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PubMed2006

Conservation of alternative polyadenylation patterns in mammalian genes.

BACKGROUND: Alternative polyadenylation is a widespread mechanism contributing to transcript diversity in eukaryotes. Over half of mammalian genes are alternatively polyadenylated. Our understanding of poly(A) site evolution is limited by the lack of a reliable identification of conserved, equivalent poly(A) sites among species. We introduce here a working definition of conserved poly(A) sites as sites that are both (i) properly aligned in human and mouse orthologous 3' untranslated regions (UTRs) and (ii) supported by EST or cDNA data in both species. RESULTS: We identified about 4800 such conserved poly(A) sites covering one third of the orthologous gene set studied. Characteristics of conserved poly(A) sites such as processing efficiency and tissue-specificity were analyzed. Conserved sites show a higher processing efficiency but no difference in tissular distribution when compared to non-conserved sites. In general, alternative poly(A) sites are species-specific and involve minor, non-conserved sites that are unlikely to play essential roles. However, there are about 500 genes with conserved tandem poly(A) sites. A significant fraction of these conserved tandems display a conserved arrangement of major/minor sites in their 3' UTR, suggesting that these alternative 3' ends may be under selection. CONCLUSION: This analysis allows us to identify potential functional alternative poly(A) sites and provides clues on the selective mechanisms at play in the appearance of multiple poly(A) sites and their maintenance in the 3' UTRs of genes.

3' Untranslated Regions↗
PubMed2006

Identifying potential indicators of conservation value using natural heritage occurrence data.

Conservation planning based on the occurrence of rare species has been criticized as being too limited in scope to conserve biodiversity as a whole. Conversely, planning based on indicator taxa may lack sufficient focus to conserve those species in greatest need of conservation. An alternative approach is to identify a variety of species at risk that are associated with areas of conservation value, which is defined based on species-independent characteristics. We identified potential indicators of conservation value using occurrence data on species at risk and independent information on conservation value that incorporated indices of ecosystem integrity. We propose a taxonomically diverse group of indicator species that are strongly associated with areas of exceptional ecosystem integrity, to serve as a focus for further research and in planning for biodiversity conservation. We identify potential indicator species by defining a null model in which species at risk are equally associated with areas of high ecosystem integrity, then by conducting randomization tests to identify noncompliant species in the state of Michigan, USA. Areas of high ecosystem integrity are selected using criteria to flag (1) secure biotic communities with structural integrity and few exotic species, (2) natural areas subjected to expert review, (3) contiguous relict areas of forest interior, (4) contiguous areas of unmodified wetland, and (5) all these areas combined. We determine the spatial occurrence of species at risk using data from Michigan's statewide Natural Heritage database. The potential indicators include plants, insects, and birds. Their species identity and distribution of occurrences varies with the five scenarios, and together the species broadly cover the entire state. These species at risk, many of which occur throughout the Great Lakes region, may be used to identify additional areas potentially high in conservation value and to monitor their conservation. The ecological criteria and numerical methods we employ may be broadly applicable as Heritage Program databases in North America and parts of Latin America grow to become representative of species distributions.

Animals↗
PubMed1989

Evolutionary conservation of protein regions in the protonmotive cytochrome b and their possible roles in redox catalysis.

The amino acid sequences of the protonmotive cytochrome b from seven representative and phylogenetically diverse species have been compared to identify protein regions or segments that are conserved during evolution. The sequences analyzed included both prokaryotic and eukaryotic examples as well as mitochondrial cytochrome b and chloroplast b6 proteins. The principal conclusion from these analyses is that there are five protein regions--each comprising about 20 amino acid residues--that are consistently conserved during evolution. These domains are evident despite the low density of invariant residues. The two most highly conserved regions, spanning approximately consensus residues 130-150 and 270-290, are located in extramembrane loops and are hypothesized to constitute part of the Qo reaction center. The intramembrane, hydrophobic protein regions containing the heme-ligating histidines are also conserved during evolution. It was found, however, that the conservation of the protein segments extramembrane to the histidine residues ligating the low potential b566 heme group showed a higher degree of sequence conservation. The location of these conserved regions suggests that these extramembrane segments are also involved in forming the Qo reaction center. A protein segment putatively constituting a portion of the Qi reaction center, located approximately in the region spanned by consensus residues 20-40, is conserved in species as divergent as mouse and Rhodobacter. This region of the protein shows substantially less sequence conservation in the chloroplast cytochrome b6. The catalytic role of these conserved regions is strongly supported by locations of residues that are altered in mutants resistant to inhibitors of cytochrome b electron transport.

Amino Acid Sequence↗
PubMed1991

Adhesive small bowel obstruction in children: the place and predictors of success for conservative treatment.

The records of 230 adhesive small bowel obstruction (ASBO) episodes in 181 patients have been reviewed to observe the place of conservative treatment and to establish criteria to predict the success of conservative trial. Immediate operation has been reserved for 81 episodes that have presented with fever and leucocytosis and/or localized abdominal tenderness, or complete obstruction. The remaining 149 episodes have initially undergone conservative trial. Although 110 episodes (73.8%) have been cured with conservative trial, 39 (26.2%) subsequently necessitated surgical intervention. No adverse occurrences have been observed during or after delayed operations. There was no strangulated bowel nor mortality both in delayed operation and conservatively treated groups. Recurrence has occurred with rate of 18.75% and 36.47% after surgery and conservative treatment, respectively, being significantly different (P less than .01), but the treatment method of the previous episode has been without influence on the method used in the recurrent obstruction (P less than .05). Among the assumed predictive criteria, age at recent laparotomy (P less than .02), time elapsed between recent laparotomy and obstructive episode (P less than .01), the primary condition necessitating laparotomy (P less than .01), the incision of previous laparotomy (P less than .05), and duration of conservative trial (P less than .01) correlated significantly with the success of conservative trial. The number of previous laparotomies and obstructive episodes (P less than .05) have not showed correlation. By the conservative approach used in selected patients with ASBO, 40% overall have been spared operation, without any adverse occurrences. Using the proposed criteria, the success rate of conservative treatment can be predicted.

Adolescent↗
PubMed1996

Possibility of conservative local treatment after combined chemotherapy and preoperative irradiation for locally advanced noninflammatory breast cancer.

PURPOSE: The aims of this prospective study were to evaluate the outcome and the possibility of breast conservation therapy for patients with locally advanced noninflammatory breast cancer after primary chemotherapy followed by external preoperative irradiation. METHODS AND MATERIALS: Between April 1982 and June 1990, 97 patients with locally advanced nonmetastatic and noninflammatory breast cancer were treated. The median follow-up was 93 months from the beginning of treatment. The induction treatment consisted of four courses of chemotherapy (doxorubicin, vincristine, cyclophosphamide, 5-fluorouracil) followed by preoperative irradiation (45 Gy to the breast and nodal areas). A fifth course of chemotherapy was given after irradiation therapy. Three different loco-regional approaches were proposed, depending on the tumoral response. In 37 patients (38%) with residual tumor larger than 3 cm in diameter or located behind the nipple or with bifocal tumors, mastectomy and axillary dissection were performed. Sixty other patients (62%) benefited from conservative treatment: 33 patients (34%) achieved complete remission and no surgery was done but additional radiation boost was given to the initial tumor bed; 27 patients (28%) who had a residual mass less than or equal to 3 cm in diameter were treated by wide excision and axillary dissection followed by a boost to the excision site. After completion of local therapy, all patients received a sixth course of chemotherapy. A maintenance adjuvant chemotherapy regimen without anthracycline was prescribed (12 monthly cycles). RESULTS: The 5-year actuarial loco-regional relapse rate was 16% after radiotherapy alone, 16% following wide excision and radiotherapy, and 5.4% following mastectomy. The 5-year loco-regional relapse rate was significantly higher after conservative local treatment (wide excision and radiotherapy, and radiotherapy alone) than after mastectomy (p= 0.04). After conservative local treatment, the 5-year breast conserving rate of patients with loco-regional disease-free status was 84%. For all patients included in this study, the 5-year breast-conserving rate of those who were loco-regional disease-free was 52%. In multivariate analysis, the possibility of breast conservative treatment was significantly related to the initial tumor size and age (more conservative treatment for tumor size < 6cm and age < 50 years). Five- and 10-year overall survival rates and disease-free survival rates were 80, 69, 73, and 61% respectively. Five- and 10-year overall survival rates were not influenced by the local treatment (conservative vs. nonconservative local treatment, p = 0.9). On the other hand, local failure significantly decreased the 5- and 10-year overall survival rates (p , 0.0001). In multivariate analysis, three factors had a significant impact on overall survival and disease-free survival: tumor response after induction chemotherapy, initial tumor size, and clinical stage. Arm lymphedema was noted in 12.5% (8 out of 64) of the patients treated with axillary dissection and in 3% (1 out of 33) without axillary dissection. Cosmetic results were satisfactory in 79% of patients after wide excision and radiotherapy and in 71% of patients treated by radiotherapy alone. CONCLUSIONS: Induction chemotherapy followed by preoperative irradiation may permit the selection of some patients with locally advanced breast cancer for conservative treatment. However, the impact of this treatment modality on long-term survival remains to be established.

Adult↗
PubMed2006

Conservation of residual acoustic hearing after cochlear implantation.

OBJECTIVE: This study was designed to test the hypothesis that partial hearing conservation is attainable after cochlear implantation with a long perimodiolar electrode. Surgical strategies for hearing conservation during cochlear implantation are described. STUDY DESIGN: Prospective, single-subject, repeated-measures design. SETTING: Academic tertiary care center. PATIENTS: Twenty-eight severely to profoundly hearing-impaired adult cochlear implant recipients who had some measurable hearing preoperatively. INTERVENTION: Cochlear implantation using Nucleus Freedom Contour Advance electrode. MAIN OUTCOME MEASURES: Preimplant and postimplant pure-tone thresholds and speech recognition scores were obtained to determine the incidence and degree of conserved hearing at a mean interval of 9 (+/-3.9) months. RESULTS: Thirty-two percent of subjects experienced complete conservation of hearing (0- to 10-dB loss), and 57% experienced partial conservation of hearing (>11 dB) after implantation. However, open-set speech recognition was partially conserved in only one subject. Cochlear implant performance was not better in patients with conservation of residual hearing. CONCLUSION: Conservation of pure-tone hearing was possible in 89% of implanted patients; however, residual speech perception was not conserved with this long perimodiolar electrode. A ceiling effect tends to inflate the prevalence of hearing conservation in implantation studies of severely to profoundly hearing-impaired patients.

Adult↗
PubMed2006

Conservative treatment of thoracic outlet syndrome. A review of the literature.

Thoracic outlet syndrome (TOS) is a debated topic. While there are many clinical studies concerning the efficacy of surgical treatment, there are few regarding conservative treatment. It has not yet been established whether or not conservative treatment is effective and what the best treatment is. The aims of this study were to evaluate the efficacy of conservative treatment in TOS with particular reference to physiotherapy, orthotics, and taping and to make general recommendations for conservative treatment. The literature was reviewed. Medical databases consulted: Medline, Embase, CINAHL, Current Awareness, Pedro, Cochrane Library, Medscape. We used the following key words: thoracic outlet syndrome, double crush syndrome, entrapment, conservative, treatment, rehabilitation, and management. Languages of the articles reviewed: English, French, German, Spanish, Italian, and Portuguese. This analysis focussed on 10 studies of conservative treatment and 3 studies comparing the outcomes of conservative and surgical treatment, published from 1983 to 2001. This review found no randomised controlled trials, systematic reviews, or meta-analyses. Conservative treatment seems to be effective at reducing symptoms, improving function, and facilitating return to work, also when compared to surgery. We could not establish whether or not conservative treatment was better than no treatment or placebo, or what type of conservative treatment was the best.

Databases, Bibliographic↗
PubMed2026

Beauty bias in butterfly research and conservation.

Conservation biases have been documented since the first emergence of the concept of biodiversity in the 1980s,1,2,3 showing a systematic disproportion in the allocation of research and conservation efforts among taxa.4,5,6,7,8,9,10,11 One factor underlying this disproportion, gaining prominence in recent literature, is species' perceived beauty, shaped by human visual preferences.12,13,14,15,16,17 Here, we integrate a large-scale survey of the perceived beauty of European butterflies yielding >21,000 survey completions from >100 countries into a time-explicit network linking species' beauty, public attention, research and conservation efforts, and the EU regulatory framework. We found that species beauty is consistently associated with public attention, research, and conservation efforts in a temporally structured pattern compatible with a cumulative beauty bias. Research effort and public attention concentrate on widespread and visually attractive species, whereas species included in the legal conservation framework, particularly the Convention on the Conservation of European Wildlife and Natural Habitats (hereafter, Bern Convention, BC, 1979)18 and the EU Habitats Directive (hereafter, HD, 1992)19 are disproportionately represented by visually appealing and historically protected taxa. Because these frameworks guide funding and management actions, early associations between species beauty and BC/HD inclusion have contributed to long-lasting institutional patterns in butterfly research and conservation. By contrast, European IUCN Red Lists20,21 do not overrepresent beautiful species and identify more inconspicuous taxa as threatened. This mismatch reveals a tension between scientific assessments of extinction risk and historically embedded conservation priorities. Our findings suggest that recognizing beauty bias is vital for aligning conservation with actual ecological urgency. VIDEO ABSTRACT.

Animals↗
PubMed2004

Sequence and structural analysis of cellular retinoic acid-binding proteins reveals a network of conserved hydrophobic interactions.

Proteins in the intracellular lipid-binding protein (iLBP) family show remarkably high structural conservation despite their low-sequence identity. A multiple-sequence alignment using 52 sequences of iLBP family members revealed 15 fully conserved positions, with a disproportionately high number of these (n=7) located in the relatively small helical region. The conserved positions displayed high structural conservation based on comparisons of known iLBP crystal structures. It is striking that the beta-sheet domain had few conserved positions, despite its high structural conservation. This observation prompted us to analyze pair-wise interactions within the beta-sheet region to ask whether structural information was encoded in interacting amino acid pairs. We conducted this analysis on the iLBP family member, cellular retinoic acid-binding protein I (CRABP I), whose folding mechanism is under study in our laboratory. Indeed, an analysis based on a simple classification of hydrophobic and polar amino acids revealed a network of conserved interactions in CRABP I that cluster spatially, suggesting a possible nucleation site for folding. Significantly, a small number of residues participated in multiple conserved interactions, suggesting a key role for these sites in the structure and folding of CRABP I. The results presented here correlate well with available experimental evidence on folding of CRABPs and their family members and suggest future experiments. The analysis also shows the usefulness of considering pair-wise conservation based on a simple classification of amino acids, in analyzing sequences and structures to find common core regions among homologues.

Amino Acid Sequence↗
PubMed2003

Optimal conservation effort for a population in a stochastic environment.

We study the optimal conservation effort for a population in a fluctuating environment. The survivorship of a population is affected by unpredictable environmental fluctuation (noise) and can be improved by conservation effort accompanied by a cost. The optimal effort level is the one that minimizes the total cost, defined as the weighted sum of the population extinction risk and the economic cost of conservation effort. The optimal effort depends on the variance and the probability distribution of the noise, the relative importance of the population's survival vs. the economic cost, the effectiveness of conservation effort, and the time scope over which we optimize. The analysis of dynamic programming illustrates that the choice of extinction risk function greatly affects the optimal effort level. The conservation effort level that is the best solution of a multiple-year optimization may be higher than that for the corresponding single-year optimization, if the population is relatively safe. However, the conservation level for the multiple-year optimization becomes lower than for the single-year optimization if the population is endangered. In a similar manner, the optimal conservation effort level for the problem with a short time scope is either higher or lower than that for the problem with a long time scope, depending on the extinction risk of the population. Next, for each parameter of the model, we define five different sensitivities of extinction probability or of the total cost. We then study the mean increase in the total cost caused by the uncertainty of parameters. To achieve the best conservation result, we need to invest the limited research effort to the parameter with the largest effect to the optimal effort level, rather than to those with large impacts on the extinction probability or on the total cost. The recommended policy should depend critically on the choice of the criterion to optimize, which shows the importance of theoretical study of the relationship in performing proper decision making in conservation practice.

Animals↗
PubMed2003

A VSA-based strategy for placing conservation buffers in agricultural watersheds.

Conservation buffers have the potential to reduce agricultural nonpoint source pollution and improve terrestrial wildlife habitat, landscape biodiversity, flood control, recreation, and aesthetics. Conservation buffers, streamside areas and riparian wetlands are being used or have been proposed to control agricultural nonpoint source pollution. This paper proposes an innovative strategy for placing conservation buffers based on the able source area (VSA) hydrology. VSAs are small, variable but predictable portion of a watershed that regularly contributes to runoff generation. The VSA-based strategy involves the following three steps: first, identifying VSAs in landscapes based on natural characteristics such as hydrology, land use/cover, topography and soils; second, targeting areas within VSAs for conservation buffers; third, refining the size and location of conservation buffers based on other factors such as weather, environmental objectives, available funding and other best management practices. Building conservation buffers in VSAs allows agricultural runoff to more uniformly enter buffers and stay there longer, which increases the buffer's capacity to remove sediments and nutrients. A field-scale example is presented to demonstrate the effectiveness and cost-effectiveness of the within-VSA conservation buffer scenario relative to a typical edge-of-field buffer scenario. The results enhance the understanding of hydrological processes and interactions between agricultural lands and conservation buffers in agricultural landscapes, and provide practical guidance for land resource managers and conservationists who use conservation buffers to improve water quality and amenity values of agricultural landscape.

Agriculture↗
PubMed2005

Do developmental initiatives influence local attitudes toward conservation? A case study from the Kalakad-Mundanthurai Tiger Reserve, India.

We evaluated the conservation attitudes of the local villagers living adjacent to the Kalakad-Mundanthurai Tiger Reserve in southern India 6 years after implementation of a World Bank funded eco-development project. We assessed attitudes towards three facets of conservation: the tiger, an emblematic species signifying India's commitment to wildlife conservation; the forest, a principle source of fuel-wood and other products; and the Forest Department, which manages the forest. More specifically we predicted that (i) attitudes would be an effective predictor of resource use interest in the forest and (ii) benefits obtained from the EDP would create more favorable attitudes towards conservation and the protected area employees. Twelve villages located within 3 km from the reserve boundary were chosen and 2-3% of the households interviewed with regard to their attitudes towards these three facets of conservation, their household resource use patterns, wealth, sex, age and length of residency. We found significant associations between wealth, sex, age and both tiger and forest conservation. Providing benefits has not changed the underlying attitudes of the communities. The poorer sections of society, whether receiving benefits or not, tended to support tiger conservation because conserving wildlife did not affect their livelihood in any way, whereas both the rich and poor had misgivings about forest conservation due to dependency on forest products. We conclude that the eco-development project has not effectively addressed the most important of the local concerns.

Age Distribution↗
PubMed2005

Conservation and behavioral neuroendocrinology.

The total number of threatened species of vertebrates is likely to be more than 10,000, with approximately one quarter of the world's mammal species, one eighth of the birds and one third of the amphibians threatened with extinction. The rate of loss of animal species and hence of biodiversity is increasing and may become even greater as ecosystems become affected by climate change due to global warming. Behavioral neuroendocrinology, which considers interactions between behavior and neuroendocrine function in animals from all vertebrate taxa, can contribute to animal conservation. Research with laboratory animals can address questions in basic biology relevant to conservation and develop methods for use with threatened animals. Field work with free-living animals considers the basic biology of new species and the use of endocrine tools to assess the susceptibility of species to threats. Non-invasive measurements of hormone concentrations, especially fecal steroids, are extensively used to assess reproductive function and the stress status of animals in captive breeding programs and in the wild. Biodiversity and natural selection both depend on individual variation, and conservation programs often work with animals on an individual basis. The consideration of data from individuals is essential in conservation endocrinology. Direct contributions to conservation programs are challenging as study situations are determined by practical conservation concerns. Indirect contributions such as the provision of scientific input to conservation plans and participation in public education programs offer significant benefits for conservation programs. Directly and indirectly, there are many opportunities for behavioral neuroendocrinologists to contribute to conservation.

Animals↗
PubMed2002

Sequence conservation in families whose members have little or no sequence similarity: the four-helical cytokines and cytochromes.

Proteins for which there are good structural, functional and genetic similarities that imply a common evolutionary origin, can have sequences whose similarities are low or undetectable by conventional sequence comparison procedures. Do these proteins have sequence conservation beyond the simple conservation of hydrophobic and hydrophilic character at specific sites and if they do what is its nature? To answer these questions we have analysed the structures and sequences of two superfamilies: the four-helical cytokines and cytochromes c'-b(562). Members of these superfamilies have sequence similarities that are either very low or not detectable. The cytokine superfamily has within it a long chain family and a short chain family. The sequences of known representative structures of the two families were aligned using structural information. From these alignments we identified the regions that conserve the same main-chain conformation: the common core (CC). For members of the same family, the CC comprises some 50% of the individual structures; for the combination of both families it is 30%. We added homologous sequences to the structural alignment. Analysis of the residues occurring at sites within the CCs showed that 30% have little or no conservation, whereas about 40% conserve the polar/neutral or hydrophobic/neutral character of their residues. The remaining 30% conserve hydrophobic residues with strong or medium limitations on their volume variations. Almost all of these residues are found at sites that form the "buried spine" of each helix (at sites i, i+3, i+7, i+10, etc., or i, i+4, i+7, i+11, etc.) and they pack together at the centre of each structure to give a pattern of residue-residue contacts that is almost absolutely conserved. These CC conserved hydrophobic residues form only 10-15% of all the residues in the individual structures.A similar analysis of the cytochromes c'-b(562), which bind haem and have a very different function to that of the cytokines, gave very similar results. Again some 30% of the CC residues have hydrophobic residues with strong or medium conservation. Most of these form the buried spine of each helix and play the same role as those in the cytokines. The others, and some spine residues bind the haem co-factor.

Automation↗
PubMed2001

The conserved residues of the ligand-binding domains of steroid receptors are located in the core of the molecules.

The relationship between conserved residues and biochemical functions of steroid receptors was investigated. Pairwise three-dimensional (3D) alignment of the ligand-binding domains of the human estrogen (1A52) and progesterone (1A28) receptors revealed two conserved domains; Asn313-Ser456 and Gln471-Lys531 (numbering reflects the sequence in the human estrogen receptor). Alignment of the protein sequences of 39 steroid receptors revealed 36 highly conserved residues (i.e., the residues commonly found in more than 80% of sequences aligned). They were distributed throughout the sequences but formed a contiguous 3D structure. Most of these highly conserved residues were buried in the ligand-binding domain, but several residues were exposed on the surface. The well-known functions commonly associated with the ligand-binding domain of steroid receptors are ligand binding, HSP90 binding, transcriptional activation and dimerization. The relationship between the residues and these functions were checked. To determine the residues involved in dimerization, the differences between the solvent accessibilities of the monomeric and dimeric forms were calculated. These results revealed 32 residues of 1A52 and 15 residues of 1A28 potentially involved in dimerization. Their distribution areas do not overlap greatly. Comparing these putative dimerization sites with highly conserved residues, many of the exposed conserved residues were observed on the side of the domain opposite are the dimerization sites. Some highly conserved residues are located in a steroid-binding site and in transcriptional activation domain. However, few of them were observed in the HSP90 binding site. These results indicate that the core structure made by most of the highly conserved residues among the ligand-binding domains of steroid receptors is important. These conserved residues may be essential for conformational change in the ligand-binding domain from its inactive to active form.

Amino Acid Motifs↗
PubMed2001

Enrichment of regulatory signals in conserved non-coding genomic sequence.

MOTIVATION: Whole genome shotgun sequencing strategies generate sequence data prior to the application of assembly methodologies that result in contiguous sequence. Sequence reads can be employed to indicate regions of conservation between closely related species for which only one genome has been assembled. Consequently, by using pairwise sequence alignments methods it is possible to identify novel, non-repetitive, conserved segments in non-coding sequence that exist between the assembled human genome and mouse whole genome shotgun sequencing fragments. Conserved non-coding regions identify potentially functional DNA that could be involved in transcriptional regulation. RESULTS: Local sequence alignment methods were applied employing mouse fragments and the assembled human genome. In addition, transcription factor binding sites were detected by aligning their corresponding positional weight matrices to the sequence regions. These methods were applied to a set of transcripts corresponding to 502 genes associated with a variety of different human diseases taken from the Online Mendelian Inheritance in Man database. Using statistical arguments we have shown that conserved non-coding segments contain an enrichment of transcription factor binding sites when compared to the sequence background in which the conserved segments are located. This enrichment of binding sites was not observed in coding sequence. Conserved non-coding segments are not extensively repeated in the genome and therefore their identification provides a rapid means of finding genes with related conserved regions, and consequently potentially related regulatory mechanism. Conserved segments in upstream regions are found to contain binding sites that are co-localized in a manner consistent with experimentally known transcription factor pairwise co-occurrences and afford the identification of novel co-occurring Transcription Factor (TF) pairs. This study provides a methodology and more evidence to suggest that conserved non-coding regions are biologically significant since they contain a statistical enrichment of regulatory signals and pairs of signals that enable the construction of regulatory models for human genes. CONTACT: samuel.levy@celera.com.

Algorithms↗
PubMed2005

Small fitness effect of mutations in highly conserved non-coding regions.

Comparison of human and mouse genomes has revealed that many non-coding regions have levels of sequence conservation similar to protein-coding genes. These regions have attracted a lot of attention as potentially functional genomic sequences. However, little is known about the effect mutations in these conserved non-coding regions have on fitness and how many of them are present in the human genome as deleterious polymorphisms. To gain insight into the selective constraints imposed on conserved non-coding and protein-coding regions, we compared substitution rates in primate and rodent lineages and analyzed the density and allele frequencies of human polymorphism. Genomic regions conserved between primate and rodent groups show higher relative conservation within rodents than within primates. Thus, our analysis indicates a genome-wide relaxation of selective constraint in the primate lineage, which most likely resulted from a smaller effective population size. We found that this relaxation is much more profound in conserved non-coding regions than in protein-coding regions, and that mutations at a large proportion of sites in conserved non-coding regions are associated with very small fitness effect. Data on human polymorphism are also consistent with very weak selection in conserved non-coding regions. This staggering enrichment in sites at the borderline of neutrality can be explained by assuming an important role for synergistic epistasis in the evolution of non-coding regions. Our results suggest that most individual mutations in conserved non-coding regions are only slightly deleterious but are numerous and may have a significant cumulative impact on fitness.

Algorithms↗
PubMed2003

Conservation of human alternative splice events in mouse.

Human and mouse genomes share similar long-range sequence organization, and have most of their genes being homologous. As alternative splicing is a frequent and important aspect of gene regulation, it is of interest to assess the level of conservation of alternative splicing. We examined mouse transcript data sets (EST and mRNA) for the presence of transcripts that both make spliced-alignment with the draft mouse genome sequence and demonstrate conservation of human transcript-confirmed alternative and constitutive splice junctions. This revealed 15% of alternative and 67% of constitutive splice junctions as conserved; however, these numbers are patently dependent on the extent of transcript coverage. Transcript coverage of conserved splice patterns is found to correlate well between human and mouse. A model, which extrapolates from observed levels of conservation at increasing levels of transcript support, estimates overall conservation of 61% of alternative and 74% of constitutive splice junctions, albeit with broad confidence intervals. Observed numbers of conserved alternative splicing events agreed with those expected on the basis of the model. Thus, it is apparent that many, and probably most, alternative splicing events are conserved between human and mouse. This, combined with the preservation of alternative frame stop codons in conserved frame breaking events, indicates a high level of commonality in patterns of gene expression between these two species.

Alternative Splicing↗