Re-evaluation of the linkage relationship between chromosome 11p loci and the gene for bipolar affective disorder in the Old Order Amish

Reanalysis of an Old Order Amish pedigree, to include several new individuals and two changes in clinical status, markedly reduces the probability of linkage between bipolar affective disorder and the Harvey-ras-1 oncogene and insulin loci on chromosome 11. This linkage can be excluded using a large lateral extension of the original Amish pedigree.     

Iron meteorite evidence for early formation and catastrophic disruption of protoplanets

In our Solar System, the planets formed by collisional growth from smaller bodies. Planetesimals collided to form Moon-to-Mars-sized protoplanets in the inner Solar System in 0.1-1 Myr, and these collided more energetically to form planets. Insights into the timing and nature of collisions during planetary accretion can be gained from meteorite studies. In particular, iron meteorites offer the best constraints on early stages of planetary accretion because most are remnants of the oldest bodies, which accreted and melted in <1.5 Myr, forming silicate mantles and iron-nickel metallic cores. Cooling rates for various groups of iron meteorites suggest that if the irons cooled isothermally in the cores of differentiated bodies, as conventionally assumed, these bodies were 5-200 km in diameter. This picture is incompatible, however, with the diverse cooling rates observed within certain groups, most notably the IVA group, but the large uncertainties associated with the measurements do not preclude it. Here we report cooling rates for group IVA iron meteorites that range from 100 to 6,000 K Myr(-1), increasing with decreasing bulk Ni. Improvements in the cooling rate model, smaller error bars, and new data from an independent cooling rate indicator show that the conventional interpretation is no longer viable. Our results require that the IVA meteorites cooled in a 300-km-diameter metallic body that lacked an insulating mantle. This body probably formed approximately 4,500 Myr ago in a 'hit-and-run' collision between Moon-to-Mars-sized protoplanets. This demonstrates that protoplanets of approximately 10(3) km size accreted within the first 1.5 Myr, as proposed by theory, and that fragments of these bodies survived as asteroids.     

Detectable clonal mosaicism and its relationship to aging and cancer

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.     

Displaced tables in Latin: the Tables for the Seven Planets for 1340

The anonymous set of astronomical tables preserved in Paris, Bibliothèque nationale de France, MS lat. 10262, is the first set of displaced tables to be found in a medieval Latin text. These tables are a reworking of the standard Alfonsine tables and yield the same results. However, the mean motions are defined differently, the presentation of the tables is unprecedented, and some new functions are introduced for computing true planetary longitudes. The absence of any instructions as well as unusual technical terms in the headings make it difficult to appreciate the cleverness that went into the construction of these tables that are extant in a unique copy. In this article we provide a detailed analysis of these tables and their underlying parameters. The displaced tables are typical of a pervasive tendency in Islamic science to provide extensive and elegant numerical tables for the convenience of practitioners. The underlying astronomical theory is neither questioned nor affected. Edward S. Kennedy      

ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma

Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.     

Regulation of the mevalonate pathway

The mevalonate pathway produces isoprenoids that are vital for diverse cellular functions, ranging from cholesterol synthesis to growth control. Several mechanisms for feedback regulation of low-density-lipoprotein receptors and of two enzymes involved in mevalonate biosynthesis ensure the production of sufficient mevalonate for several end-products. Manipulation of this regulatory system could be useful in treating certain forms of cancer as well as heart disease.