Common variation at 10p12.31 near MLLT10 influences meningioma risk

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.     

Accurate whole human genome sequencing using reversible terminator chemistry

DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally used long (400-800 base pair) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intraspecies genetic variation. Here we report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost. Single molecules of DNA are attached to a flat surface, amplified in situ and used as templates for synthetic sequencing with fluorescent reversible terminator deoxyribonucleotides. Images of the surface are analysed to generate high-quality sequence. We demonstrate application of this approach to human genome sequencing on flow-sorted X chromosomes and then scale the approach to determine the genome sequence of a male Yoruba from Ibadan, Nigeria. We build an accurate consensus sequence from >30x average depth of paired 35-base reads. We characterize four million single-nucleotide polymorphisms and four hundred thousand structural variants, many of which were previously unknown. Our approach is effective for accurate, rapid and economical whole-genome re-sequencing and many other biomedical applications.     

Essay Review: Ptolemy's Geography,An Annotated Translation of the Theoretical Chapters by J. Lennart Berggren and Alexander Jones

The coming of mathematicians to the United States fleeing the spread of Nazism presented a serious problem to the American mathematical community. The persistence of the Depression had endangered the promising growth of mathematics in the United States. Leading mathematicians were concerned about the career prospects of their students. They (and others) feared that placing large numbers of refugees would exacerbate already present nationalistic and anti-Semitic sentiments. The paper surveys a sequence of events in which the leading mathematicians reacted to the foreign-born and to the spread of Nazism, culminating in the decisions by the American Mathematical Society to found the journal Mathematical reviews and to form a War Preparedness Committee in September 1939. The most obvious consequence of the migration was an enlarged role for applied mathematics.     

The patterns and dynamics of genomic instability in metastatic pancreatic cancer

Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.     

Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.     

The Lunar Theories of Tycho Brahe and Christian Longomontanus in the Progymnasmata and Astronomia Danica

Tycho Brahe's lunar theory, mostly the work of his assistant Christian Longomontanus, published in the Progymnasmata (1602), was the most advanced and accurate lunar theory yet developed. Its principal innovations are: the introduction of equant motion for the first inequality in order to separate the determination of direction and distance; a more accurate limit for the second inequality although requiring a more complex calculation; additional inequalities of the variation and, in place of the annual inequality in Tycho's earlier theory, a reduction in the equation of time; in the latitude theory a variation of the inclination of the orbital plane and an inequality of the motion of the nodes; a reduction in the range of variation of distance, parallax, and apparent diameter. Some of these were already present in Tycho's earlier lunar theory (1599), but all were changed in notable ways. Twenty years later Longomontanus published a modified version of the lunar theory in Astronomia Danica (1622), for the purpose of facilitating the calculation through new correction tables, and also explained his reasons for parts of the theory in the Progymnasmata. This paper is a technical study of both lunar theories.