Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.     

Raman crystal lasers in the visible and near-infrared

Raman lasers based on potassium gadolinium tungstate and lead tungstate crystals pumped by a≈120 ps Nd: YAG laser at 1.064/μm were developed. High reflection mirrors for the Stokes wavelength have been used to generate near-infrared and eye safe spectral region of 1.15 - 1.32/μm. Second harmonic generation of the generated Raman lasers was observed. Eifficient multiple Stokes and anti-Stokes picosecond generation in 64 crystals have been shown to exhibit stimulated Raman scattering on about 700 lines covering the whole visible and near-infrared spectrum. All stimulated Raman scattering (SRS) wavelengths in the visible and near-infrared spectrum are identified and attributed to the SRS-active vibration modes of these crystals.     

Analysis of the DNA sequence and duplication history of human chromosome 15

Here we present a finished sequence of human chromosome 15, together with a high-quality gene catalogue. As chromosome 15 is one of seven human chromosomes with a high rate of segmental duplication, we have carried out a detailed analysis of the duplication structure of the chromosome. Segmental duplications in chromosome 15 are largely clustered in two regions, on proximal and distal 15q; the proximal region is notable because recombination among the segmental duplications can result in deletions causing Prader-Willi and Angelman syndromes. Sequence analysis shows that the proximal and distal regions of 15q share extensive ancient similarity. Using a simple approach, we have been able to reconstruct many of the events by which the current duplication structure arose. We find that most of the intrachromosomal duplications seem to share a common ancestry. Finally, we demonstrate that some remaining gaps in the genome sequence are probably due to structural polymorphisms between haplotypes; this may explain a significant fraction of the gaps remaining in the human genome.     

Chemical investigation of hassium (element 108)

The periodic table provides a classification of the chemical properties of the elements. But for the heaviest elements, the transactinides, this role of the periodic table reaches its limits because increasingly strong relativistic effects on the valence electron shells can induce deviations from known trends in chemical properties. In the case of the first two transactinides, elements 104 and 105, relativistic effects do indeed influence their chemical properties, whereas elements 106 and 107 both behave as expected from their position within the periodic table. Here we report the chemical separation and characterization of only seven detected atoms of element 108 (hassium, Hs), which were generated as isotopes (269)Hs (refs 8, 9) and (270)Hs (ref. 10) in the fusion reaction between (26)Mg and (248)Cm. The hassium atoms are immediately oxidized to a highly volatile oxide, presumably HsO(4), for which we determine an enthalpy of adsorption on our detector surface that is comparable to the adsorption enthalpy determined under identical conditions for the osmium oxide OsO(4). These results provide evidence that the chemical properties of hassium and its lighter homologue osmium are similar, thus confirming that hassium exhibits properties as expected from its position in group 8 of the periodic table.     

Systematic assessment of copy number variant detection via genome-wide SNP genotyping

SNP genotyping has emerged as a technology to incorporate copy number variants (CNVs) into genetic analyses of human traits. However, the extent to which SNP platforms accurately capture CNVs remains unclear. Using independent, sequence-based CNV maps, we find that commonly used SNP platforms have limited or no probe coverage for a large fraction of CNVs. Despite this, in 9 samples we inferred 368 CNVs using Illumina SNP genotyping data and experimentally validated over two-thirds of these. We also developed a method (SNP-Conditional Mixture Modeling, SCIMM) to robustly genotype deletions using as few as two SNP probes. We find that HapMap SNPs are strongly correlated with 82% of common deletions, but the newest SNP platforms effectively tag about 50%. We conclude that currently available genome-wide SNP assays can capture CNVs accurately, but improvements in array designs, particularly in duplicated sequences, are necessary to facilitate more comprehensive analyses of genomic variation.     

A genome-wide comparison of recent chimpanzee and human segmental duplications

We present a global comparison of differences in content of segmental duplication between human and chimpanzee, and determine that 33% of human duplications (> 94% sequence identity) are not duplicated in chimpanzee, including some human disease-causing duplications. Combining experimental and computational approaches, we estimate a genomic duplication rate of 4-5 megabases per million years since divergence. These changes have resulted in gene expression differences between the species. In terms of numbers of base pairs affected, we determine that de novo duplication has contributed most significantly to differences between the species, followed by deletion of ancestral duplications. Post-speciation gene conversion accounts for less than 10% of recent segmental duplication. Chimpanzee-specific hyperexpansion (> 100 copies) of particular segments of DNA have resulted in marked quantitative differences and alterations in the genome landscape between chimpanzee and human. Almost all of the most extreme differences relate to changes in chromosome structure, including the emergence of African great ape subterminal heterochromatin. Nevertheless, base per base, large segmental duplication events have had a greater impact (2.7%) in altering the genomic landscape of these two species than single-base-pair substitution (1.2%).     

Regional,individual and political determinants of FOMC members' key macroeconomic forecasts

We study Federal Open Market Committee members' individual forecasts of inflation and unemployment in the period 1992–2004. Our results imply that Governors and Bank presidents forecast differently, with Governors submitting lower inflation and higher unemployment rate forecasts than bank presidents. For Bank presidents we find a regional bias, with higher district unemployment rates being associated with lower inflation and higher unemployment rate forecasts. Bank presidents' regional bias is more pronounced during the year prior to their elections or for nonvoting bank presidents. Career backgrounds or political affiliations also affect individual forecast behavior.     

Closing gaps in the human genome with fosmid resources generated from multiple individuals

The human genome sequence has been finished to very high standards; however, more than 340 gaps remained when the finished genome was published by the International Human Genome Sequencing Consortium in 2004. Using fosmid resources generated from multiple individuals, we targeted gaps in the euchromatic part of the human genome. Here we report 2,488,842 bp of previously unknown euchromatic sequence, 363,114 bp of which close 26 of 250 euchromatic gaps, or 10%, including two remaining euchromatic gaps on chromosome 19. Eight (30.7%) of the closed gaps were found to be polymorphic. These sequences allow complete annotation of several human genes as well as the assignment of mRNAs. The gap sequences are 2.3-fold enriched in segmentally duplicated sequences compared to the whole genome. Our analysis confirms that not all gaps within 'finished' genomes are recalcitrant to subcloning and suggests that the paired-end-sequenced fosmid libraries could prove to be a rich resource for completion of the human euchromatic genome.