To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1 . In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P <5×10 −8 , bringing the number of known independent signals for CRC to approximately 100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs, somatic drivers, and support a role of immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of underlying biology, and impact personalized screening strategies and drug development.

The molar mass and ionic strength dependence of the dimensions of hydrophobically modified poly(vinylpyridinium) cations are demonstrated to be almost perfectly described by a theoretical expression derived on the basis of only excluded volume considerations. Generally, the effective charge density of the polyions decreases significantly with increasing hydrophobicity and with increasing polarizability of the gegenions. Unexpectedly, the intrinsic excluded volume effect which becomes dominating at high ionic strength not only depends on the hydrophobicity of the polyion but also significantly increases with decreasing polarizability of the gegenions (i.e., if the iodide gegenions are replaced by chloride gegenions). Measurements in different solvents reveal that the effective charge density does not linearly depend on the dielectric constant in the regime 20 ≤ ε ≤ 190. It is shown that the introduction of the electrostatic persistence length leads to less consistent results, although the experimental data could be fitted equally well.

ENCODE 3 (2012-2017) expanded production and added new types of assays 8 (Fig. 1, Extended Data Fig. 1), which revealed landscapes of RNA binding and the 3D organization of chromatin via methods such as chromatin interaction analysis by paired-end tagging (ChIA-PET) and Hi-C chromosome conformation capture. Phases 2 and 3 delivered 9,239 experiments (7,495 in human and 1,744 in mouse) in more than 500 cell types and tissues, including mapping of transcribed regions and transcript isoforms, regions of transcripts recognized by RNA-binding proteins, transcription factor binding regions, and regions that harbour specific histone modifications, open chromatin, and 3D chromatin interactions. The results of all of these experiments are available at the ENCODE portal (http://www.encodeproject.org). These efforts, combined with those of related projects and many other laboratories, have produced a greatly enhanced view of the human genome (Fig. 2), identifying 20,225 protein-coding and 37,595 noncoding genes

The coil contraction of sodium polymethacrylate in dilute aqueous sodium chloride solution (0.1 N, pH = 9) was monitored by static and dynamic light scattering when the Na+ ions were partly replaced by Ca2+ or Cu2+ ions. The effect was quantified as a function of polyion and bivalent metal ion concentration. The impact of Cu2+ ions on the chain conformation and the solubility of sodium polymethacrylate was observed to be larger than the corresponding effect of Ca2+ ions. This difference was ascribed to complexation of the carboxylate group with bivalent metal cations which is larger for the Cu2+ than for the Ca2+ ion. Even at the largest extent of contraction observed close to the precipitation threshold, the ratio of the radius of gyration and the hydrodynamic radius remained unchanged in contrast to the coil−globule transition observed for neutral polymer systems below the ϑ-temperature.

Human gene expression is regulated by over two thousand transcription factors and chromatin regulators. Effector domains within these proteins can activate or repress transcription. However, for many of these regulators we do not know what type of transcriptional effector domains they contain, their location in the protein, their activation and repression strengths, and the amino acids that are necessary for their functions. Here, we systematically measure the transcriptional effector activity of >100,000 protein fragments (each 80 amino acids long) tiling across most chromatin regulators and transcription factors in human cells (2,047 proteins). By testing the effect they have when recruited at reporter genes, we annotate 307 new activation domains and 592 new repression domains, a ~5-fold increase over the number of previously annotated effectors. Complementary rational mutagenesis and deletion scans across all the effector domains reveal aromatic and/or leucine residues interspersed with acidic, proline, serine, and/or glutamine residues are necessary for activation domain activity. Additionally, the majority of repression domain sequences contain either sites for SUMOylation, short interaction motifs for recruiting co-repressors, or are structured binding domains for recruiting other repressive proteins. Surprisingly, we discover bifunctional domains that can both activate and repress and can dynamically split a cell population into high- and low-expression subpopulations. Our systematic annotation and characterization of transcriptional effector domains provides a rich resource for understanding the function of human transcription factors and chromatin regulators, engineering compact tools for controlling gene expression, and refining predictive computational models of effector domain function.