Average relatedness coefficients between spouses across overlapping 3.6 Mb regions throughout the genome, plotted against their recombination rate.

<p>The MHC is plotted in red. A) European American sample. B) African sample.</p

Distribution of relatedness coefficients across the MHC region among couples in the two samples.

<p>A) European American sample. B) African sample.</p

A software process development,assessment and improvement framework,for the medical device industry

This paper describes a software process development, assessment and improvement framework, structured to ensure regulatory compliance for the software developed in medical devices. Software is becoming an increasingly important aspect of medical devices and medical device regulation. Medical devices can only be marketed if compliance and approval from the appropriate regulatory bodies of the Food and Drug Administration (US requirement), and the European Commission under its Medical Device Directives (CE marking requirement) is achieved. Integrated into the design process of medical devices, is the requirement of the production and maintenance of a device technical file, incorporating a design history file. Design history illustrates the well documented, defined and controlled processes and outputs, undertaken in the development of medical devices and for our particular consideration with this framework - the software components

Human recombination hot spots hidden within regions of strong marker association

The fine-scale distribution of meiotic recombination events in the human genome can be inferred from patterns of haplotype diversity in human populations but only directly studied by high-resolution sperm typing. Both approaches indicate that crossovers are heavily clustered into narrow recombination hot spots. However, our direct understanding of hot-spot properties and distributions is largely limited to sperm typing in the major histocompatibility complex (MHC). We now describe the analysis of an unremarkable 206 kb region on human chromosome 1, revealing localised regions of linkage disequilibrium (LD) breakdown that mark the locations of sperm crossover hot spots. The distribution, intensity and morphology of these hot spots are strikingly similar to those in the MHC. However, we also accidentally detected additional hot spots within regions of strong association. Coalescent analysis of genotype data detected most of the hot spots, but revealed significant differences between sperm crossover frequencies and “historical” recombination rates. This raises the possibility that some hot spots, in particular those in regions of strong association, may have evolved very recently and not left their full imprint on haplotype diversity. These results suggest that hot spots could be very abundant and possibly fluid features of the human genome

Concordance between pedigree-based and HapMap2 population-averaged LD-based estimates of recombination.

<p>(A) Comparison of sex-averaged pedigree rates and LD-based rates at the 50 kb scale shows high correlation (Spearman's , ). Recombination in PAR1 is dominated by crossovers in males, and the LD-based map is informative about male recombination (Spearman's , ). (B) Rates in the LD-based map (5 kb scale, at 500 bp intervals) averaged over the best-resolved 10% of paternal crossovers (n = 12, resolution 13 kb–45 kb, maximum extent shown by vertical black dotted lines), centred such that they all have their midpoint at 0 (red dotted line). PAR1-wide average LD-based rate of 9.06 cM/Mb is shown with the horizontal black dashed line. The LD-based map has a rate significantly elevated above the average rate at crossover midpoints ().</p

Separate LD-based recombination rates in PAR1 in three human continental groups, around the binding sites of the PRDM9 B allele.

<p>The B and other alleles predicted to bind similar motifs predominate in Europe and East Asia (91% frequency), but not in Africa (58% frequency). In PAR1, the recombination pattern is consistent with being activated by PRDM9, as both Asian and European populations show a much stronger increase in rate at these binding sites than Africans (<i>P</i> = 0.002 African/Asian, <i>P</i> = 0.02 African/European).</p

New sex-specific pedigree-based genetic maps (10 kb scale).

<p>The male map (blue) shows intense crossover activity throughout PAR1, with particularly high rates towards the telomeric end. Fine-scale variation in rates could not be estimated in two regions (1–1.4 Mb and 2–2.25 Mb, build 36) due to large unmapped and repetitive sequences and lack of genotyped SNPs. The female map (red) has a low rate through much of PAR1, and a trend of increasing rate towards the pseudoautosomal boundary. Vertical black tick marks show marker positions.</p

The rate of GC-biased substitutions in human and chimpanzee, in human hotspots, suggests no sharing of human and chimpanzee hotspots in PAR1.

<p>These plots show histograms for the estimated increase in the rate of GC-biased transition substitutions in regions overlapping human hotspots (red) and coldspots (blue), relative to the rest of PAR1 in: (A) Human: High recombination rate regions show a significant excess of GC-biased transitions in humans (+0.21% per base) while low recombination rate regions show a lower substitution bias towards GC transitions (−0.05% per base) relative to regions with intermediate rates. The difference between hotspots and coldspots is significant (). (B) Chimpanzee: There is no systematic increase in the rate of GC-biased transitions in chimpanzee (−0.01% per base) in regions containing human hotspots. The difference between hotspots and coldspots is not significant ().</p

Results of predicting divergence rate of different types of substitutions from human recombination rate, after regressing out effects of GC content, CpG content and the divergence rate of other types of substitutions in unique DNA.

<p>Mutations potentially due to the deamination of 5-methyl Cytosine in a CpG context in either species were excluded. Only transitions are significantly correlated with human recombination rate.</p

Additional file 1: Table S1. of A population-based study of homicide deaths in Ontario, Canada using linked death records

Rates of homicide, neoplasm, and cardiovascular deaths per 100,000 population and rate ratios by sex and by material deprivation and residential instability indices. (DOCX 22 kb