Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection

Tuberculosis poses a global health emergency, which has been compounded by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. We used whole-genome sequencing to compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent or reactivated disease. We sequenced 33 Mtb isolates from nine macaques with an average genome coverage of 93% and an average read depth of 117×. Based on the distribution of SNPs observed, we calculated the mutation rates for these disease states. We found a similar mutation rate during latency as during active disease or in a logarithmically growing culture over the same period of time. The pattern of polymorphisms suggests that the mutational burden in vivo is because of oxidative DNA damage. We show that Mtb continues to acquire mutations during disease latency, which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance.     

MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis

The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1-associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR = 5.0, 95% CI = 3.5-7.1; P = 4 x 10(-23), n = 852). This association extended to hypertensive ESKD (OR = 2.2, 95% CI = 1.5-3.4; n = 433), but not type 2 diabetic ESKD (n = 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.     

A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility

Multiple sclerosis is a common disease with proven heritability, but, despite large-scale attempts, no underlying risk genes have been identified. Traditional linkage scans have so far identified only one risk haplotype for multiple sclerosis (at HLA on chromosome 6), which explains only a fraction of the increased risk to siblings. Association scans such as admixture mapping have much more power, in principle, to find the weak factors that must explain most of the disease risk. We describe here the first high-powered admixture scan, focusing on 605 African American cases and 1,043 African American controls, and report a locus on chromosome 1 that is significantly associated with multiple sclerosis.     

Insolation-driven changes in atmospheric circulation over the past 116,000 years in subtropical Brazil

During the last glacial period, large millennial-scale temperature oscillations--the 'Dansgaard/Oeschger' cycles--were the primary climate signal in Northern Hemisphere climate archives from the high latitudes to the tropics. But whether the influence of these abrupt climate changes extended to the tropical and subtropical Southern Hemisphere, where changes in insolation are thought to be the main direct forcing of climate, has remained unclear. Here we present a high-resolution oxygen isotope record of a U/Th-dated stalagmite from subtropical southern Brazil, covering the past 116,200 years. The oxygen isotope signature varies with shifts in the source region and amount of rainfall in the area, and hence records changes in atmospheric circulation and convective intensity over South America. We find that these variations in rainfall source and amount are primarily driven by summer solar radiation, which is controlled by the Earth's precessional cycle. The Dansgaard/Oeschger cycles can be detected in our record and therefore we confirm that they also affect the tropical hydrological cycle, but that in southern subtropical Brazil, millennial-scale climate changes are not as dominant as they are in the Northern Hemisphere.     

Mimicry of ice structure by surface hydroxyls and water of a beta-helix antifreeze protein

Insect antifreeze proteins (AFP) are much more effective than fish AFPs at depressing solution freezing points by ice-growth inhibition. AFP from the beetle Tenebrio molitor is a small protein (8.4 kDa) composed of tandem 12-residue repeats (TCTxSxxCxxAx). Here we report its 1.4-A resolution crystal structure, showing that this repetitive sequence translates into an exceptionally regular beta-helix. Not only are the 12-amino-acid loops almost identical in the backbone, but also the conserved side chains are positioned in essentially identical orientations, making this AFP perhaps the most regular protein structure yet observed. The protein has almost no hydrophobic core but is stabilized by numerous disulphide and hydrogen bonds. On the conserved side of the protein, threonine-cysteine-threonine motifs are arrayed to form a flat beta-sheet, the putative ice-binding surface. The threonine side chains have exactly the same rotameric conformation and the spacing between OH groups is a near-perfect match to the ice lattice. Together with tightly bound co-planar external water, three ranks of oxygen atoms form a two-dimensional array, mimicking an ice section.     

New stochastic model for geomagnetic reversals

A non-stationary model for geomagnetic reversals is proposed. From the model, a mean length of all polarity intervals of 1.6 m.y. is predicted.