Genetic Variation in Human Gene Regulatory Factors Uncovers Regulatory Roles in Local Adaptation and Disease

Differences in gene regulation have been suggested to play essential roles in the evolution of phenotypic changes. Although DNA changes in cis-regulatory elements affect only the regulation of its corresponding gene, variations in gene regulatory factors (trans) can have a broader effect, because the expression of many target genes might be affected. Aiming to better understand how natural selection may have shaped the diversity of gene regulatory factors in human, we assembled a catalog of all proteins involved in controlling gene expression. We found that at least five DNA-binding transcription factor classes are enriched among genes located in candidate regions for selection, suggesting that they might be relevant for understanding regulatory mechanisms involved in human local adaptation. The class of KRAB-ZNFs, zinc-finger (ZNF) genes with a Krüppel-associated box, stands out by first, having the most genes located on candidate regions for positive selection. Second, displaying most nonsynonymous single nucleotide polymorphisms (SNPs) with high genetic differentiation between populations within these regions. Third, having 27 KRAB-ZNF gene clusters with high extended haplotype homozygosity. Our further characterization of nonsynonymous SNPs in ZNF genes located within candidate regions for selection, suggests regulatory modifications that might influence the expression of target genes at population level. Our detailed investigation of three candidate regions revealed possible explanations for how SNPs may influence the prevalence of schizophrenia, eye development, and fertility in humans, among other phenotypes. The genetic variation we characterized here may be responsible for subtle to rough regulatory changes that could be important for understanding human adaptation

Application of Chiral Lanthanide-induced Shift Reagents to Optically Active Cations: the Use of Tris[3-(trifluoromethylhydroxymethylene)-( + )-camphorato]europium(III) to Determine the Enantiomeric Purity of Tris(phenanthroline)ruthenium(II) Dichloride

In non-polar solvents, chiral europium complexes provide attractive n. m. r. shift reagents to resolve spectra of optically active cations, and, in particular, for tris(phenanthroline)ruthenium dichloride,^1H n. m. r. shift differences of up to 0.7 p.p.m. between isomers easily permit the determination of absolute enantiomeric purity

Hopping and clustering of oxygen vacancies in SrTiO3 by anelastic relaxation

The complex elastic compliance s11(w,T) of SrTiO3-d has been measured as a function of the O deficiency d < 0.01. The two main relaxation peaks in the absorption are identified with hopping of isolated O vacancies over a barrier of 0.60 eV and reorientation of pairs of vacancies involving a barrier of 1 eV. The pair binding energy is ~0.2 eV and indications for additional clustering, possibly into chains, is found already at d ~0.004. The anistropic component of the elastic dipole of an O vacancy is Deltalambda = 0.026.Comment: 4 pages, 4 figures, submitted to Phys. Rev. Let

Non-linear Elastic Response in Solid Helium: critical velocity or strain

Torsional oscillator experiments show evidence of mass decoupling in solid 4He. This decoupling is amplitude dependent, suggesting a critical velocity for supersolidity. We observe similar behavior in the elastic shear modulus. By measuring the shear modulus over a wide frequency range, we can distinguish between an amplitude dependence which depends on velocity and one which depends on some other parameter like displacement. In contrast to the torsional oscillator behavior, the modulus depends on the magnitude of stress, not velocity. We interpret our results in terms of the motion of dislocations which are weakly pinned by 3He impurities but which break away when large stresses are applied

Relocation of the Enhancer transposon in maize

Controlling elements have the ability to activate and deactivate standard genes. One of the unique features of controlling elements is their ability to transpose from one position along the chromosome to another. In this study, the transposition of the controlling element En was examined within the distal two-thirds of the 3L maize chromosome arm;Stable germinal mutations representing losses of En were selected from three autonomously mutating al alleles. The insertion of En at a new location was confirmed by crosses of the stable mutants to responsive tester lines. The position of En at the primary transposition site was determined by backcrossing to an al et line using standard three-point tester lines. Secondary transpositions were detected by Chi-square comparisons of progeny to parental En linkage studies;Although En positions were found throughout the segment of chromosome examined, their distribution was not random and some regions of the chromosome were more likely to contain an inserted En. En\u27s from all three autonomously mutating source alleles showed the same regional preferences and distributions of transposed En\u27s from the three alleles were not significantly different in Chi-square tests. Both primary and secondary sites of insertion were located within these regions. No differences were found between the distribution of primary sites of insertion and the distribution of secondary sites;The difference in En transpositional activity within different chromosomal regions may be due to the replication patterns of the maize DNA or to the percentage of A-T base pairs within these regions. Correlations between the pattern produced by En on a standard allele and the En position were also examined. While an association between transposition and pattern change was observed, no correlation between pattern and linkage position was found

Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity.

The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β(2)-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles