抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

NAMD is a parallel molecular dynamics code designed for high-performance simulation of large biomolecular systems. NAMD scales to hundreds of processors on high-end parallel platforms, as well as tens of processors on low-cost commodity clusters, and also runs on individual desktop and laptop computers. NAMD works with AMBER and CHARMM potential functions, parameters, and file formats. This article, directed to novices as well as experts, first introduces concepts and methods used in the NAMD program, describing the classical molecular dynamics force field, equations of motion, and integration methods along with the efficient electrostatics evaluation algorithms employed and temperature and pressure controls used. Features for steering the simulation across barriers and for calculating both alchemical and conformational free energy differences are presented. The motivations for and a roadmap to the internal design of NAMD, implemented in C++ and based on Charm++ parallel objects, are outlined. The factors affecting the serial and parallel performance of a simulation are discussed. Finally, typical NAMD use is illustrated with representative applications to a small, a medium, and a large biomolecular system, highlighting particular features of NAMD, for example, the Tcl scripting language. The article also provides a list of the key features of NAMD and discusses the benefits of combining NAMD with the molecular graphics/sequence analysis software VMD and the grid computing/collaboratory software BioCoRE. NAMD is distributed free of charge with source code at www.ks.uiuc.edu.

/pdf/scalable-molecular-dynamics-with-namd-51o1z7rwp8.pdf

Scalable molecular dynamics with NAMD

/pdf/scalable-molecular-dynamics-with-namd-3j7xyc70g4.pdf

Scalable Molecular Dynamics with NAMD

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

https://cdr.lib.unc.edu/downloads/v692t8920

A global reference for human genetic variation.

Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

Population Genetics of Molecular Evolution

An optical trap and method for measuring both transverse and longitudinal forces on a trapped particle (4). Laser light sources (12) generate first and second light beams that are focused to the trap region (26) in a counter-propagating manner for trapping the particle (4). Detectors (22, 24) measure changes in power deflections of the light beams leaving the trap region (26), and changes in power concentrations of the light beams leaving the trap region (26). A processor (14) calculates the transverse forces on the particle (4) based upon the measured changes in the power deflections of the light beams, and calculates the longitudinal forces on the particle (4) based upon the measured changes in the power concentrations of the light beams. A single beam optical trap and method are also disclosed, where the second optical beam is generated by a reflection of the first optical beam off of the trapped particle.

A light-force sensor and method for measuring axial optical-trap forces from changes in light momentum along an optic axis

Poly(ADP-ribosyl)ation of nuclear proteins is responsible for major changes in the high-order chromatin structure. The effects of this post-translation modification on nuclear architecture were examined at different Mg2+ concentrations using scanning force microscopy. A quantitative analysis of the internucleosomal distance, the width, and the volume of chromatin fibers imaged in tapping mode reveals that poly(ADP-ribosyl)ation induces a complete relaxation and decondensation of the chromatin structure. Our data, on the center-to-center distance between adjacent nucleosomes and on the fiber width, indicate that the poly(ADP-ribosyl)ated fibers remain significantly decondensed even in the presence of Mg2+. Our results also show that the Mg2+ assumes an important role in the folding of chromatin structure, but Mg2+ is not able to restore the native feature of chromatin, when the fibers are depleted of H1/H5 histones. The combined effect of post-translation modification and cation ions on the chromatin struc...

Effect of Poly(ADP-ribosyl)ation and Mg2+ Ions on Chromatin Structure Revealed by Scanning Force Microscopy†

DNA replication errors that escape polymerase proofreading and mismatch repair (MMR) can lead to base substitution and frameshift mutations. Such mutations can disrupt gene function, reduce fitness, and promote diseases such as cancer and are also the raw material of molecular evolution. To analyze with limited bias genomic features associated with DNA polymerase errors, we performed a genome-wide analysis of mutations that accumulate in MMR-deficient diploid lines of Saccharomyces cerevisiae. These lines were derived from a common ancestor and were grown for 160 generations, with bottlenecks reducing the population to one cell every 20 generations. We sequenced to between 8- and 20-fold coverage one wild-type and three mutator lines using Illumina Solexa 36-bp reads. Using an experimentally aware Bayesian genotype caller developed to pool experimental data across sequencing runs for all strains, we detected 28 heterozygous single-nucleotide polymorphisms (SNPs) and 48 single-nt insertion/deletions (indels) from the data set. This method was evaluated on simulated data sets and found to have a very low false-positive rate (∼6 × 10−5) and a false-negative rate of 0.08 within the unique mapping regions of the genome that contained at least sevenfold coverage. The heterozygous mutations identified by the Bayesian genotype caller were confirmed by Sanger sequencing. All of the mutations were unique to a given line, except for a single-nt deletion mutation which occurred independently in two lines. All 48 indels, composed of 46 deletions and two insertions, occurred in homopolymer (HP) tracts [i.e., 47 poly(A) or (T) tracts, 1 poly(G) or (C) tract] between 5 and 13 bp long. Our findings are of interest because HP tracts are present at high levels in the yeast genome (>77,400 for 5- to 20-nt HP tracts), and frameshift mutations in these regions are likely to disrupt gene function. In addition, they demonstrate that the mutation pattern seen previously in mismatch repair defective strains using a limited number of reporters holds true for the entire genome.

/pdf/detection-of-heterozygous-mutations-in-the-genome-of-2k2cg8r201.pdf

Detection of Heterozygous Mutations in the Genome of Mismatch Repair Defective Diploid Yeast Using a Bayesian Approach

Recent work in atomic force microscopy (AFM) of deoxyribonucleic acid (DNA) has relied on immobilizing DNA molecules by drying a small volume of buffered DNA solution onto cleaved mica When imaging in air, relative humidity has been known to affect both the resolution and measured height of the DNA strands We present data of measured height versus humidity for DNA and attached gold labels, and we propose a model for this data based on swelling of coadsorbed buffer salts upon exposure to moisture In this model, small particles (eg, DNA) stay near the top of the swelling salt layer, whereas larger particles (eg, gold spheres) tend to be anchored down to the substrate until a moderate humidity is reached At high humidity (around 65%), the salt layer becomes fluid-like and susceptible to tip-induced motion; the salts are either removed from the scan area or aggregate into island structures, depending on initial salt concentration on the surface

Carlos Bustamante

Papers

Population Genetics of Molecular Evolution

A light-force sensor and method for measuring axial optical-trap forces from changes in light momentum along an optic axis

Effect of Poly(ADP-ribosyl)ation and Mg2+ Ions on Chromatin Structure Revealed by Scanning Force Microscopy†

Detection of Heterozygous Mutations in the Genome of Mismatch Repair Defective Diploid Yeast Using a Bayesian Approach

Humidity effects on atomic force microscopy of gold-labeled DNA on mica.