Aggregation of Oscillating Subsystems

In previous work, the analysis of the effects of aggregating simple dynamic systems has been studied by applying methods developed for thermodynamic systems in order to take account of stochastic effects. This approach is based on the Master Equation for the probability density of the contents of a vector of system levels. The goal of these studies is to determine the dynamic characteristics of systems composed of a population of sub-systems with the same dynamic structure while accounting for novel behavior that is introduced by the process of aggregating the sub-systems into the larger system.     

The DNA sequence and comparative analysis of human chromosome 5

Chromosome 5 is one of the largest human chromosomes and contains numerous intrachromosomal duplications, yet it has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding conservation with non-mammalian vertebrates, suggesting that they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-coding genes including the protocadherin and interleukin gene families. We also completely sequenced versions of the large chromosome-5-specific internal duplications. These duplications are very recent evolutionary events and probably have a mechanistic role in human physiological variation, as deletions in these regions are the cause of debilitating disorders including spinal muscular atrophy.     

A 15.65-solar-mass black hole in an eclipsing binary in the nearby spiral galaxy M 33

Stellar-mass black holes are found in X-ray-emitting binary systems, where their mass can be determined from the dynamics of their companion stars. Models of stellar evolution have difficulty producing black holes in close binaries with masses more than ten times that of the Sun (>10; ref. 4), which is consistent with the fact that the most massive stellar black holes known so far all have masses within one standard deviation of 10. Here we report a mass of (15.65 +/- 1.45) for the black hole in the recently discovered system M 33 X-7, which is located in the nearby galaxy Messier 33 (M 33) and is the only known black hole that is in an eclipsing binary. To produce such a massive black hole, the progenitor star must have retained much of its outer envelope until after helium fusion in the core was completed. On the other hand, in order for the black hole to be in its present 3.45-day orbit about its (70.0 +/- 6.9) companion, there must have been a 'common envelope' phase of evolution in which a significant amount of mass was lost from the system. We find that the common envelope phase could not have occurred in M 33 X-7 unless the amount of mass lost from the progenitor during its evolution was an order of magnitude less than what is usually assumed in evolutionary models of massive stars.     

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.     

Transferability of tag SNPs in genetic association studies in multiple populations

A general question for linkage disequilibrium-based association studies is how power to detect an association is compromised when tag SNPs are chosen from data in one population sample and then deployed in another sample. Specifically, it is important to know how well tags picked from the HapMap DNA samples capture the variation in other samples. To address this, we collected dense data uniformly across the four HapMap population samples and eleven other population samples. We picked tag SNPs using genotype data we collected in the HapMap samples and then evaluated the effective coverage of these tags in comparison to the entire set of common variants observed in the other samples. We simulated case-control association studies in the non-HapMap samples under a disease model of modest risk, and we observed little loss in power. These results demonstrate that the HapMap DNA samples can be used to select tags for genome-wide association studies in many samples around the world.     

A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization

Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.     

Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility

The World Health Organization conservatively estimates that 80 million people suffer from infertility worldwide. Male factors are believed to be responsible for 20-50% of all infertility cases, but microdeletions of the Y chromosome are the only genetic defects altering human spermatogenesis that have been reported repeatedly. We focused our work on infertile men with a normal somatic karyotype but typical spermatozoa mainly characterized by large heads, a variable number of tails and an increased chromosomal content (OMIM 243060). We performed a genome-wide microsatellite scan on ten infertile men presenting this characteristic phenotype. In all of these men, we identified a common region of homozygosity harboring the aurora kinase C gene (AURKC) with a single nucleotide deletion in the AURKC coding sequence. In addition, we show that this founder mutation results in premature termination of translation, yielding a truncated protein that lacks the kinase domain. We conclude that the absence of AURKC causes male infertility owing to the production of large-headed multiflagellar polyploid spermatozoa.     

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.