A high-quality human reference panel reveals the complexity and distribution of genomic structural variants

Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals

Skewed X-inactivation is common in the general female population

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants

Organizational dynamics in a corporate-type irrigation organization: an analysis of the National Irrigation Administration in the Philippines

In International Irrigation Management Institute (IIMI). Advancements in IIMI's research 1989-91: a selection of papers presented at Internal Program Reviews. Colombo, Sri Lanka: International Irrigation Management Institute (IIMI)

"Literary and Artistic Voices" in T.D. Regehr's Mennonites in Canada, 1939-1970: A Response, Two Observations, and Some Questions [Book Review]

Purpose: An elevated serum PSA level cannot distinguish between local, regional recurrences and the presence of distant metastases after treatment with curative intent for prostate cancer. With the advent of salvage treatment such as cryotherapy, it has become important to localize the site of recurrence (local or distant). In this study the potential of 11C-choline PET to identify site of recurrence was investigated in patients with rising PSA after external beam radiotherapy (EBRT). Methods and Materials: 70 patients with histological proven prostate cancer treated with EBRT and showing biochemical recurrence as defined by ASTRO consensus statement and 10 patients without recurrence underwent a PET scan using 400 MBq 11C-choline intravenously. Biopsy-proven histology from the site of suspicion, findings with other imaging modalities, clinical follow-up and/ or response to adjuvant therapy were used as comparative references. Results: None of the 10 patients without biochemical recurrence had a positive PET scan. 57/70 patients with biochemical recurrence (median PSA 9.1 ng/mL; mean PSA 12.3 ng/mL) showed an abnormal uptake pattern (sensitivity 81%). The site of recurrence was only local in 41/ 57 patients (mean PSA 11.1 ng/mL at scan), locoregionally and/ or distant in 16/57 patients (mean PSA 17.7 ng/mL). Overall the PPV and NPV for 11C-choline PET scan were 1.0 and 0.44 respectively. Accuracy was 84%. Conclusions: 11C-choline PET scan is a sensitive technique to identify the site of recurrence in patients with PSA relapse after EBRT for prostate cancer.</p

Detection of recurrence in patients with PSA relapse after external beam radiotherapy using 11C-choline PET

Purpose: An elevated serum PSA level cannot distinguish between local, regional recurrences and the presence of distant metastases after treatment with curative intent for prostate cancer. With the advent of salvage treatment such as cryotherapy, it has become important to localize the site of recurrence (local or distant). In this study the potential of 11C-choline PET to identify site of recurrence was investigated in patients with rising PSA after external beam radiotherapy (EBRT). Methods and Materials: 70 patients with histological proven prostate cancer treated with EBRT and showing biochemical recurrence as defined by ASTRO consensus statement and 10 patients without recurrence underwent a PET scan using 400 MBq 11C-choline intravenously. Biopsy-proven histology from the site of suspicion, findings with other imaging modalities, clinical follow-up and/ or response to adjuvant therapy were used as comparative references. Results: None of the 10 patients without biochemical recurrence had a positive PET scan. 57/70 patients with biochemical recurrence (median PSA 9.1 ng/mL; mean PSA 12.3 ng/mL) showed an abnormal uptake pattern (sensitivity 81%). The site of recurrence was only local in 41/ 57 patients (mean PSA 11.1 ng/mL at scan), locoregionally and/ or distant in 16/57 patients (mean PSA 17.7 ng/mL). Overall the PPV and NPV for 11C-choline PET scan were 1.0 and 0.44 respectively. Accuracy was 84%. Conclusions: 11C-choline PET scan is a sensitive technique to identify the site of recurrence in patients with PSA relapse after EBRT for prostate cancer