Integrated detection and population-genetic analysis of SNPs and copy number variation

Dissecting the genetic basis of disease risk requires measuring all forms of genetic variation, including SNPs and copy number variants (CNVs), and is enabled by accurate maps of their locations, frequencies and population-genetic properties. We designed a hybrid genotyping array (Affymetrix SNP 6.0) to simultaneously measure 906,600 SNPs and copy number at 1.8 million genomic locations. By characterizing 270 HapMap samples, we developed a map of human CNV (at 2-kb breakpoint resolution) informed by integer genotypes for 1,320 copy number polymorphisms (CNPs) that segregate at an allele frequency >1%. More than 80% of the sequence in previously reported CNV regions fell outside our estimated CNV boundaries, indicating that large (>100 kb) CNVs affect much less of the genome than initially reported. Approximately 80% of observed copy number differences between pairs of individuals were due to common CNPs with an allele frequency >5%, and more than 99% derived from inheritance rather than new mutation. Most common, diallelic CNPs were in strong linkage disequilibrium with SNPs, and most low-frequency CNVs segregated on specific SNP haplotypes.     

Crossover assurance and crossover interference are distinctly regulated by the ZMM proteins during yeast meiosis

Meiotic crossing-over is highly regulated such that each homolog pair typically receives at least one crossover (assurance) and adjacent crossovers are widely spaced (interference). Here we provide evidence that interference and assurance are mechanistically distinct processes that are separated by mutations in a new ZMM (Zip, Msh, Mer) protein from Saccharomyces cerevisiae, Spo16. Like other zmm mutants, spo16 cells have defects in both crossing-over and synaptonemal complex formation. Unlike in previously characterized zmm mutants, the residual crossovers in spo16 cells show interference comparable to that in the wild type. Spo16 interacts with a second ZMM protein, Spo22 (also known as Zip4), and spo22 mutants also show normal interference. Notably, assembly of the MutS homologs Msh4 and Msh5 on chromosomes occurs in both spo16 and spo22, but not in other zmm mutants. We suggest that crossover interference requires the normal assembly of recombination complexes containing Msh4 and Msh5 but does not require Spo16- and Spo22-dependent extension of synaptonemal complexes. In contrast, crossover assurance requires all ZMM proteins and full-length synaptonemal complexes.     

Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections

The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.     

Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy

Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11, SOS1 and KRAS mutations causes approximately 60% of Noonan syndrome cases, and PTPN11 mutations cause 90% of LEOPARD syndrome cases. Here, we report that 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals) and two of six individuals with LEOPARD syndrome without PTPN11 mutations have missense mutations in RAF1, which encodes a serine-threonine kinase that activates MEK1 and MEK2. Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding. Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase impaired. Our findings further implicate increased RAS signaling in pathological cardiomyocyte hypertrophy.     

Conservation of Y-linked genes during human evolution revealed by comparative sequencing in chimpanzee

The human Y chromosome, transmitted clonally through males, contains far fewer genes than the sexually recombining autosome from which it evolved. The enormity of this evolutionary decline has led to predictions that the Y chromosome will be completely bereft of functional genes within ten million years. Although recent evidence of gene conversion within massive Y-linked palindromes runs counter to this hypothesis, most unique Y-linked genes are not situated in palindromes and have no gene conversion partners. The 'impending demise' hypothesis thus rests on understanding the degree of conservation of these genes. Here we find, by systematically comparing the DNA sequences of unique, Y-linked genes in chimpanzee and human, which diverged about six million years ago, evidence that in the human lineage, all such genes were conserved through purifying selection. In the chimpanzee lineage, by contrast, several genes have sustained inactivating mutations. Gene decay in the chimpanzee lineage might be a consequence of positive selection focused elsewhere on the Y chromosome and driven by sperm competition.     

An integrated view of the chemistry and mineralogy of martian soils

The mineralogical and elemental compositions of the martian soil are indicators of chemical and physical weathering processes. Using data from the Mars Exploration Rovers, we show that bright dust deposits on opposite sides of the planet are part of a global unit and not dominated by the composition of local rocks. Dark soil deposits at both sites have similar basaltic mineralogies, and could reflect either a global component or the general similarity in the compositions of the rocks from which they were derived. Increased levels of bromine are consistent with mobilization of soluble salts by thin films of liquid water, but the presence of olivine in analysed soil samples indicates that the extent of aqueous alteration of soils has been limited. Nickel abundances are enhanced at the immediate surface and indicate that the upper few millimetres of soil could contain up to one per cent meteoritic material.     

Water alteration of rocks and soils on Mars at the Spirit rover site in Gusev crater

Gusev crater was selected as the landing site for the Spirit rover because of the possibility that it once held a lake. Thus one of the rover's tasks was to search for evidence of lake sediments. However, the plains at the landing site were found to be covered by a regolith composed of olivine-rich basaltic rock and windblown 'global' dust. The analyses of three rock interiors exposed by the rock abrasion tool showed that they are similar to one another, consistent with having originated from a common lava flow. Here we report the investigation of soils, rock coatings and rock interiors by the Spirit rover from sol (martian day) 1 to sol 156, from its landing site to the base of the Columbia hills. The physical and chemical characteristics of the materials analysed provide evidence for limited but unequivocal interaction between water and the volcanic rocks of the Gusev plains. This evidence includes the softness of rock interiors that contain anomalously high concentrations of sulphur, chlorine and bromine relative to terrestrial basalts and martian meteorites; sulphur, chlorine and ferric iron enrichments in multilayer coatings on the light-toned rock Mazatzal; high bromine concentration in filled vugs and veins within the plains basalts; positive correlations between magnesium, sulphur and other salt components in trench soils; and decoupling of sulphur, chlorine and bromine concentrations in trench soils compared to Gusev surface soils, indicating chemical mobility and separation.     

Lithospheric structure of the Rio Grande rift

A high-resolution, regional passive seismic experiment in the Rio Grande rift region of the southwestern United States has produced new images of upper-mantle velocity structure and crust-mantle topography. Synthesizing these results with geochemical and other geophysical evidence reveals highly symmetric lower-crustal and upper-mantle lithosphere extensional deformation, suggesting a pure-shear rifting mechanism for the Rio Grande rift. Extension in the lower crust is distributed over a region four times the width of the rift's surface expression. Here we propose that the laterally distributed, pure shear extension is a combined effect of low strain rate and a regionally elevated geotherm, possibly abetted by pre-existing lithospheric structures, at the time of rift initiation. Distributed extension in the lower crust and mantle has induced less concentrated vertical mantle upwelling and less vigorous small-scale convection than would have arisen from more localized deformation. This lack of highly focused mantle upwelling may explain a deficit of rift-related volcanics in the Rio Grande rift compared to other major rift systems such as the Kenya rift.     

The effect of acetylcholine on adrenal function in the hypophysectomized dog

Résumé Après injection d'acétylcholine, les chiens hypophysectomisés ne secrètent pas d'hydrocortisone, mais présentent une élevation d'épinéphrine et de norépinéphrine dans le sang veineux surrénal. Aucun changement ne fut observé dans la concentration de la phényléthanolamine-N-methyl transférase dans ces glandes. Ces expériences indiquent que la relation médullaire surrénale corticale que nous avons mentionée précédemment fonctionne indépendamment de la secrétion de catécholamines, engendrée par l'Ach, de la glande surrénale.