Strong Purifying Selection at Synonymous Sites in D. melanogaster

Synonymous sites are generally assumed to be subject to weak selective constraint. For this reason, they are often neglected as a possible source of important functional variation. We use site frequency spectra from deep population sequencing data to show that, contrary to this expectation, 22% of four-fold synonymous (4D) sites in D. melanogaster evolve under very strong selective constraint while few, if any, appear to be under weak constraint. Linking polymorphism with divergence data, we further find that the fraction of synonymous sites exposed to strong purifying selection is higher for those positions that show slower evolution on the Drosophila phylogeny. The function underlying the inferred strong constraint appears to be separate from splicing enhancers, nucleosome positioning, and the translational optimization generating canonical codon bias. The fraction of synonymous sites under strong constraint within a gene correlates well with gene expression, particularly in the mid-late embryo, pupae, and adult developmental stages. Genes enriched in strongly constrained synonymous sites tend to be particularly functionally important and are often involved in key developmental pathways. Given that the observed widespread constraint acting on synonymous sites is likely not limited to Drosophila, the role of synonymous sites in genetic disease and adaptation should be reevaluated

CorGen—measuring and generating long-range correlations for DNA sequence analysis

CorGen is a web server that measures long-range correlations in the base composition of DNA and generates random sequences with the same correlation parameters. Long-range correlations are characterized by a power-law decay of the auto correlation function of the GC-content. The widespread presence of such correlations in eukaryotic genomes calls for their incorporation into accurate null models of eukaryotic DNA in computational biology. For example, the score statistics of sequence alignment and the performance of motif finding algorithms are significantly affected by the presence of genomic long-range correlations. We use an expansion-randomization dynamics to efficiently generate the correlated random sequences. The server is available a

A Solvable Sequence Evolution Model and Genomic Correlations

We study a minimal model for genome evolution whose elementary processes are single site mutation, duplication and deletion of sequence regions and insertion of random segments. These processes are found to generate long-range correlations in the composition of letters as long as the sequence length is growing, i.e., the combined rates of duplications and insertions are higher than the deletion rate. For constant sequence length, on the other hand, all initial correlations decay exponentially. These results are obtained analytically and by simulations. They are compared with the long-range correlations observed in genomic DNA, and the implications for genome evolution are discussed.Comment: 4 pages, 4 figure

Modeling CRISPR gene drives for suppression of invasive rodents using a supervised machine learning framework

Funding: This study was supported by funding from New Zealand’s Predator Free 2050 program under Predator Free 2050 Ltd. award SS/05/01 to PWM, and from National Institutes of Health award R01GM127418 to PWM. PG-D received funding from the New Zealand BioHeritage National Science Challenge (contract 1617-28-033 A to Manaaki Whenua – Landcare Research) and from Natural Environment Research Council grant NE/S011641/1 under the Newton Latam programme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

PENYELESAIAN SENGKETA PERTANAHAN ANTAR MASYARAKAT DESA OLEH KEPALA DESA DITINJAU DARI TEORI KEADILAN (Studi di Desa Donowarih dan Desa Landungsari)

The object of this research is the role of village heads in resolving land disputes between village communities in terms of the theory of justice. The purpose of this study is to know the implementation of the village head's obligations in resolving disputes between village communities, especially in the land sector and to analyze the types of land disputes in the village that can be resolved by the village head. The method used in this legal research is the sociological juridical method, by taking the research location in Malang Regency which is precisely in Donowarih Village, Karangploso District and in Landungsari Village, Dau District. The data in this study were obtained from the results of interviews and literature studies as material for analysis. The data analysis technique used is descriptive qualitative. The results of this study indicate: First: Land disputes that can be resolved by the head is based on the Decree of the Head of the National Land Agency of the Republic of Indonesia Number 34 of 2007 about the Technical Guidelines for Handling and Resolving the Problems of Typology Land that have occurred in Landungsari and Donowarih Villages namely Land mastery and land Ownership, Limits or Land Plots. Second: The obligation of the village head to resolve disputes between village communities, especially in the land sector, is carried out through alternative mediation dispute resolution, through several stages of deliberation, then if the parties are dissatisfied with the meditation result then they can submit other legal efforts through litigation channels, and in practice the settlement of disputes between villagers by the village head, especially in the land sector, has not fully brought justice to the community. Third: There are several problems in the implementation of land dispute resolution between village communities by the village head due to the lack of professionalism of the village head as a mediato

Faster than Neutral Evolution of Constrained Sequences: The Complex Interplay of Mutational Biases and Weak Selection

Comparative genomics has become widely accepted as the major framework for the ascertainment of functionally important regions in genomes. The underlying paradigm of this approach is that most of the functional regions are assumed to be under selective constraint, which in turn reduces the rate of evolution relative to neutrality. This assumption allows detection of functional regions through sequence conservation. However, constraint does not always lead to sequence conservation. When purifying selection is weak and mutation is biased, constrained regions can even evolve faster than neutral sequences and thus can appear to be under positive selection. Moreover, conservation estimates depend also on the orientation of selection relative to mutational biases and can vary over time. In the light of recent data of the ubiquity of mutational biases and weak selective forces, these effects should reduce the power of conservation analyses to define functional regions using comparative genomics data. We argue that the estimation of true mutational biases and the use of explicit evolutionary models are essential to improve methods inferring the action of natural selection and functionality in genome sequences

Bifunctional Anti-Huntingtin Proteasome-Directed Intrabodies Mediate Efficient Degradation of Mutant Huntingtin Exon 1 Protein Fragments

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a trinucleotide (CAG)n repeat expansion in the coding sequence of the huntingtin gene, and an expanded polyglutamine (>37Q) tract in the protein. This results in misfolding and accumulation of huntingtin protein (htt), formation of neuronal intranuclear and cytoplasmic inclusions, and neuronal dysfunction/degeneration. Single-chain Fv antibodies (scFvs), expressed as intrabodies that bind htt and prevent aggregation, show promise as immunotherapeutics for HD. Intrastriatal delivery of anti-N-terminal htt scFv-C4 using an adeno-associated virus vector (AAV2/1) significantly reduces the size and number of aggregates in HDR6/1 transgenic mice; however, this protective effect diminishes with age and time after injection. We therefore explored enhancing intrabody efficacy via fusions to heterologous functional domains. Proteins containing a PEST motif are often targeted for proteasomal degradation and generally have a short half life. In ST14A cells, fusion of the C-terminal PEST region of mouse ornithine decarboxylase (mODC) to scFv-C4 reduces htt exon 1 protein fragments with 72 glutamine repeats (httex1-72Q) by ∼80–90% when compared to scFv-C4 alone. Proteasomal targeting was verified by either scrambling the mODC-PEST motif, or via proteasomal inhibition with epoxomicin. For these constructs, the proteasomal degradation of the scFv intrabody proteins themselves was reduced<25% by the addition of the mODC-PEST motif, with or without antigens. The remaining intrabody levels were amply sufficient to target N-terminal httex1-72Q protein fragment turnover. Critically, scFv-C4-PEST prevents aggregation and toxicity of httex1-72Q fragments at significantly lower doses than scFv-C4. Fusion of the mODC-PEST motif to intrabodies is a valuable general approach to specifically target toxic antigens to the proteasome for degradation