Genome stability, progressive kidney failure and aging

Two new studies report mutations in FAN1 and three other genome-stability genes that tie the DNA damage response to progressive kidney failure and the dysfunction of several other organs. These findings provide clues to the underlying causes of tissue decline and may add a series of genes to the growing list of genome maintenance factors that protect against premature aging.     

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ～10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.     

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.     

Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits

We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.     

Habitat and nesting biology of Mountain Plovers in Wyoming

Although previous research has considered habitat associations and breeding biology of Mountain Plovers in Wyoming at discrete sites, no study has considered these attributes at a statewide scale. We located 55 Mountain Plover nests in 6 counties across Wyoming during 2002 and 2003. Nests occurred in 2 general habitat types: grassland and desert-shrub. Mean estimated hatch date was 26 June ( n = 31) in 2002 and 21 June ( n = 24) in 2003. Mean hatch date was not related to latitude or elevation. Hatch success of nests was inferred in 2003 by the presence of eggshell fragments in the nest scrape. Eggs in 14 of 22 (64%) known-fate nests hatched. All grassland sites and 90% of desert sites were host to ungulate grazers, although prairie dogs were absent at 64% of nest sites. Nest plots had less grass coverage and reduced grass height compared with random plots. More than 50% of nests occurred on elevated plateaus. The Mountain Plover's tendency to nest on arid, elevated plateaus further substantiates claims that the bird is also a disturbed- prairie species.     

Effects of grazing exclusions on rangeland vegetation and soils, east central Idaho

Nineteen exclosures on sagebrush steppe and shadscale rangelands, varying in age from 18 to 38 years, were sampled for plant species richness, plant composition, indicators of soil erosion, ground cover, vegetative cover, and herb-low shrub layer screening cover. Features within the exclosures were compared with adjacent sites of the same size that were open to grazing by livestock and wildlife. Species richness typically was slightly greater inside exclosures than in adjacent grazed sites (median = 2 more species inside exclosures), but the difference was not significant ( P = 0.16). Similarity of plant community composition between exclosures and adjacent grazed sites ranged from 45% to 82%. Evidences of soil movement, soil pedestals, and soil flow patterns were all more pronounced outside exclosures than inside ( P ≤ 0.02), even though many sites were on flat to mild slopes (median slope = 12%). Meta-analysis of the 19 exclosure sites indicated that grazing exclusion resulted in less bare ground cover compared with adjacent grazed sites ( P ≤ 0.05). The effect of grazing exclusion on visible soil surface cryptogams was significant ( P ≤ 0.05), with generally greater cover inside exclosures. Cryptogam cover differences between grazed sites and exclosures tended to increase with the number of years of grazing exclusion ( r = 0.64, P = 0.046). Pseudoroegneria spicata , a principal livestock forage, averaged greater basal cover inside exclosures than outside on 4 of 10 sites where it occurred, although no exclosure sites had greater P. spicata cover on grazed sites. Meta-analysis of the 10 sites indicated that grazing exclusion resulted in greater P. spicata cover compared with adjacent grazed areas ( P ≤ 0.05). Poa secunda , a short-growing grass that initiates growth early in the spring and is not important livestock forage, averaged greater basal cover outside exclosures on 5 of 15 sites where it occurred. Meta-analysis of the 15 sites indicated a significant treatment effect ( P ≤ 0.05), with greater Poa secunda basal cover outside exclosures. Grazing exclusion resulted in greater screening cover in the herb-low shrub layer (0-0.5 m height; P ≤ 0.05). These results indicate that despite improved livestock grazing management over the past half century, livestock grazing still can limit the potential of native plant communities in sagebrush steppe ecosystems, and that the health of semiarid ecosystems can improve with livestock exclusion in the absence of other disturbances. A few exclosure sites were similar for the measured parameters, suggesting that these sites were ecologically stable and that exclusion of livestock grazing was not sufficient to move succession toward more pristine conditions, at least within the time periods studied. Managed disturbance such as fire or mechanical brush treatments may be necessary to restore herb productivity on these ecologically stable sites.