A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability

Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07-1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner.     

伟人的足迹:《杰弗瑞·英加姆·泰勒的生平与成就》简评

《杰弗瑞·英加姆·泰勒的生平与成就》一书的作者为乔治·班切尔（GeopBatchelor），剑桥大学出版社1996年出版。本书作者系泰勒1945－48年间的研究生，后来成为泰勒在剑桥大学的同事，他也是泰勒论文集的编纂者。班切尔希望，本传记能使人们全面了解泰勒这位科学英才的生活、思想、研究特点，以及他对实验研究的真知灼见和对现实问题的关注。传记指出：流体力学能发展到今天这样高的水平，应归功于该领域的“三杰”：杰弗瑞·英加姆·泰勒（（；erxlzleIilzra’llTaylor和他的两位同行：冯·卡门（】卜o主犯vonlcalt’lart和路德维希·…     

Postsynaptic translation affects the efficacy and morphology of neuromuscular junctions

Long-term synaptic plasticity may be associated with structural rearrangements within the neuronal circuitry. Although the molecular mechanisms governing such activity-controlled morphological alterations are mostly elusive, polysomal accumulations at the base of developing dendritic spines and the activity-induced synthesis of synaptic components suggest that localized translation is involved during synaptic plasticity. Here we show that large aggregates of translational components as well as messenger RNA of the postsynaptic glutamate receptor subunit DGluR-IIA are localized within subsynaptic compartments of larval neuromuscular junctions of Drosophila melanogaster. Genetic models of junctional plasticity and genetic manipulations using the translation initiation factors eIF4E and poly(A)-binding protein showed an increased occurrence of subsynaptic translation aggregates. This was associated with a significant increase in the postsynaptic DGluR-IIA protein levels and a reduction in the junctional expression of the cell-adhesion molecule Fasciclin II. In addition, the efficacy of junctional neurotransmission and the size of larval neuromuscular junctions were significantly increased. Our results therefore provide evidence for a postsynaptic translational control of long-term junctional plasticity.     

An equatorial oscillation in Saturn's middle atmosphere

The middle atmospheres of planets are driven by a combination of radiative heating and cooling, mean meridional motions, and vertically propagating waves (which originate in the deep troposphere). It is very difficult to model these effects and, therefore, observations are essential to advancing our understanding of atmospheres. The equatorial stratospheres of Earth and Jupiter oscillate quasi-periodically on timescales of about two and four years, respectively, driven by wave-induced momentum transport. On Venus and Titan, waves originating from surface-atmosphere interaction and inertial instability are thought to drive the atmosphere to rotate more rapidly than the surface (superrotation). However, the relevant wave modes have not yet been precisely identified. Here we report infrared observations showing that Saturn has an equatorial oscillation like those found on Earth and Jupiter, as well as a mid-latitude subsidence that may be associated with the equatorial motion. The latitudinal extent of Saturn's oscillation shows that it obeys the same basic physics as do those on Earth and Jupiter. Future highly resolved observations of the temperature profile together with modelling of these three different atmospheres will allow us determine the wave mode, the wavelength and the wave amplitude that lead to middle atmosphere oscillation.     

Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1(P29S)) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1(P29S) showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.     

Mutations in BRIP1 confer high risk of ovarian cancer

Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through whole-genome sequencing of 457 Icelanders, were imputed to 41,675 Icelanders genotyped using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer (N of affected individuals = 656). We discovered a rare (0.41% allelic frequency) frameshift mutation, c.2040_2041insTT, in the BRIP1 (FANCJ) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, P = 2.8 × 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced lifespan by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, c.1702_1703del, was seen in 2 out of 144 subjects with ovarian cancer and 1 out of 1,780 control subjects (P = 0.016). This allele was also associated with breast cancer (seen in 6/927 cases; P = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation show loss of the wild-type allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer.     

PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene

PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4-3.9, P = 0.0025). The results show that PALB2 is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition.     

新科学家"趣味科普问答"(续)

问题14：大象是如何喝水的？它难道能在喝水的同时呼吸吗？解答：大象先把水吸入鼻子,再把长鼻子前端放在嘴里边喷边喝。一头成年象的鼻子一次可吸入10升左右的水。为了使鼻子里的水更好地流到嘴里,大象在喝水时常会向后微微仰起头。如大多数哺乳动物一样,大象的气管与食管是分开的,因而,它在喝水的同时完全可以呼吸,二者之间并无矛盾。唯一可能发生问题的情形也许是：当象鼻子刚刚朝嘴项项完水而变空且水正沿喉管下咽时,若此刻象用鼻子呼吸则可能被呛。事实上,刚出生的人类婴儿也有在吮吸乳汁的同时用鼻子呼吸的能力。不过数月之后…     

Fine-scale recombination rate differences between sexes, populations and individuals

Meiotic recombinations contribute to genetic diversity by yielding new combinations of alleles. Recently, high-resolution recombination maps were inferred from high-density single-nucleotide polymorphism (SNP) data using linkage disequilibrium (LD) patterns that capture historical recombination events. The use of these maps has been demonstrated by the identification of recombination hotspots and associated motifs, and the discovery that the PRDM9 gene affects the proportion of recombinations occurring at hotspots. However, these maps provide no information about individual or sex differences. Moreover, locus-specific demographic factors like natural selection can bias LD-based estimates of recombination rate. Existing genetic maps based on family data avoid these shortcomings, but their resolution is limited by relatively few meioses and a low density of markers. Here we used genome-wide SNP data from 15,257 parent-offspring pairs to construct the first recombination maps based on directly observed recombinations with a resolution that is effective down to 10 kilobases (kb). Comparing male and female maps reveals that about 15% of hotspots in one sex are specific to that sex. Although male recombinations result in more shuffling of exons within genes, female recombinations generate more new combinations of nearby genes. We discover novel associations between recombination characteristics of individuals and variants in the PRDM9 gene and we identify new recombination hotspots. Comparisons of our maps with two LD-based maps inferred from data of HapMap populations of Utah residents with ancestry from northern and western Europe (CEU) and Yoruba in Ibadan, Nigeria (YRI) reveal population differences previously masked by noise and map differences at regions previously described as targets of natural selection.