SUMMARY We report the construction and analysis of 4,836 heterozygous diploid deletion mutants covering 98.4% of the fission yeast genome. This resource provides a powerful tool for biotechnological and eukaryotic cell biology research. Comprehensive gene dispensability comparisons with budding yeast, the first time such studies have been possible between two eukaryotes, revealed that 83% of single copy orthologues in the two yeasts had conserved dispensability. Gene dispensability differed for certain pathways between the two yeasts, including mitochondrial translation and cell cycle checkpoint control. We show that fission yeast has more essential genes than budding yeast and that essential genes are more likely than non-essential genes to be single copy, broadly conserved and to contain introns. Growth fitness analyses determined sets of haploinsufficient and haploproficient genes for fission yeast, and comparisons with budding yeast identified specific ribosomal proteins and RNA polymerase subunits, which may act more generally to regulate eukaryotic cell growth.

A large number of putative cis-regulatory sequences have been annotated in the human genome, but the genes they control remain poorly defined. To bridge this gap, we generate maps of longrange chromatin interactions centered on 18,943 well-annotated promoters for protein-coding genes in 27 human cell/tissue types. We use this information to infer the target genes of 70,329 candidate regulatory elements, and suggest potential regulatory function for 27,325 non-coding sequence variants associated with 2,117 physiological traits and diseases. Integrative analysis of these promoter-centered interactome maps reveals widespread enhancer-like promoters involved in gene regulation and common molecular pathways underlying distinct groups of human traits and diseases.

34 These authors contributed equally to the work.Key Words: CD38, oxytocin, mutation, polymorphism, autism, high-functioning autism Author information Correspondence and requests for materials should be addressed to H. Higashida (haruhiro@med.kanazawa-u.ac.jp). 3 ABSTRACTThe neurobiological basis of autism spectrum disorder (ASD) remains poorly understood.Given the role of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play a role in the etiology of ASD. Here, we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons.In studies of the association between CD38 and autism, we analyzed 10 single nucleotide polymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAs mainly from a case-control study in Japan, and Caucasian cases mainly recruited to the Autism Genetic Resource Exchange (AGRE). The SNPs of CD38, rs6449197 (p<0.040) and rs3796863 (p<0.005) showed significant associations with a subset of ASD (IQ>70; designated as high-functioning autism (HFA)) in the U.S. 104 AGRE family trios, but not with Japanese 188 HFA subjects. A mutation that caused tryptophan to replace arginine at amino acid residue 140 (R140W; (rs1800561, 4693C>T)) was found in 0.6%-4.6% of the Japanese population and was associated with ASD in the smaller case-control study. The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort OT plasma levels were lower in subjects with the T allele than in those without. One proband with the T allele who was taking nasal OT spray showed relief of symptoms. The two variant CD38 poloymorphysms tested may be of interest with regard of the pathophysiology of ASD.4

This paper presents a novel linear programming approach to do protein 3-dimensional (3D) structure prediction via threading. Based on the contact map graph of the protein 3D structure template, the protein threading problem is formulated as a large scale integer programming (IP) problem. The IP formulation is then relaxed to a linear programming (LP) problem, and then solved by the canonical branch-and-bound method. The final solution is globally optimal with respect to energy functions. In particular, our energy function includes pairwise interaction preferences and allowing variable gaps which are two key factors in making the protein threading problem NP-hard. A surprising result is that, most of the time, the relaxed linear programs generate integral solutions directly. Our algorithm has been implemented as a software package RAPTOR-RApid Protein Threading by Operation Research technique. Large scale benchmark test for fold recognition shows that RAPTOR significantly outperforms other programs at the fold similarity level. The CAFASP3 evaluation, a blind and public test by the protein structure prediction community, ranks RAPTOR as top 1, among individual prediction servers, in terms of the recognition capability and alignment accuracy for Fold Recognition (FR) family targets. RAPTOR also performs very well in recognizing the hard Homology Modeling (HM) targets. RAPTOR was implemented at the University of Waterloo and it can be accessed at http://www.cs.uwaterloo.ca/~j3xu/RAPTOR_form.htm.