Amit Majithia and colleagues employ a pooled assay in human macrophages to assess the functional effects of all possible missense variants in PPARG. Their study shows the value of saturation mutagenesis and prospective experimental characterization to support diagnostic interpretation of newly discovered missense variants in disease-related genes. Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty1,2. For example, mutations in PPARG cause Mendelian lipodystrophy3,4 and increase risk of type 2 diabetes (T2D)5. Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single–amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.

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Prospective functional classification of all possible missense variants in PPARG

A facile one-pot method to fabricate photoluminescent carbon dots (CDs) was developed by the hydrothermal treatment of amino acids at mild temperatures Derived from three different kinds of amino acids including serine, histidine, and cystine, the resultant CDs show uniform spherical morphology with the diameters in the range of ∼25–47 nm These amino acid derived CDs also manifest excellent photoluminescence behavior with the quantum yields (QYs) of ∼75% and high stability More importantly, this method provides the opportunity to modify the sizes, structures, and photoluminescent behavior of CDs by the utilization of diversified amino acids with different structural characteristics

A facile hydrothermal approach towards photoluminescent carbon dots from amino acids.

The major histocompatibility complex (MHC) plays an important role in immune response. Avian MHCs are not well characterized, only reporting highly compact Galliformes MHCs and extensively fragmented zebra finch MHC. We report the first genomic structure of an endangered Pelecaniformes (crested ibis) MHC containing 54 genes in three regions spanning ~500 kb. In contrast to the loose BG (26 loci within 265 kb) and Class I (11 within 150) genomic structures, the Core Region is condensed (17 within 85). Furthermore, this Region exhibits a COL11A2 gene, followed by four tandem MHC class II αβ dyads retaining two suites of anciently duplicated “αβ” lineages. Thus, the crested ibis MHC structure is entirely different from the known avian MHC architectures but similar to that of mammalian MHCs, suggesting that the fundamental structure of ancestral avian class II MHCs should be “COL11A2-IIαβ1-IIαβ2.” The gene structures, residue characteristics, and expression levels of the five class I genes reveal inter-locus functional divergence. However, phylogenetic analysis indicates that these five genes generate a well-supported intra-species clade, showing evidence for recent duplications. Our analyses suggest dramatic structural variation among avian MHC lineages, help elucidate avian MHC evolution, and provide a foundation for future conservation studies.

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Genomic organization of the crested ibis MHC provides new insight into ancestral avian MHC structure

Antibodies are glycoproteins produced by the immune system as a dynamically adaptive line of defense against invading pathogens. Very elegant and specific mutational mechanisms allow B lymphocytes to produce a large and diversified repertoire of antibodies, which is modified and enhanced throughout all adulthood. One of these mechanisms is somatic hypermutation, which stochastically mutates nucleotides in the antibody genes, forming new sequences with different properties and, eventually, higher affinity and selectivity to the pathogenic target. As somatic hypermutation involves fast mutation of antibody sequences, this process can be described using a Markov substitution model of molecular evolution. Here, using large sets of antibody sequences from mice and humans, we infer an empirical amino acid substitution model AB, which is specific to antibody sequences. Compared with existing general amino acid models, we show that the AB model provides significantly better description for the somatic evolution of mice and human antibody sequences, as demonstrated on large next generation sequencing (NGS) antibody data. General amino acid models are reflective of conservation at the protein level due to functional constraints, with most frequent amino acids exchanges taking place between residues with the same or similar physicochemical properties. In contrast, within the variable part of antibody sequences we observed an elevated frequency of exchanges between amino acids with distinct physicochemical properties. This is indicative of a sui generis mutational mechanism, specific to antibody somatic hypermutation. We illustrate this property of antibody sequences by a comparative analysis of the network modularity implied by the AB model and general amino acid substitution models. We recommend using the new model for computational studies of antibody sequence maturation, including inference of alignments and phylogenetic trees describing antibody somatic hypermutation in large NGS data sets. The AB model is implemented in the open-source software CodonPhyML (http://sourceforge.net/projects/codonphyml) and can be downloaded and supplied by the user to ProGraphMSA (http://sourceforge.net/projects/prographmsa) or other alignment and phylogeny reconstruction programs that allow for user-defined substitution models.

/pdf/antibody-specific-model-of-amino-acid-substitution-for-4mbcf6t1nr.pdf

Antibody-Specific Model of Amino Acid Substitution for Immunological Inferences from Alignments of Antibody Sequences

One-dimensional (1-D) coordination polymer and mononuclear copper(II) complexes, ([Cu(nphen)(asn)]ClO4)n (1) and [Cu(nphen)(gln)(H2O)]ClO4·H2O (2) (nphen = 5-nitro-110-phenanthroline, asn = asparagine, gln = glutamine), have been synthesized and characterized by IR spectroscopy, ESI-MS, CHN analysis, and single-crystal X-ray diffraction. These binary and ternary complexes of copper(II) with nphen, asn, and gln have been investigated using potentiometric methods in 0.1 M KCl aqueous ionic media at 298.2 K. The protonation constants of the ligands and the stability constants of 1 and 2 have been calculated from the potentiometric data using the “BEST” software package. The potentiometric results have been analyzed using the “SPE” software package, and the distribution curves for the copper-containing species have been determined for the ternary systems. The CT-DNA-binding properties of these complexes have been investigated by thermal denaturation measurements and both absorption and emission spectr...

Synthesis, crystal structure, stability studies, DNA/albumin interactions, and antimicrobial activities of two Cu(II) complexes with amino acids and 5-nitro-1,10-phenanthroline

Thank you for reading bioinformatics for geneticists. As you may know, people have search numerous times for their favorite novels like this bioinformatics for geneticists, but end up in harmful downloads. Rather than reading a good book with a cup of coffee in the afternoon, instead they are facing with some malicious virus inside their laptop. bioinformatics for geneticists is available in our book collection an online access to it is set as public so you can download it instantly. Our digital library saves in multiple countries, allowing you to get the most less latency time to download any of our books like this one. Merely said, the bioinformatics for geneticists is universally compatible with any devices to read.

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Bioinformatics For Geneticists