Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility.

Rare inactivating mutations in BRCA1, BRCA2, ATM, TP53 and CHEK2 confer relative risks for breast cancer between about 2 and more than 10, but more common variants in these genes are generally considered of little or no clinical significance. Under the polygenic model for breast cancer carriers of multiple low-penetrance alleles are at high risk, but few such alleles have been reliably identified. We analysed 1037 potentially functional single nucleotide polymorphisms (SNPs) in candidate cancer genes in 473 women with two primary breast cancers and 2463 controls.

Elevated rates of sister chromatid exchange at chromosome ends.

Chromosome ends are known hotspots of meiotic recombination and double-strand breaks. We monitored mitotic sister chromatid exchange (SCE) in telomeres and subtelomeres and found that 17% of all SCE occurs in the terminal 0.1% of the chromosome.

Metacontrast masking and the cortical representation of surface color: dynamical aspects of edge integration and contrast gain control.

This paper reviews recent theoretical and experimental work supporting the idea that brightness is computed in a series of neural stages involving edge integration and contrast gain control. It is proposed here that metacontrast and paracontrast masking occur as byproducts of the dynamical properties of these neural mechanisms. The brightness computation model assumes, more specifically, that early visual neurons in the retina, and cortical areas V1 and V2, encode local edge signals whose magnitudes are proportional to the logarithms of the luminance ratios at luminance edges within the retinal image.

Case-control, kin-cohort and meta-analyses provide no support for STK15 F31I as a low penetrance colorectal cancer allele.

Recently, homozygosity for T91A single-nucleotide polymorphism (SNP) in the serine/threonine kinase (STK15) gene, which generates the substitution F31I has been proposed to increase the risk of a number of tumours including colorectal cancer (CRC). To further evaluate the relationship between STK15 F31I and risk of CRC, we genotyped 2558 CRC cases and 2680 controls for this polymorphism. We found no evidence that homozygosity for the STK15 31I genotype confers an increased risk of CRC (odds ratio=0.

Search for low penetrance alleles for colorectal cancer through a scan of 1467 non-synonymous SNPs in 2575 cases and 2707 controls with validation by kin-cohort analysis of 14 704 first-degree relatives.

To identify low penetrance susceptibility alleles for colorectal cancer (CRC), we genotyped 1467 non-synonymous SNPs mapping to 871 candidate cancer genes in 2575 cases and 2707 controls. nsSNP selection was biased towards those predicted to be functionally deleterious. One SNP AKAP9 M463I remained significantly associated with CRC risk after stringent adjustment for multiple testing.

A 360-kb interchromosomal duplication of the human HYDIN locus.

The HYDIN gene located in human chromosome band 16q22.2 is a large gene encompassing 423 kb of genomic DNA that has been suggested as a candidate for an autosomal recessive form of congenital hydrocephalus. We have found that the human HYDIN locus has been very recently duplicated, with a nearly identical 360-kb paralogous segment inserted on chromosome 1q21.

Lck SH3 domain function is required for T-cell receptor signals regulating thymocyte development.

Thymocyte development is shaped by signals from the T-cell antigen receptor. The strength of receptor signaling determines developmental progression as well as deletion of self-reactive T cells. Receptor stimulation of the extracellular signal-regulated kinase (ERK) pathway plays an important regulatory role during thymocyte development.

Variants in the GH-IGF axis confer susceptibility to lung cancer.

We conducted a large-scale genome-wide association study in UK Caucasians to identify susceptibility alleles for lung cancer, analyzing 1529 cases and 2707 controls. To increase the likelihood of identifying disease-causing alleles, we genotyped 1476 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 871 candidate cancer genes, biasing SNP selection toward those predicted to be deleterious. Statistically significant associations were identified for 64 nsSNPs, generating a genome-wide significance level of P=0.

Exonic STK11 deletions are not a rare cause of Peutz-Jeghers syndrome.

Background: Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant cancer predisposition syndrome characterised by oro-facial pigmentation and hamartomatous polyposis of the gastrointestinal tract. A causal germline mutation in STK11 can be identified in 30% to 80% of PJS patients.

Methods: Here we report the comprehensive mutational analysis of STK11 in 38 PJS probands applying conventional PCR based mutation detection methods and the recently introduced MLPA (multiplex ligation dependent probe amplification) technique developed for the identification of exonic deletions/duplications.

Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia.

We conducted a large-scale association study to identify low-penetrance susceptibility alleles for chronic lymphocytic leukemia (CLL), analyzing 992 patients and 2707 healthy controls. To increase the likelihood of identifying disease-causing alleles we genotyped 1467 coding nonsynonymous single nucleotide polymorphisms (nsSNPs) in 865 candidate cancer genes, biasing nsSNP selection toward those predicted to be deleterious. Preeminent associations were identified in SNPs mapping to genes pivotal in the DNA damage-response and cell-cycle pathways, including ATM F858L (odds ratio [OR] = 2.

Human centromeric chromatin is a dynamic chromosomal domain that can spread over noncentromeric DNA.

Human centromeres are specialized chromatin domains containing the centromeric histone H3 variant CENP-A. CENP-A nucleosomes are interspersed with nucleosomes containing histone H3 dimethylated at lysine 4, distinguishing centromeric chromatin (CEN chromatin) from flanking heterochromatin that is defined by H3 lysine 9 methylation. To understand the relationship between chromatin organization and the genomic structure of human centromeres, we compared molecular profiles of three endogenous human centromeres, defined by uninterrupted higher-order alpha-satellite DNA, with human artificial chromosomes that contain discontinuous blocks of higher-order alpha-satellite DNA and noncentromeric DNA.

The highest luminance anchoring rule in achromatic color perception: some counterexamples and an alternative theory.

It has been hypothesized that lightness is computed in a series of stages involving: (1) extraction of local contrast or luminance ratios at borders; (2) edge integration, to combine contrast or luminance ratios across space; and (3) anchoring, to relate the relative lightness scale computed in Stage 2 to the scale of real-world reflectances. The results of several past experiments have been interpreted as supporting the highest luminance anchoring rule, which states that the highest luminance in a scene always appears white. We have previously proposed a quantitative model of achromatic color computation based on a distance-dependent edge integration mechanism.

The Y deletion gr/gr and susceptibility to testicular germ cell tumor.

Testicular germ cell tumor (TGCT) is the most common cancer in young men. Despite a considerable familial component to TGCT risk, no genetic change that confers increased risk has been substantiated to date. The human Y chromosome carries a number of genes specifically involved in male germ cell development, and deletion of the AZFc region at Yq11 is the most common known genetic cause of infertility.

The evolutionary dynamics of alpha-satellite.

Alpha-satellite is a family of tandemly repeated sequences found at all normal human centromeres. In addition to its significance for understanding centromere function, alpha-satellite is also a model for concerted evolution, as alpha-satellite repeats are more similar within a species than between species. There are two types of alpha-satellite in the human genome; while both are made up of approximately 171-bp monomers, they can be distinguished by whether monomers are arranged in extremely homogeneous higher-order, multimeric repeat units or exist as more divergent monomeric alpha-satellite that lacks any multimeric periodicity.