Variation in gene expression is thought to make a significant contribution to phenotypic diversity among individuals within populations. Although high-throughput cDNA sequencing offers a unique opportunity to delineate the genomewide architecture of regulatory variation, new statistical methods need to be developed to capitalize on the wealth of information contained in RNA-seq data sets. To this end, we developed a powerful and flexible hierarchical Bayesian model that combines information across loci to allow both global and locus-specific inferences about allele-specific expression (ASE). We applied our methodology to a large RNA-seq data set obtained in a diploid hybrid of two diverse Saccharomyces cerevisiae strains, as well as to RNA-seq data from an individual human genome. Our statistical framework accurately quantifies levels of ASE with specified false-discovery rates, achieving high reproducibility between independent sequencing platforms. We pinpoint loci that show unusual and biologically interesting patterns of ASE, including allele-specific alternative splicing and transcription termination sites. Our methodology provides a rigorous, quantitative, and high-resolution tool for profiling ASE across whole genomes. [Supplemental material is available for this article.]Gene expression is the fundamental initial step in the process by which static genomic information gives rise to dynamic organismal phenotypes. Variation in gene expression has the potential to contribute significantly to phenotypic diversity within species and divergence between species (Britten and Davidson 1971;King and Wilson 1975). There is a diverse array of well-characterized examples of phenotypes influenced by regulatory polymorphisms, ranging from pelvic morphology in sticklebacks (Chan et al. 2010) to malaria susceptibility in humans (Tournamille et al. 1995). Although heritable variation in gene expression levels appears to be ubiquitous among individuals within species, an understanding of the distribution of regulatory variation and the mechanisms by which regulatory polymorphisms act remains limited (Rockman and Kruglyak 2006;Skelly et al. 2009).Heritable differences in gene expression between individuals are ultimately caused by polymorphisms that affect the expression level of either one or both alleles (cis-acting or trans-acting polymorphisms, respectively) in a diploid. A powerful approach for identifying cis-acting regulatory variation is measuring allelespecific expression (ASE). An observation of differential allelic expression in a heterozygote indicates the presence of one or more variants that act in cis to affect the expression level of the gene. (Knight et al. 2003). A unifying theme of these studies has been that ASE is widespread both within and between a wide variety of species.More recently, high-throughput sequencing has been used to assess ASE (Degner et al. 2009;Main et al. 2009;Zhang et al. 2009;Emerson et al. 2010;Heap et al. 2010;McManus et al. 2010;Montgomery et al. 2010;Pickrell et al. 2010), whic...

To better understand the quantitative characteristics and structure of phenotypic diversity, we measured over 14,000 transcript, protein, metabolite, and morphological traits in 22 genetically diverse strains of Saccharomyces cerevisiae. More than 50% of all measured traits varied significantly across strains [false discovery rate (FDR) = 5%]. The structure of phenotypic correlations is complex, with 85% of all traits significantly correlated with at least one other phenotype (median = 6, maximum = 328). We show how high-dimensional molecular phenomics data sets can be leveraged to accurately predict phenotypic variation between strains, often with greater precision than afforded by DNA sequence information alone. These results provide new insights into the spectrum and structure of phenotypic diversity and the characteristics influencing the ability to accurately predict phenotypes.

The C-terminal domain (CTD) of Topo II is dispensable for its catalytic activity yet essential for Topo II function in chromosome segregation during mitosis. Here, Edgerton et al. resolve the role of the Topo II CTD during mitosis in yeast, showing that it functions noncatalytically via the Haspin-H3 T3-Phos pathway to recruit Ipl1/Aurora B to mitotic inner centromeres.

PurposeArtemisin-based combination therapies became the recommended therapy in Côte-d’Ivoire in 2005, but both chloroquine (CQ) and sulfadoxine/pyrimethamine (SP) have been heavily used for many decades. Despite this long history, little is known about the geographical distribution of drug resistance–conferring genotypes outside the capital city of Abidjan. In this work, we compared the prevalence of drug-resistant genotypes in Bonoua, an urban area, and Samo, a rural agricultural area, in southeastern Côte-d’Ivoire, about 59 km from Abidjan.Patients and methodsSamples were collected from symptomatic patients in both sites during the rainy season in 2005. Genomic DNA was isolated and codons associated with resistance to CQ and SP were analyzed: pfcrt codons Cys-72-Ser, Val-73-Val, Met-74-Ile, Arg-75-Glu, Lys-76-Thr; pfdhfr codons Ala-16-Val, Arg-51-Ile, Cys-59-Arg, Ser-108-Arg/Thr, and Ile-164-Leu; pfdhps codons Ser-436-Ala, Ala-437-Gly, Lys-540-Glu, Ala-581-Gly, and Ala-613-Thr/Ser.ResultsA limited number of genotypes were found in Bonoua compared with Samo. In both sites, the triple-mutant allele CVIET of pfcrt predominated: 100% in Bonoua and 86.2% in Samo. The wild-type allele, NCSI of pfdhfr, was common − 50% in Bonoua and 38.7% in Samo – but the triple-mutant IRNI and double-mutant NRNI were also frequent (IRNI, 32.6% in Bonoua and 19.4% in Samo; NRNI, 15.2% in Bonoua and 9.7% in Samo). In Samo, a wide range of different genotypes of Pfdhps was observed, with alleles carrying the Gly-437 codon fixed in Bonoua and comprising 73% of the isolates in Samo.ConclusionAlthough these two sites are only 8 km apart, they belonged to very different ecological environments. The overall prevalence of alleles of single-nucleotide polymorphisms associated with resistance to CQ and SP in both locations was among the highest of the region by 2005, although the more rural site showed a more diverse set of alleles and mixed infections. Continued surveillance of these markers will be a useful tool for drug policy, as both CQ and SP are still frequently used years after withdrawal, and SP is recommended by the World Health Organization for intermittent preventive therapy for pregnant women and infants. Data analyzed herein are among the first to be generated during the year of artemisin-based combination-therapy introduction in Côte-d’Ivoire and could be of some interest for malaria policy-makers.

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