心血管病因探索新进展

美国《科学》杂志对发达国家中处于领先死困的心脏疾病的两类鲜为人知的致病因素给予特别关注：其一,导致往往丧命的心脏缺陷的突变的基因;其二,最近发现的与堵塞动脉的斑块形成有联系的一些感染……1993年夏,波士顿塞尔特球星雷杰·刘易斯摔死网球场,世人震惊。但这种摔死有其常发人群。隔不了几年,又有一位著名的年轻运动员,成为未检出的遗传性心脏不良的牺牲者、没有前兆的摔死于运动事件。这些病例,提供了极好的例证,说明心脏病不必从中年发展动脉硬化开始,它能隐匿地起自心脏本身的遗传性缺陷。从先天性心脏畸形,到致死的心…     

Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy

Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case- and population-specific factors in the dissection of susceptibility variants in complex diseases.     

Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon

Kras is commonly mutated in colon cancers, but mutations in Nras are rare. We have used genetically engineered mice to determine whether and how these related oncogenes regulate homeostasis and tumorigenesis in the colon. Expression of K-Ras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek-dependent manner. N-Ras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc-mutant colonic tumor, activation of K-Ras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This K-Ras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant K-Ras were hypersensitive to inhibition of Raf, but not Mek. These studies demonstrate clear phenotypic differences between mutant Kras and Nras, and suggest that the oncogenic phenotype of mutant K-Ras might be mediated by noncanonical signaling through Ras effector pathways.     

Caterpillar-induced nocturnal plant volatiles repel conspecific females

Plants respond to insect herbivory by synthesizing and releasing complex blends of volatile compounds, which provide important host-location cues for insects that are natural enemies of herbivores. The effects of these volatile blends on herbivore behaviour have been investigated to only a limited extent, in part because of the assumption that herbivore-induced volatile emissions occur mainly during the light phase of the photoperiod. Because many moths-whose larvae are some of the most important insect herbivores-are nocturnal, herbivore-induced plant volatiles have not hitherto been considered to be temporally available as host-location cues for ovipositing females. Here we present chemical and behavioural assays showing that tobacco plants (Nicotiana tabacum) release herbivore-induced volatiles during both night and day. Moreover, several volatile compounds are released exclusively at night and are highly repellent to female moths (Heliothis virescens). The demonstration that tobacco plants release temporally different volatile blends and that lepidopteran herbivores use induced plant signals released during the dark phase to choose sites for oviposition adds a new dimension to our understanding of the role of chemical cues in mediating tritrophic interactions.     

Graphs in cultures (II): A study in ethnomathematics

Western culture is but one of several with an interest in continuous tracing of figures. This paper discusses and analyzes that interest as it is evidenced in Africa among the Bushoong and Tshokwe. Included are figures, statements about the cultural context, and associated geometric and topological ideas. Emphasis is on the structure of the figures and also, where possible, processes of construction are elaborated.     

Systematic generation of high-resolution deletion coverage of the Drosophila melanogaster genome

In fruit fly research, chromosomal deletions are indispensable tools for mapping mutations, characterizing alleles and identifying interacting loci. Most widely used deletions were generated by irradiation or chemical mutagenesis. These methods are labor-intensive, generate random breakpoints and result in unwanted secondary mutations that can confound phenotypic analyses. Most of the existing deletions are large, have molecularly undefined endpoints and are maintained in genetically complex stocks. Furthermore, the existence of haplolethal or haplosterile loci makes the recovery of deletions of certain regions exceedingly difficult by traditional methods, resulting in gaps in coverage. Here we describe two methods that address these problems by providing for the systematic isolation of targeted deletions in the D. melanogaster genome. The first strategy used a P element-based technique to generate deletions that closely flank haploinsufficient genes and minimize undeleted regions. This deletion set has increased overall genomic coverage by 5-7%. The second strategy used FLP recombinase and the large array of FRT-bearing insertions described in the accompanying paper to generate 519 isogenic deletions with molecularly defined endpoints. This second deletion collection provides 56% genome coverage so far. The latter methodology enables the generation of small custom deletions with predictable endpoints throughout the genome and should make their isolation a simple and routine task.     

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.