant species.

Animals↗
PubMed1975

Proposal concerning mechanism of evolution of the genome of Escherichia coli.

Many pairs of genes whose gene products are functionally related lie either 90 degrees or 180 degrees apart on the circular map of the E. coli chromosome. A mechanism of evolution is proposed that involves two sequential duplications of an ancestral genome, followed by mutation and divergence of function of replicate genes.

Biological Evolution↗
PubMed1989

Structural and functional analysis of insulin-like growth factors.

The insulin and insulin-like growth factor family of peptides are proteins with similar structural characteristics whose functions have diverged during evolution. Recent studies have provided a great deal of information regarding structural characteristics of these peptides, the structures of the genes that control their biosynthesis, and determination of their receptor structures. Initially these factors were believed to function as classical hormones and the endocrine regulation of their blood concentrations was studied intensively. More recently several cell types have been shown to secrete these peptides and the autocrine and paracrine regulation of insulin-like growth factor secretion by cells and tissues has received extensive characterization. Following secretion into interstitial fluids the IGF's associate with high affinity, soluble binding proteins. These proteins are capable of modulating receptor binding and growth factor biological activity. The structure of these proteins and the variables that control their secretion are currently being determined. In spite of this information significant gaps in our knowledge exist regarding the mechanisms by which these peptides stimulate replication.

Animals↗
PubMed2005

Conservation of pregnancy-specific glycoprotein (PSG) N domains following independent expansions of the gene families in rodents and primates.

BACKGROUND: Rodent and primate pregnancy-specific glycoprotein (PSG) gene families have expanded independently from a common ancestor and are expressed virtually exclusively in placental trophoblasts. However, within each species, it is unknown whether multiple paralogs have been selected for diversification of function, or for increased dosage of monofunctional PSG. We analysed the evolution of the mouse PSG sequences, and compared them to rat, human and baboon PSGs to attempt to understand the evolution of this complex gene family. RESULTS: Phylogenetic tree analyses indicate that the primate N domains and the rodent N1 domains exhibit a higher degree of conservation than that observed in a comparison of the mouse N1 and N2 domains, or mouse N1 and N3 domains. Compared to human and baboon PSG N domain exons, mouse and rat PSG N domain exons have undergone less sequence homogenisation. The high non-synonymous substitution rates observed in the CFG face of the mouse N1 domain, within a context of overall conservation, suggests divergence of function of mouse PSGs. The rat PSG family appears to have undergone less expansion than the mouse, exhibits lower divergence rates and increased sequence homogenisation in the CFG face of the N1 domain. In contrast to most primate PSG N domains, rodent PSG N1 domains do not contain an RGD tri-peptide motif, but do contain RGD-like sequences, which are not conserved in rodent N2 and N3 domains. CONCLUSION: Relative conservation of primate N domains and rodent N1 domains suggests that, despite independent gene family expansions and structural diversification, mouse and human PSGs retain conserved functions. Human PSG gene family expansion and homogenisation suggests that evolution occurred in a concerted manner that maintains similar functions of PSGs, whilst increasing gene dosage of the family as a whole. In the mouse, gene family expansion, coupled with local diversification of the CFG face, suggests selection both for increased gene dosage and diversification of function. Partial conservation of RGD and RGD-like tri-peptides in primate and rodent N and N1 domains, respectively, supports a role for these motifs in PSG function.

Amino Acid Motifs↗
PubMed2003

How potent is potent? Evaluation of sexual function and bother in men who report potency after treatment for prostate cancer: data from CaPSURE.

OBJECTIVES: To characterize the association between potency and comprehensive sexual function. The accurate assessment of sexual function is critical for the evaluation of outcomes after treatment of prostate cancer. The assessments of potency typically used in this context, however, may be oversimplified. METHODS: CaPSURE is a large, observational database of men with prostate cancer. Participants complete health-related quality-of-life questionnaires, including the University of California, Los Angeles Prostate Cancer Index, every 6 months after treatment. A total of 5135 men completed at least one questionnaire and did not use medications for erectile function. The men were categorized as potent or impotent based on their ability to have erections and/or intercourse in the prior 4 weeks. Using the remaining questions on the Prostate Cancer Index, sexual function and bother scores were calculated for each group. RESULTS: Of the 5135 men, 27.4% were potent. The mean sexual function scores were 56 and 13 for potent and impotent men, respectively (P <0.0001). The corresponding mean bother scores were 62 and 36 (P <0.0001). The function scores ranged from 0 to 100 and 0 to 92 among potent and impotent men, respectively, and bother scores from 0 to 100 in both groups. Function was inversely associated with age in both groups, but bother did not change among potent men and ameliorated among impotent men. Individual Prostate Cancer Index questions correlated with potency to a variable extent. CONCLUSIONS: Although potent and impotent men have divergent sexual function and bother scores after treatment, the wide range of these scores in both groups denotes a complex picture of sexual function. The simple documentation of potency after treatment provides an insufficient measure of sexual health-related quality of life and should be supplemented with more comprehensive measures.

Aged↗
PubMed2001

Neuroglobin is up-regulated by and protects neurons from hypoxic-ischemic injury.

Globins are oxygen-binding heme proteins present in bacteria, protists, fungi, plants, and animals. Their functions have diverged widely in evolution, and include binding, transport, scavenging, detoxification, and sensing of gases like oxygen, nitric oxide, and carbon monoxide. Neuroglobin (Ngb) is a recently discovered monomeric globin with high affinity for oxygen and preferential localization to vertebrate brain. No function for Ngb is known, but its affinity for oxygen and its expression in cerebral neurons suggest a role in neuronal responses to hypoxia or ischemia. Here we report that Ngb expression is increased by neuronal hypoxia in vitro and focal cerebral ischemia in vivo, and that neuronal survival after hypoxia is reduced by inhibiting Ngb expression with an antisense oligodeoxynucleotide and enhanced by Ngb overexpression. Both induction of Ngb and its protective effect show specificity for hypoxia over other stressors. We conclude that hypoxia-inducible Ngb expression helps promote neuronal survival from hypoxic-ischemic insults.

Animals↗
PubMed2004

Gene duplication and speciation in Drosophila: evidence from the Odysseus locus.

The importance of gene duplication in evolution has long been recognized. Because duplicated genes are prone to diverge in function, gene duplication could plausibly play a role in species differentiation. However, experimental evidence linking gene duplication with speciation is scarce. Here, we show that a hybrid-male sterility gene, Odysseus (OdsH), arose by gene duplication in the Drosophila genome. OdsH has evolved at a very high rate, whereas its most immediate paralog, unc-4, is nearly identical among species in the Drosophila melanogaster subgroup. The disparity in their sequence evolution is echoed by the divergence in their expression patterns in both soma and reproductive tissues. We suggest that duplicated genes that have yet to evolve a stable function at the time of speciation may be candidates for "speciation genes," which is broadly defined as genes that contribute to differential adaptation between species.

Amino Acid Sequence↗
PubMed1997

Early divergence of magnocellular and parvocellular functional subsystems in the embryonic primate visual system.

In both human and Old World primates visual information is conveyed by two parallel pathways: the magnocellular (M) and parvocellular (P) streams that project to separate layers of the lateral geniculate nucleus and are involved primarily in motion and color/form discrimination. The present study provides evidence that retinal ganglion cells in the macaque monkey embryo diverge into M and P subtypes soon after their last mitotic division and that optic axons project directly and selectively to either the M or P moieties of the developing lateral geniculate nucleus. Thus, initial M projections from the eyes overlap only in prospective layers 1 and 2, whereas initial P projections overlap within prospective layers 3-6. We suggest that the divergence of the M and P pathways requires developmental mechanisms different from those underlying competition-driven segregation of initially intermixed eye-specific domains in the primate visual system.

Animals↗
PubMed2003

DNA microarray analysis of functionally discrete human brain regions reveals divergent transcriptional profiles.

Transcriptional profiles within discrete human brain regions are likely to reflect structural and functional specialization. Using DNA microarray technology, this study investigates differences in transcriptional profiles of highly divergent brain regions (the cerebellar cortex and the cerebral cortex) as well as differences between two closely related brain structures (the anterior cingulate cortex and the dorsolateral prefrontal cortex). Replication of this study across three independent laboratories, to address false-positive and false-negative results using microarray technology, is also discussed. We find greater than a thousand transcripts to be differentially expressed between cerebellum and cerebral cortex and very few transcripts to be differentially expressed between the two neocortical regions. We further characterized transcripts that were found to be specifically expressed within brain regions being compared and found that ontological classes representing signal transduction machinery, neurogenesis, synaptic transmission, and transcription factors were most highly represented.

Aged↗
PubMed2001

Post-prandial lipaemia and endothelial function among healthy men.

BACKGROUND: There is evidence that elevated post-prandial lipoproteins adversely affect progression and outcome of cardiovascular disease. Traditional risk factors are associated with impaired endothelium-mediated vasodilatation. However, studies regarding the relationship between post-prandial lipaemia and endothelial function are divergent. METHODS: Twelve healthy non-smokers were included in this study. Before and after intake of a lipid cocktail rich in dairy fat, we tested endothelial-dependent (acetylcholine 0.8-160 mg/min per 100 ml forearm tissue) and -independent (sodium nitroprussid 0.6 microgram/min) vascular function in the forearm vascular bed with plethysmography. Moreover, we tested the effect of 1-NMMA, a competitive inhibitor of the NO synthetase, on base-line flow. Extent of post-prandial lipaemia was assessed with the increases in triglycerides and retinyl-palmitate, a marker for intestinally derived lipoproteins. RESULTS: Baseline flow was higher after the test meal than during fasting (preprandial 6.5 +/- 0.5 ml/min* 100 ml tissue, post-prandial 8.0 +/- 0.5, p = 0.03), but similar after 1-NMMA (p = 0.85). Before and after intake of the test meal, there was no significant difference in acetylcholine-induced endothelium-dependent vasodilatation (repeated measurement ANOVA, p = 0.22). At the highest acetylcholine dose, forearm flow was very similar (fasting 18.4 +/- 1.9, post-prandial 17.9 +/- 1.9, p = 0.75). At maximum acetylcholine dose, there was a weak inverse but non-significant correlation between forearm flow and post-prandial triglyceridaemia (r = -0.38, p = 0.23) and intestinally derived lipoproteins (chylomicrons r = -0.29, p = 0.35, chylomicron remnants r = -0.15, p = 0.63). However, at the lowest acetylcholine dose there was a suggestion for a positive correlation between change in flow and post-prandial lipaemia (triglyceridaemia, r = 0.53, p = 0.07; chylomicrons, r = 0.41, p = 0.18 and remnants, r = 0.51, p = 0.09). Endothelium-independent vasodilatation in response to sodium nitroprusside did not significantly change (p = 0.23). CONCLUSION: Our results suggest that among healthy men post-prandial lipaemia is not associated with a notable impairment of endothelium-mediated vascular function in forearm resistance vessels.

Adult↗
PubMed2003

Allelic variation in srtAs of Streptococcus suis strains.

Streptococcus suis NCTC10234 possesses five srtA homologs: srtA encodes sortase, which anchors surface proteins with an LPXTG motif to the cell wall, while the functions of the other four homologs (the srtBCD cluster and srtE) remain unknown. The genetic organization of the srtA region was found to be conserved in the 59 S. suis strains examined in this study. Although the srtAs in three of these strains showed strong sequence divergence, their functions were verified to be overlapping by genetic complementation, indicating the functional conservation of srtAs during the evolution of these strains. These results indicate the importance of an srtA-mediated cell wall sorting system for displaying proteins on the surface of S. suis.

Alleles↗
PubMed2025

Orthrus: Towards Evolutionary and Functional RNA Foundation Models.

In the face of rapidly accumulating genomic data, our ability to accurately predict key mature RNA properties that underlie transcript function and regulation remains limited. Pre-trained genomic foundation models offer an avenue to adapt learned RNA representations to biological prediction tasks. However, existing genomic foundation models are trained using strategies borrowed from textual domains that do not leverage biological domain knowledge. Here, we introduce Orthrus, a Mamba-based mature RNA foundation model pre-trained using a novel self-supervised contrastive learning objective with biological augmentations. Orthrus is trained by maximizing embedding similarity between curated pairs of RNA transcripts, where pairs are formed from splice isoforms of 10 model organisms and transcripts from orthologous genes in 400+ mammalian species from the Zoonomia Project. This training objective results in a latent representation that clusters RNA sequences with functional and evolutionary similarities. We find that the generalized mature RNA isoform representations learned by Orthrus significantly outperform genomic foundation models on mRNA property prediction tasks, and requires only a fraction of fine-tuning data to do so. Finally, we show that Orthrus is capable of capturing divergent biological function of individual transcript isoforms.

Journal Article↗
PubMed2002

Impact of the presence of paralogs on sequence divergence in a set of mouse-human orthologs.

Using a large set of orthologous human and mouse gene pairs, we have characterized genes that have been retained in duplicate in human over timescales comparable to the time of speciation of human and mouse. Orthologous gene pairs for which a paralogous gene has been present for much or all of the time since speciation show an increased rate of nonsynonymous substitution. We have related rate of divergence to functional classification using the Gene Ontology terms. Protein function was found, in some cases, to have a larger impact on rate of evolution than the presence or absence of a paralog. No evidence was found that genes that have been retained in duplicate are weighted toward any functional categories. An increase in the ratio of nonsynonymous to synonymous changes following duplication has previously been reported. However, because amino acid sequences include conservative as well as more freely evolving sites, the ratio of nonsynonymous to synonymous changes tends to be higher for closely related pairs. By measuring the divergence of orthologs only and comparing between genes for which a paralogous gene is either present or absent, we have compared gene pairs that share a common divergence time. We have also found that shorter genes have a higher probability of being found duplicated in the human genome, possibly reflecting a mutational effect.

Alleles↗
PubMed2006

Tracing the origin of functional and conserved domains in the human proteome: implications for protein evolution at the modular level.

BACKGROUND: The functional repertoire of the human proteome is an incremental collection of functions accomplished by protein domains evolved along the Homo sapiens lineage. Therefore, knowledge on the origin of these functionalities provides a better understanding of the domain and protein evolution in human. The lack of proper comprehension about such origin has impelled us to study the evolutionary origin of human proteome in a unique way as detailed in this study. RESULTS: This study reports a unique approach for understanding the evolution of human proteome by tracing the origin of its constituting domains hierarchically, along the Homo sapiens lineage. The uniqueness of this method lies in subtractive searching of functional and conserved domains in the human proteome resulting in higher efficiency of detecting their origins. From these analyses the nature of protein evolution and trends in domain evolution can be observed in the context of the entire human proteome data. The method adopted here also helps delineate the degree of divergence of functional families occurred during the course of evolution. CONCLUSION: This approach to trace the evolutionary origin of functional domains in the human proteome facilitates better understanding of their functional versatility as well as provides insights into the functionality of hypothetical proteins present in the human proteome. This work elucidates the origin of functional and conserved domains in human proteins, their distribution along the Homo sapiens lineage, occurrence frequency of different domain combinations and proteome-wide patterns of their distribution, providing insights into the evolutionary solution to the increased complexity of the human proteome.

Animals↗
PubMed1978

On localization for double Fourier series.

The localization theorems for Fourier series of functions of a single variable are classical and easy to prove. The situation is different for Fourier series of functions of several variables, even if one restricts consideration to rectangular, in particular square, partial sums. We show that the answer to the problem can be obtained by considering the notion of generalized bounded variation, which we introduced. Given a nondecreasing sequence {lambda(n)} of positive numbers such that Sigma 1/lambda(n) diverges, a function g defined on an interval I of R(1) is said to be of Lambda-bounded variation (LambdaBV) if Sigma|g(a(n)) - g(b(n))|/lambda(n) converges for every sequence of nonoverlapping intervals (a(n), b(n)) [unk]I. If lambda(n) = n, we say that g is of harmonic bounded variation (HBV). The definition suitably modified can be extended to functions of several variables. We show that in the case of two variables the localization principle holds for rectangular partial sums if LambdaBV = HBV, and that if LambdaBV is not contained in HBV, then the localization principle does not hold for LambdaBV even in the case of square partial sums.

Journal Article↗
PubMed1997

The evolution of plant nuclear genes.

We analyze the evolutionary dynamics of three of the best-studied plant nuclear multigene families. The data analyzed derive from the genes that encode the small subunit of ribulose-1,5-bisphosphate carboxylase (rbcS), the gene family that encodes the enzyme chalcone synthase (Chs), and the gene family that encodes alcohol dehydrogenases (Adh). In addition, we consider the limited evolutionary data available on plant transposable elements. New Chs and rbcS genes appear to be recruited at about 10 times the rate estimated for Adh genes, and this is correlated with a much smaller average gene family size for Adh genes. In addition, duplication and divergence in function appears to be relatively common for Chs genes in flowering plant evolution. Analyses of synonymous nucleotide substitution rates for Adh genes in monocots reject a linear relationship with clock time. Replacement substitution rates vary with time in a complex fashion, which suggests that adaptive evolution has played an important role in driving divergence following gene duplication events. Molecular population genetic studies of Adh and Chs genes reveal high levels of molecular diversity within species. These studies also reveal that inter- and intralocus recombination are important forces in the generation allelic novelties. Moreover, illegitimate recombination events appear to be an important factor in transposable element loss in plants. When we consider the recruitment and loss of new gene copies, the generation of allelic diversity within plant species, and ectopic exchange among transposable elements, we conclude that recombination is a pervasive force at all levels of plant evolution.

Alcohol Dehydrogenase↗
PubMed2005

A convergent-divergent approach to context processing, general intellectual functioning, and the genetic liability to schizophrenia.

Convergent and divergent validity are critically important in developing psychological measures that reveal interpretable deficits in disordered populations. This article reports on 2 studies that evaluated the validity of context processing measures. In Experiment 1, a confirmatory factor analysis of data from 481 healthy adults established the convergent validity of 2 context processing measures and showed that context processing accounted for significant amounts of variance in standard IQ and working memory measures. In Experiment 2, 20 schizophrenia patients, 16 of their healthy siblings, and 28 controls were evaluated using a novel, short context processing measure, the dot pattern expectancy (DPX) task. The DPX was sensitive to specific deficits in schizophrenia patients and their healthy siblings. These findings support the construct validity of context processing measures, suggest context processing is a component of intellectual functioning, and demonstrate that brief context processing measures remain sensitive to psychopathological deficits.

Adult↗