Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and?a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.     

Adjustment of vibratory signals to ambient temperature in a host-searching parasitoid

Abstract.  Certain ichneumonid parasitoids (Hymenoptera) use self-produced vibrations transmitted on plant substrate, so-called vibrational sounding, to locate their immobile concealed pupal hosts. An ambient temperature dependency with higher frequencies and intensities at higher temperatures is postulated because signals are of myogenic origin. Here, temperature influence on vibratory signals is analysed in the temperate parasitoid Pimpla turionellae under different thermal conditions using plant-stem models to elicit host-searching behaviour. Signals are measured with laser Doppler vibrometry and analysed for time parameters and frequency components applying fast-Fourier transformations. The results reveal an unexpected effect of ambient temperature on signals produced by the female wasps. Although average values of time parameters (pulse trains, pulse train periods, inter pulse duration) are unchanged by ambient temperature, the frequency parameters show an inverse thermal effect. Within the temperature range tested (8–26 °C), decreasing temperature leads to significantly higher frequency and intensity of the self-produced vibrations in the temperate species. This inverse thermal effect may be explained by a temperature-coupled signal production in the frequency domain to compensate negative low-temperature effects on the mechanoreceptors by increased muscle activity. The option of heterothermy to produce signals reliably during vibrational sounding under low temperature is also discussed.     

Exploring Risk for Echinococcosis Spillover in Northern Minnesota Tribal Communities

EcoHealth - Echinococcus spp. are zoonotic cestode parasites with a worldwide distribution and a complex, two-host life cycle involving carnivore definitive hosts and small mammal or ungulate...     

Juvenile Chinook salmon,Oncorhynchus tshawytscha,use of the Elwha river estuary prior to dam removal

The estuary of the Elwha River, on Washington’s Olympic Peninsula, has been degraded and simplified over the past century from sediment retention behind two large dams, levee construction, and channelization. With the removal of Elwha Dam and initiation of Glines Canyon Dam’s removal in fall 2011, sediment deposits will change the estuary and affect anadromous and nearshore marine fishes. Juvenile Chinook salmon commonly use estuaries and the river’s population is part of an Evolutionarily Significant Unit listed as Threatened under the U.S. Endangered Species Act. This study reports on monthly sampling in part of the river’s estuary from March 2007 through September 2011 to characterize the seasonal changes in relative abundance of yearlings and sub-yearlings, and size distributions prior to dam removal. Most (69 %) of the yearlings were caught in April, when this life history type was released from the hatchery, and to a lesser extent in May (28 %) and June (3 %). Yearlings caught in the estuary were smaller than those released from the hatchery (means: 153 mm?±?28 SD vs. 175 mm?±?5 SD), suggesting more rapid departure by larger fish. Sub-yearlings were much more abundant in the estuary, and were caught from March through November, increasing in mean fork length by 8.7 mm month^-1. The hatchery-origin sub-yearlings were not marked externally and so were not distinguishable from natural origin fish. However, 39 % of the sub-yearlings were caught prior to June, when sub-yearlings were released from the hatchery, indicating substantial use of the estuary by natural-origin fish. Thus, even in a reduced state after a century of dam operation, the highly modified estuary was used over many months by juvenile Chinook salmon. The information on juvenile Chinook salmon prior to dam removal provides a basis for comparison to patterns in the future, when the anticipated increase in estuarine complexity may further enhance habitat use by juvenile Chinook salmon.     

Medical applications of array CGH and the transformation of clinical cytogenetics

Microarray-based comparative genomic hybridization (array CGH) merges molecular diagnostics with traditional chromosome analysis and is transforming the field of cytogenetics. Prospective studies of individuals with developmental delay and dysmorphic features have demonstrated that array CGH has the ability to detect any genomic imbalance including deletions, duplications, aneuploidies and amplifications. Detection rates for chromosome abnormalities with array CGH range from 5-17% in individuals with normal results from prior routine cytogenetic testing. In addition, copy number variants (CNVs) were identified in all studies. These CNVs may include large-scale variation and can confound the diagnostic interpretations. Although cytogeneticists will require additional training and laboratories must become appropriately equipped, array CGH holds the promise of being the initial diagnostic tool in the identification of visible and submicroscopic chromosome abnormalities in mental retardation and other developmental disabilities.     

Comparison of dot chromosome sequences from D. melanogaster and D. virilis reveals an enrichment of DNA transposon sequences in heterochromatic domains

Background

Chromosome four of Drosophila melanogaster, known as the dot chromosome, is largely heterochromatic, as shown by immunofluorescent staining with antibodies to heterochromatin protein 1 (HP1) and histone H3K9me. In contrast, the absence of HP1 and H3K9me from the dot chromosome in D. virilis suggests that this region is euchromatic. D. virilis diverged from D. melanogaster 40 to 60 million years ago.

Results

Here we describe finished sequencing and analysis of 11 fosmids hybridizing to the dot chromosome of D. virilis (372,650 base-pairs) and seven fosmids from major euchromatic chromosome arms (273,110 base-pairs). Most genes from the dot chromosome of D. melanogaster remain on the dot chromosome in D. virilis, but many inversions have occurred. The dot chromosomes of both species are similar to the major chromosome arms in gene density and coding density, but the dot chromosome genes of both species have larger introns. The D. virilis dot chromosome fosmids have a high repeat density (22.8%), similar to homologous regions of D. melanogaster (26.5%). There are, however, major differences in the representation of repetitive elements. Remnants of DNA transposons make up only 6.3% of the D. virilis dot chromosome fosmids, but 18.4% of the homologous regions from D. melanogaster; DINE-1 and 1360 elements are particularly enriched in D. melanogaster. Euchromatic domains on the major chromosomes in both species have very few DNA transposons (less than 0.4 %).

Conclusion

Combining these results with recent findings about RNAi, we suggest that specific repetitive elements, as well as density, play a role in determining higher-order chromatin packaging.     

A novel series of [3.2.1] azabicyclic biaryl ethers as α3β4 and α6/4β4 nicotinic receptor agonists

We report the synthesis of a series of [3.2.1]azabicyclic biaryl ethers as selective agonists of α3- and α6-containing nicotinic receptors. In particular, compound 17a from this series is a potent α3β4 and α6/4β4 receptor agonist in terms of both binding and functional activity. Compound 17a also shows potent in vivo activity in CNS-mediated animal models that are sensitive to antipsychotic drugs. Compound 17a may thus be a useful tool for studying the role of α3β4 and α6/4β4 nicotinic receptors in CNS pharmacology.