The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

Haplotype block structure is conserved across mammals. PLoS genetics 2: e121. doi: 10.1371/journal.pgen.0020121

Genetic variation in genomes is organized in haplotype blocks, and species-specific block structure is defined by differential contribution of population history effects in combination with mutation and recombination events. Haplotype maps characterize the common patterns of linkage disequilibrium in populations and have important applications in the design and interpretation of genetic experiments. Although evolutionary processes are known to drive the selection of individual polymorphisms, their effect on haplotype block structure dynamics has not been shown. Here, we present a high-resolution haplotype map for a 5-megabase genomic region in the rat and compare it with the orthologous human and mouse segments. Although the size and fine structure of haplotype blocks are species dependent, there is a significant interspecies overlap in structure and a tendency for blocks to encompass complete genes. Extending these findings to the complete human genome using haplotype map phase I data reveals that linkage disequilibrium values are significantly higher for equally spaced positions in genic regions, including promoters, as compared to intergenic regions, indicating that a selective mechanism exists to maintain combinations of alleles within potentially interacting coding and regulatory regions. Although this characteristic may complicate the identification of causal polymorphisms underlying phenotypic traits, conservation of haplotype structure may be employed for the identification and characterization of functionally important genomic regions

The Cdk1/Cdk2 homolog CDKA;1 controls the recombination landscape in Arabidopsis

Little is known how patterns of cross-over (CO) numbers and distribution during meiosis are established. Here, we reveal that cyclin-dependent kinase A;1 (CDKA;1), the homolog of human Cdk1 and Cdk2, is a major regulator of meiotic recombination in Arabidopsis. Arabidopsis plants with reduced CDKA;1 activity experienced a decrease of class I COs, especially lowering recombination rates in centromere-proximal regions. Interestingly, this reduction of type I CO did not affect CO assurance, a mechanism by which each chromosome receives at least one CO, resulting in all chromosomes exhibiting similar genetic lengths in weak loss-of-function cdka;1 mutants. Conversely, an increase of CDKA;1 activity resulted in elevated recombination frequencies. Thus, modulation of CDKA;1 kinase activity affects the number and placement of COs along the chromosome axis in a dose-dependent manner.</p

Many novel mammalian microRNA candidates identified by extensive cloning and RAKE analysis

MicroRNAs are 20- to 23-nucleotide RNA molecules that can regulate gene expression. Currently >400 microRNAs have been experimentally identified in mammalian genomes, whereas estimates go up to 1000 and beyond. Here we show that many more mammalian microRNAs exist. We discovered novel microRNA candidates using two approaches: testing of computationally predicted microRNAs by a modified microarray-based detection system, and cloning and sequencing of large numbers of small RNAs from different human and mouse tissues. Together these efforts experimentally identified 348 novel mouse and 81 novel human microRNA candidate genes. Most novel microRNAs candidates are not conserved beyond mammals, and ~10% are taxon-specific. Our analyses indicate that the entire microRNA repertoire is not remotely exhausted

Comparison of the Haplotype Block Densities between Syntenic Regions of Rat, Mouse, and Human (Same Genome Segments as Shown in Figure 1)

<p>The scatter plots show log₁₀ of the amount of haplotype blocks per 100-kb bin in rat (horizontal) against log₁₀ of the amount of haplotype blocks seen in syntenic region of mouse (A) and human (B) genome (vertical). Data points for gene-containing and intergenic genomic bins are shown as closed and open blocks, respectively. Observed correlations of haplotype block densities are significant in linear (<i>r</i> = +0.5530; <i>p</i> < 0.0001 [A] and <i>r</i> = +0.4563; <i>p</i> = 0.0005 [B]) as well as in log-transformed space (<i>r</i> = +0.6795; <i>p</i> < 0.0001 [A] and <i>r</i> = +0.3209; <i>p</i> = 0.0180 [B]).</p

Analysis of LD Decay for Functionally Different Segments of the Human Genome

<div><p>(A) The graph shows average values of |D′| and their confidence limits (± standard deviation) as a function of the physical distance between SNPs for the following categories: (1) both SNPs reside in the same gene (blue line), (2) the SNPs reside in two different genes (green line), (3) both SNPs reside in the same intergenic region (red line), (4) one SNP resides in the gene and the other in the 30 kb upstream region of the same gene (purple line), and (5) one SNP resides in the gene and the other in the 30 kb downstream region of the same gene (gray line).</p><p>(B) Frequency distribution spectrum of |D′| values for SNP pairs at 100-kb distance. High |D′| values (>0.8) are overrepresented for equally spaced SNPs in a gene and its flanking regions as compared to intergenic regions.</p><p>(C) Frequency distribution of high LD values (|D′| > 0.5) for SNP pairs at 450-kb distance. Higher LD values are observed between a gene and its upstream region.</p><p>(D) Frequency distribution of high LD values (|D′| > 0.5) for SNP pairs at 650-kb distance. Higher LD values are observed between a gene and its upstream region.</p><p>The bin with |D′| = 1 is isolated to a separate bin in panels (B–D) as there is a considerable frequency bias for this |D′| value. Similar graphs plotted for separate human populations are available as <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020121#pgen-0020121-sg003" target="_blank">Figures S3</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020121#pgen-0020121-sg004" target="_blank">S4</a>, and S5.</p></div

Patterns of LD for Orthologous Genomic Segments of Approximately 5 Mb in Rat, Human, and Mouse

<p>LD plots for orthologous genomic segments in rat (A), human (B), and mouse (C) are shown. For each panel, the following information is shown: LD plot (top), haplotype blocks in SNP coordinates (middle), and physical map and haplotype blocks in physical coordinates (bottom). The haplotype map has a gradient representation for |D′| values that assists visual comparison of haplotype structure. Haplotype blocks were built with stringent criteria, sometimes resulting in splitting of visually recognized blocks. Three characteristic haplotype blocks that are conserved cross-species have been color-coded and are discussed in the text. Similar plots for a second mouse set, two other human populations, and the combined human set are available as <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020121#pgen-0020121-sg001" target="_blank">Figures S1</a> and <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020121#pgen-0020121-sg002" target="_blank">S2</a>.</p

The value of the world's ecosystem services and natural capital

The services of ecological systems and the natural capital stocks that produce them are critical to the functioning of the Earth's life-support system. They contribute to human welfare, both directly and indirectly, and therefore represent part of the total economic value of the planet. We have estimated the current economic value of 17 ecosystem services for 16 biomes, based on published studies and a few original calculations. For the entire biosphere, the value (most of which is outside the market) is estimated to be in the range of US$16-54 trillion (10^(12)) per year, with an average of US$33 trillion per year. Because of the nature of the uncertainties, this must be considered a minimum estimate. Global gross national product total is around US$18 trillion per year