Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations

Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2(*)1100delC, a truncating variant that abrogates the kinase activity, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2(*)1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.     

Pneumococcal genome sequencing tracks a vaccine escape variant formed through a multi-fragment recombination event

Streptococcus pneumoniae ('pneumococcus') causes an estimated 14.5 million cases of serious disease and 826,000 deaths annually in children under 5 years of age(1). The highly effective introduction of the PCV7 pneumococcal vaccine in 2000 in the United States(2,3) provided an unprecedented opportunity to investigate the response of an important pathogen to widespread, vaccine-induced selective pressure. Here, we use array-based sequencing of 62 isolates from a US national monitoring program to study five independent instances of vaccine escape recombination(4), showing the simultaneous transfer of multiple and often large (up to at least 44 kb) DNA fragments. We show that one such new strain quickly became established, spreading from east to west across the United States. These observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the considerable value of combining genomic and epidemiological information in the surveillance and enhanced understanding of infectious diseases.     

基于Runtime的iOS编程研究与实现

在iOS开发过程中,因为系统自带方法对应的功能不足,使部分业务需求不能有效地实现.为此,首先对Runtime库的主要API接口用途进行了研究,找到可利用的接口;然后对Runtime消息转发机制进行研究,证明函数调用的实质就是消息的传递;最后通过实际案例,证明了应用Runtime可以解决系统方法不足的问题.结果 表明,通过Runtime库给系统自带的类动态添加或修改成员变量和成员方法具有可行性,可为iOS开发者提供参考和借鉴.     

Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait

The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and alpha(+)-thalassemia, a condition characterized by reduced production of the normal alpha-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria, but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying alpha(+)-thalassemia. Negative epistasis could explain the failure of alpha(+)-thalassemia to reach fixation in any population in sub-Saharan Africa.     

A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.     

Statistics of chronic disease control.

Control of the chronic diseases of middle age is increasingly important, in developed and in developing countries, as other causes of premature death decrease. It requires bigger clinical trials, and better epidemiology.     

High constant incidence in twins and other relatives of women with breast cancer

The incidence of breast cancer rises steeply between ages 25 and 50, and more slowly thereafter. In contrast, the incidence in the unaffected (contralateral) breast of women who have had breast cancer remains constant at about 0.7% per year for at least the next 20 years after diagnosis, irrespective of age at first diagnosis. The incidence in relatives of the patients seems to show a similar pattern. The incidence in a prospective study of monozygotic twins of patients was approximately constant at 1.3% per year (77 cases), again about 0.7% per breast. At ages older than a patient's age at diagnosis, her mother and sisters have an incidence of 0.3-0.4% per year. Above the index patient's age at diagnosis, the rate in relatives shows no temporal trend and is independent of the patient's age at diagnosis. A statistically simple explanation is that incidence in susceptible women increases to a high constant level by a predetermined age that varies between families, but this seems inconsistent with conventional models of carcinogenesis and susceptibility. The very high incidence in monozygotic twins of patients indicates that a high proportion, and perhaps the majority, of breast cancers arise in a susceptible minority of women.     

The epidermis both drives and restricts plant shoot growth

The size of an organism is genetically determined, yet how a plant or animal achieves its final size is largely unknown. The shoot of higher plants has a simple conserved body plan based on three major tissue systems: the epidermal (L1), sub-epidermal (L2) and inner ground and vascular (L3) tissues. Which tissue system drives or restricts growth has been a subject of debate for over a century. Here, we use dwarf, brassinosteroid biosynthesis and brassinosteroid response mutants in conjunction with tissue-specific expression of these components as tools to examine the role of the epidermis in shoot growth. We show that expression of the brassinosteroid receptor or a brassinosteroid biosynthetic enzyme in the epidermis, but not in the vasculature, of null mutants is sufficient to rescue their dwarf phenotypes. Brassinosteroid signalling from the epidermis is not sufficient to establish normal vascular organization. Moreover, shoot growth is restricted when brassinosteroids are depleted from the epidermis and brassinosteroids act locally within a leaf. We conclude that the epidermis both promotes and restricts shoot growth by providing a non-autonomous signal to the ground tissues.     

Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk

We mapped a high-penetrance gene (CRAC1; also known as HMPS) associated with colorectal cancer (CRC) in the Ashkenazi population to a 0.6-Mb region on chromosome 15 containing SCG5 (also known as SGNE1), GREM1 and FMN1. We hypothesized that the CRAC1 locus harbored low-penetrance variants that increased CRC risk in the general population. In a large series of colorectal cancer cases and controls, SNPs near GREM1 and SCG5 were strongly associated with increased CRC risk (for rs4779584, P = 4.44 x 10(-14)).