Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.     

Dynamic landforms and plant communities in a pluvial lake basin

Mapping units were developed based on landform, soils, and plant communities for the 40,000 ha of salt desert vegetation located below the maximum level of pluvial Lake Gilbert in Grass Valley, Nevada. Lake plain, beach, and bar features of the pluvial lake provide the dominant landforms. Fine textured lake sediments have produced salt- and Na-affected soils. The distribution and structure of plant communities are related to depth of the groundwater table, fluctuations in this depth, and the salt content of the groundwater. Wind and water erosion combine to continually evolve new environments for colonization by plants in this ecosystem.       

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.     

Mathematics Sent Across the Channel and the Atlantic: British Mathematical Contributions to European and American Scientific Journals, 1835–1900

This paper will consider the range of British participation in mathematics internationally during the nineteenth century through an analysis of British mathematical contributions to scientific journals outside of Britain. Viewing scientific papers contained in journals as significant indicators of research, we consider scientists who authored or read and responded in print to papers in a given area within a given group of journals to constitute a publication community. The extent of publication by British mathematicians in these journals can help characterize the role of foreign publication in nineteenth-century British mathematics. Moreover, the isolation of educational, societal, and personal circumstances which motivated British mathematicians to present their work to foreign journals highlights limited but concentrated groups of mathematicians committed to developing and strengthening international mathematical ties with Britain.     

Common variants near MC4R are associated with fat mass, weight and risk of obesity

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.     

Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles

We identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9/1,212 individuals with breast cancer from BRCA1/BRCA2 mutation-negative families but in only 2/2,081 controls (P = 0.0030), and we estimate that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2-3.2, P = 0.012). Biallelic BRIP1 mutations were recently shown to cause Fanconi anemia complementation group J. Thus, inactivating truncating mutations of BRIP1, similar to those in BRCA2, cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers.     

Breeding biology of the Double-crested Cormorant on Utah Lake

Research on the nesting of the Double - crested Cormorant ( Phalacrocorax auritus auritus ) was undertaken to determine the breeding biology of the bird on Utah Lake, Utah County, and the possible effects that diking Provo Bay would have on the cormorants breeding there. In 1973, two colonies in Provo Bay were visited weekly to determine laying dates, incubation period, clutch size, and hatching dates. Another colony, located on the dike of the Geneva Steel Works Reservoir near Orem, was visited daily during the spring and summer of 1973. At this colony egg-laying occurred from 13 April to 17 May. The average clutch size was 3.8, and the egg length and width averaged 60.50 mm x 39.05 mm. The average period of incubation was 28 days, and 29.5 percent of the eggs hatched, beginning on 20 May and ending on 9 June. The young weighed an average of 36 gm at hatching with a beak length of 17 mm and tarsometatarsal length of 11 mm. These measurements increased to 1543 gm, 73 mm, and 58 mm, respectively, in 23 days. The cormorant population on Utah Lake may be severely reduced by the proposed diking of Provo Bay.     

Winter food habits of cougars from northeastern Oregon

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