Evidence of widespread degradation of gene control regions in hominid genomes

Although sequences containing regulatory elements located close to protein-coding genes are often only weakly conserved during evolution, comparisons of rodent genomes have implied that these sequences are subject to some selective constraints. Evolutionary conservation is particularly apparent upstream of coding sequences and in first introns, regions that are enriched for regulatory elements. By comparing the human and chimpanzee genomes, we show here that there is almost no evidence for conservation in these regions in hominids. Furthermore, we show that gene expression is diverging more rapidly in hominids than in murids per unit of neutral sequence divergence. By combining data on polymorphism levels in human noncoding DNA and the corresponding human¿chimpanzee divergence, we show that the proportion of adaptive substitutions in these regions in hominids is very low. It therefore seems likely that the lack of conservation and increased rate of gene expression divergence are caused by a reduction in the effectiveness of natural selection against deleterious mutations because of the low effective population sizes of hominids. This has resulted in the accumulation of a large number of deleterious mutations in sequences containing gene control elements and hence a widespread degradation of the genome during the evolution of humans and chimpanzees

Genomic Selective Constraints in Murid Noncoding DNA

Recent work has suggested that there are many more selectively constrained, functional noncoding than coding sites in mammalian genomes. However, little is known about how selective constraint varies amongst different classes of noncoding DNA. We estimated the magnitude of selective constraint on a large dataset of mouse-rat gene orthologs and their surrounding noncoding DNA. Our analysis indicates that there are more than three times as many selectively constrained, nonrepetitive sites within noncoding DNA as in coding DNA in murids. The majority of these constrained noncoding sites appear to be located within intergenic regions, at distances greater than 5 kilobases from known genes. Our study also shows that in murids, intron length and mean intronic selective constraint are negatively correlated with intron ordinal number. Our results therefore suggest that functional intronic sites tend to accumulate toward the 5' end of murid genes. Our analysis also reveals that mean number of selectively constrained noncoding sites varies substantially with the function of the adjacent gene. We find that, among others, developmental and neuronal genes are associated with the greatest numbers of putatively functional noncoding sites compared with genes involved in electron transport and a variety of metabolic processes. Combining our estimates of the total number of constrained coding and noncoding bases we calculate that over twice as many deleterious mutations have occurred in intergenic regions as in known genic sequence and that the total genomic deleterious point mutation rate is 0.91 per diploid genome, per generation. This estimated rate is over twice as large as a previous estimate in murids

Effect of the assignment of ancestral CpG state on the estimation of nucleotide substitution rates in mammals

<p>Abstract</p> <p>Background</p> <p>Molecular evolutionary studies in mammals often estimate nucleotide substitution rates within and outside CpG dinucleotides separately. Frequently, in alignments of two sequences, the division of sites into CpG and non-CpG classes is based simply on the presence or absence of a CpG dinucleotide in either sequence, a procedure that we refer to as CpG/non-CpG assignment. Although it likely that this procedure is biased, it is generally assumed that the bias is negligible if species are very closely related.</p> <p>Results</p> <p>Using simulations of DNA sequence evolution we show that assignment of the ancestral CpG state based on the simple presence/absence of the CpG dinucleotide can seriously bias estimates of the substitution rate, because many true non-CpG changes are misassigned as CpG. Paradoxically, this bias is most severe between closely related species, because a minimum of two substitutions are required to misassign a true ancestral CpG site as non-CpG whereas only a single substitution is required to misassign a true ancestral non-CpG site as CpG in a two branch tree. We also show that CpG misassignment bias differentially affects fourfold degenerate and noncoding sites due to differences in base composition such that fourfold degenerate sites can appear to be evolving more slowly than noncoding sites. We demonstrate that the effects predicted by our simulations occur in a real evolutionary setting by comparing substitution rates estimated from human-chimp coding and intronic sequence using CpG/non-CpG assignment with estimates derived from a method that is largely free from bias.</p> <p>Conclusion</p> <p>Our study demonstrates that a common method of assigning sites into CpG and non CpG classes in pairwise alignments is seriously biased and recommends against the adoption of <it>ad hoc </it>methods of ancestral state assignment.</p

Immune Priming: Mothering Males Modulate Immunity

SummaryThe transfer of immunity from mother to offspring is widespread in animals. The father’s contribution to this is usually negligible. However, in a sex-role reversed pipefish where fathers do the mothering, fathers make an important immune priming contribution, too

A numerical investigation into sinkhole formation

Sinkholes pose danger to the environment through the associated gradual subsidence or sudden collapse of the ground that can lead to loss of lives and damage to property. Sinkholes develop in different sizes, shapes and rates all over the world. This project assists in further understanding how sinkhole development can be analysed through analytical theories and the application of numerical methods to create simulations. It involves the investigation, development and verification of numerical models aimed at determining the slope stability of differing trapdoor scenarios. The analysis will be completed through using the computer program Fast Lagrangian Analysis of Continua (FLAC). The completion of 2D numerical models gives the chance to simulate many different sinkholes, with varying material properties and different overburden depth to cavity width and length ratios. Sinkholes are analysed by strength reduction method, producing the factor of safety of the overburden above a trapdoor. The numerical study appraised sinkhole propagation with the Fast Lagrangian Analysis of Continua software to determine the slope stability of differing trapdoor scenarios. This furthered the understanding of sinkhole mechanics by providing a more realistic model in relation to an actual sinkhole formation. The extent of surface failure was investigated and found to be dependent upon the depth ratio of the sinkholes trapdoor. The many varying cases with regards to surcharge pressure and internal pressure within the cavity where tested to determine to what extent the pressure ratio affected the resulting sinkhole formed under these varying pressure conditions. Scenarios were initially tested with zero pressure ratios and then rerun with both positive and negative pressure ratios to simulate both collapse failure as well as blowout of the sinkhole. Stability Charts were developed for both the zero pressure ratio and non-zero pressure ratio scenarios and possible practical applications demonstrated to allow for quick ascertainment of conditions and the associated factor of safety or critical conditions

List-mode data acquisition based on digital electronics - State-of-the-art report

This report deals with digital radiation detection systems employing list-mode data collection, which improves data analysis capabilities. Future data acquisition systems shall also ultimately enable the movement of detection data from first responders electronically to analysis centres rather than the costly and time consuming process of moving experts and/or samples. This new technology is especially useful in crisis events, when time and resources are sparse and increased analysis capacity is required. In order to utilise the opportunities opened by these new technologies, the systems have to be interoperable, so that the data from each type of detector can easily be analysed by different analysis centres. Successful interoperability of the systems requires that European and/or international standards are devised for the digitised data format. The basis of such a format is a list of registered events detailing an estimate of the energy of the detected radiation, along with an accurate time-stamp for recorded events (and optionally other parameters describing each event).JRC.G.5-Security technology assessmen

Critical parameters and performance tests for the evaluation of digital data acquisition hardware

Recent developments of digital data acquisition systems allow real-time pre-processing of detector signals at a high count rate. These so-called pulse processing digitizers are powerful and versatile instruments offering techniques which are important for nuclear security, critical infrastructure protection, nuclear physics and radiation metrology. Certain aspects of digital data acquisition affect the performance of the total system in a critical way and therefore require special attention. This report presents a short introduction to digital data acquisition, followed by a discussion of the critical parameters which affect the performance in the lab and in the field. For some of the parameters, tests are proposed to assess the performance of digital data acquisition systems. Good practices are offered to guide the selection and evaluation of digital data acquisition systems. More general performance criteria which are not specifically related to digital data acquisition systems are discussed separately.JRC.D.4-Standards for Nuclear Safety, Security and Safeguard