Genome-wide association study of leaf architecture in the maize nested association mapping population

US maize yield has increased eight-fold in the past 80 years, with half of the gain attributed to selection by breeders. During this time, changes in maize leaf angle and size have altered plant architecture, allowing more efficient light capture as planting density has increased. Through a genome-wide association study (GWAS) of the maize nested association mapping panel, we determined the genetic basis of important leaf architecture traits and identified some of the key genes. Overall, we demonstrate that the genetic architecture of the leaf traits is dominated by small effects, with little epistasis, environmental interaction or pleiotropy. In particular, GWAS results show that variations at the liguleless genes have contributed to more upright leaves. These results demonstrate that the use of GWAS with specially designed mapping populations is effective in uncovering the basis of key agronomic traits.     

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.     

Our impasse in developing a malaria vaccine

Malaria presents a challenge to world health that to date has been beyond the abilities of researchers to conquer. This critique presents some of the strategies employed by the parasite to overcome immunity and the immunological challenges that we face to develop vaccines. A conclusion is that a vaccine must identify novel antigens or epitopes that are not normally immunogenic and which are therefore not under immune pressure and most likely to be conserved between different strains. Such antigens are most likely to be targets of cellular immunity. The case for a whole parasite blood stage vaccine is presented based on these premises.     

Newton's early computational method for dynamics

On December 13, 1679Newton sent a letter toHooke on orbital motion for central forces, which contains a drawing showing an orbit for a constant value of the force. This letter is of great importance, because it reveals the state ofNewton's development of dynamics at that time. Since the first publication of this letter in 1929,Newton's method of constructing this orbit has remained a puzzle particularly because he apparently made a considerable error in the angle between successive apogees of this orbit. In fact, it is shown here thatNewton's implicitcomputation of this orbit is quite good, and that the error in the angle is due mainly toan error of drawing in joining two segments of the oribit, whichNewton related by areflection symmetry. In addition, in the letterNewton describes quite correctly the geometrical nature of orbits under the action of central forces (accelerations) which increase with decreasing distance from the center. An iterative computational method to evaluate orbits for central forces is described, which is based onNewton's mathematical development of the concept of curvature started in 1664. This method accounts very well for the orbit obtained byNewton for a constant central force, and it gives convergent results even for forces which diverge at the center, which are discussed correctly inNewton's letterwithout usingKepler's law of areas.Newton found the relation of this law to general central forces only after his correspondence withHooke. The curvature method leads to an equation of motion whichNewton could have solvedanalytically to find that motion on a conic section with a radial force directed towards a focus implies an inverse square force, and that motion on a logarithmic spiral implies an inverse cube force.     

Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice.

Pigmentary glaucoma is a significant cause of human blindness. Abnormally liberated iris pigment and cell debris enter the ocular drainage structures, leading to increased intraocular pressure (IOP) and glaucoma. DBA/2J (D2) mice develop a form of pigmentary glaucoma involving iris pigment dispersion (IPD) and iris stromal atrophy (ISA). Using high-resolution mapping techniques, sequencing and functional genetic tests, we show that IPD and ISA result from mutations in related genes encoding melanosomal proteins. IPD is caused by a premature stop codon mutation in the Gpnmb (GpnmbR150X) gene, as proved by the occurrence of IPD only in D2 mice that are homozygous with respect to GpnmbR150X; otherwise, similar D2 mice that are not homozygous for GpnmbR150X do not develop IPD. ISA is caused by the recessive Tyrp1b mutant allele and rescued by the transgenic introduction of wildtype Tyrp1. We hypothesize that IPD and ISA alter melanosomes, allowing toxic intermediates of pigment production to leak from melanosomes, causing iris disease and subsequent pigmentary glaucoma. This is supported by the rescue of IPD and ISA in D2 eyes with substantially decreased pigment production. These data indicate that pigment production and mutant melanosomal protein genes may contribute to human pigmentary glaucoma. The fact that hypopigmentation profoundly alleviates the D2 disease indicates that therapeutic strategies designed to decrease pigment production may be beneficial in human pigmentary glaucoma.     

Microsatellites are preferentially associated with nonrepetitive DNA in plant genomes.

Microsatellites are a ubiquitous class of simple repetitive DNA sequence. An excess of such repetitive tracts has been described in all eukaryotes analyzed and is thought to result from the mutational effects of replication slippage. Large-scale genomic and EST sequencing provides the opportunity to evaluate the abundance and relative distribution of microsatellites between transcribed and nontranscribed regions and the relationship of these features to haploid genome size. Although this has been studied in microbial and animal genomes, information in plants is limited. We assessed microsatellite frequency in plant species with a 50-fold range in genome size that is mostly attributable to the recent amplification of repetitive DNA. Among species, the overall frequency of microsatellites was inversely related to genome size and to the proportion of repetitive DNA but remained constant in the transcribed portion of the genome. This indicates that most microsatellites reside in regions pre-dating the recent genome expansion in many plants. The microsatellite frequency was higher in transcribed regions, especially in the untranslated portions, than in genomic DNA. Contrary to previous reports suggesting a preferential mechanism for the origin of microsatellites from repetitive DNA in both animals and plants, our findings show a significant association with the low-copy fraction of plant genomes.     

宇宙生命化:一个真实的人类未来图景

近几年来，人类在所有科学领域取得成果的速率在惊人地加快。当我们拓展对地球的控制时，同时也在准备重塑和改造地球上的景观，为自己到地球外居住作准备。几个世纪以来，我们已经花大力改造了地球，现在，我们正准备把宇宙转变成一个充满生命的有生气的实体。我们将通过把我们的意识、技能、智力以及我们自身扩展到其他行星上来实现这个目标。我们把人类改变和改善地球环境（最终是宇宙本身）的努力总称为“生命化”。生命化是调节人类行为的一种力量，赋予地球并最终赋予整个宇宙以意识和智慧，是全部人类生产活动背后的原动力。然而，为…     

Spectral analysis of phylogenetic data

The spectral analysis of sequence and distance data is a new approach to phylogenetic analysis. For two-state character sequences, the character values at a given site split the set of taxa into two subsets, a bipartition of the taxa set. The vector which counts the relative numbers of each of these bipartitions over all sites is called a sequence spectrum. Applying a transformation called a Hadamard conjugation, the sequence spectrum is transformed to the conjugate spectrum. This conjugation corrects for unobserved changes in the data, independently from the choice of phylogenetic tree. For any given phylogenetic tree with edge weights (probabilities of state change), we define a corresponding tree spectrum. The selection of a weighted phylogenetic tree from the given sequence data is made by matching the conjugate spectrum with a tree spectrum. We develop an optimality selection procedure using a least squares best fit, to find the phylogenetic tree whose tree spectrum most closely matches the conjugate spectrum. An inferred sequence spectrum can be derived from the selected tree spectrum using the inverse Hadamard conjugation to allow a comparison with the original sequence spectrum. A possible adaptation for the analysis of four-state character sequences with unequal frequencies is considered. A corresponding spectral analysis for distance data is also introduced. These analyses are illustrated with biological examples for both distance and sequence data. Spectral analysis using the Fast Hadamard transform allows optimal trees to be found for at least 20 taxa and perhaps for up to 30 taxa. The development presented here is self contained, although some mathematical proofs available elsewhere have been omitted. The analysis of sequence data is based on methods reported earlier, but the terminology and the application to distance data are new.