Linkage disequilibrium (LD) mapping provides a powerful method for fine-structure localization of rare disease genes, but has not yet been widely applied to common disease. We sought to design a systematic approach for LD mapping and apply it to the localization of a gene (IBD5) conferring susceptibility to Crohn disease. The key issues are: (i) to detect a significant LD signal (ii) to rigorously bound the critical region and (iii) to identify the causal genetic variant within this region. We previously mapped the IBD5 locus to a large region spanning 18 cM of chromosome 5q31 (P<10(-4)). Using dense genetic maps of microsatellite markers and single-nucleotide polymorphisms (SNPs) across the entire region, we found strong evidence of LD. We bound the region to a common haplotype spanning 250 kb that shows strong association with the disease (P< 2 x 10(-7)) and contains the cytokine gene cluster. This finding provides overwhelming evidence that a specific common haplotype of the cytokine region in 5q31 confers susceptibility to Crohn disease. However, genetic evidence alone is not sufficient to identify the causal mutation within this region, as strong LD across the region results in multiple SNPs having equivalent genetic evidence-each consistent with the expected properties of the IBD5 locus. These results have important implications for Crohn disease in particular and LD mapping in general.

We report genetic maps for diploid (D) and tetraploid (AtDt) Gossypium genomes composed of sequence-tagged sites (STS) that foster structural, functional, and evolutionary genomic studies. The maps include, respectively, 2584 loci at 1.72-cM ‫006ف(‬ kb) intervals based on 2007 probes (AtDt) and 763 loci at 1.96-cM ‫005ف(‬ kb) intervals detected by 662 probes (D). Both diploid and tetraploid cottons exhibit negative crossover interference; i.e., double recombinants are unexpectedly abundant. We found no major structural changes between Dt and D chromosomes, but confirmed two reciprocal translocations between At chromosomes and several inversions. Concentrations of probes in corresponding regions of the various genomes may represent centromeres, while genome-specific concentrations may represent heterochromatin. Locus duplication patterns reveal all 13 expected homeologous chromosome sets and lend new support to the possibility that a more ancient polyploidization event may have predated the A-D divergence of 6-11 million years ago. Identification of SSRs within 312 RFLP sequences plus direct mapping of 124 SSRs and exploration for CAPS and SNPs illustrate the "portability" of these STS loci across populations and detection systems useful for marker-assisted improvement of the world's leading fiber crop. These data provide new insights into polyploid evolution and represent a foundation for assembly of a finished sequence of the cotton genome.

Identifying the genes responsible for human diseases requires combining information about gene position with clues about biological function. The recent availability of whole-genome data sets of RNA and protein expression provides powerful new sources of functional insight. Here we illustrate how such data sets can expedite disease-gene discovery, by using them to identify the gene causing Leigh syndrome, French-Canadian type (LSFC, Online Mendelian Inheritance in Man no. 220111), a human cytochrome c oxidase deficiency that maps to chromosome 2p16-21. Using four public RNA expression data sets, we assigned to all human genes a ''score'' reflecting their similarity in RNA-expression profiles to known mitochondrial genes. Using a large survey of organellar proteomics, we similarly classified human genes according to the likelihood of their protein product being associated with the mitochondrion. By intersecting this information with the relevant genomic region, we identified a single clear candidate gene, LRPPRC. Resequencing identified two mutations on two independent haplotypes, providing definitive genetic proof that LRPPRC indeed causes LSFC. LRPPRC encodes an mRNA-binding protein likely involved with mtDNA transcript processing, suggesting an additional mechanism of mitochondrial pathophysiology. Similar strategies to integrate diverse genomic information can be applied likewise to other disease pathways and will become increasingly powerful with the growing wealth of diverse, functional genomics data.

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Background: Antagonism of corticotropin‐releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF‐1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). Method: This was a multicenter, randomized, double‐blind, placebo‐controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. Results: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half‐powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2‐2016) with the HAM‐A psychic subscale score for the entire cohort at baseline (FDR‐adjusted P=.015). Conclusions: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.

A detailed comparative map of Brassica oleracea and Arabidopsis thaliana has been established based largely on mapping of Arabidopsis ESTs in two Arabidopsis and four Brassica populations. Based on conservative criteria for inferring synteny, "one to one correspondence" between Brassica and Arabidopsis chromosomes accounted for 57% of comparative loci. Based on 186 corresponding loci detected in B. oleracea and A. thaliana, at least 19 chromosome structural rearrangements differentiate B. oleracea and A. thaliana orthologs. Chromosomal duplication in the B. oleracea genome was strongly suggested by parallel arrangements of duplicated loci on different chromosomes, which accounted for 41% of loci mapped in Brassica. Based on 367 loci mapped, at least 22 chromosomal rearrangements differentiate B. oleracea homologs from one another. Triplication of some Brassica chromatin and duplication of some Arabidopsis chromatin were suggested by data that could not be accounted for by the one-to-one and duplication models, respectively. Twenty-seven probes detected three or more loci in Brassica, which represent 25.3% of the 367 loci mapped in Brassica. Thirty-one probes detected two or more loci in Arabidopsis, which represent 23.7% of the 262 loci mapped in Arabidopsis. Application of an EST-based, cross-species genomic framework to isolation of alleles conferring phenotypes unique to Brassica, as well as the challenges and opportunities in extrapolating genetic information from Arabidopsis to Brassica and to more distantly related crops, are discussed.Arabidopsis thaliana, a weed-like member of the Cruciferae family (tribe Sisymbrieae), offers many advantages for basic and applied plant research. These features include small stature, short life cycle, small genome size (2n=10, estimated physical genome size of 100-120 Mb), low frequency of repetitive sequences (∼10% of the nuclear genome; Leutwiler et al. 1984), and prolific seed production. These features, combined with research of the past several decades yielding many mutants, efficient transformation systems, detailed genetic and physical maps, the availability of several P1, YAC, and BAC libraries, and 36,569 public ESTs (http:// www.cbc.umn.edu/ResearchProjects/Arabidopsis), make A. thaliana an ideal model for further molecular and genetic study (Meyerowitz and Somerville 1994). A multinational genome research initiative aiming to completely sequence the Arabidopsis genome by year 2004 (The Multinational Science Steering Committee 1997) is ahead of schedule. Such an accomplishment will undoubtedly create new scientific challenges and opportunities. One of the core issues will be how to apply the information obtained from the Arabidopsis genome project to the improvement of the world's leading crops.The genus Brassica (tribe Brassiceae), including many important crops, is in the same taxonomic family as Arabidopsis thaliana. Such a close relationship suggests that crop plants of the genus Brassica will be among the earliest beneficiaries of a complete sequence of Ara...

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The current study is the first installment of an effort to explore the secondary gene pool for the enhancement of Upland cotton (Gossypium hirsutum L.) germplasm. We developed advanced-generation backcross populations by first crossing G. hirsutum cv. Tamcot 2111 and G. barbadense cv. Pima S6, then independently backcrossing F(1) plants to the G. hirsutum parent for three cycles. Genome-wide mapping revealed introgressed alleles at an average of 7.3% of loci in each BC(3)F(1) plant, collectively representing G. barbadense introgression over about 70% of the genome. Twenty-four BC(3)F(1) plants were selfed to generate 24 BC(3)F(2) families of 22-172 plants per family (totaling 2,976 plants), which were field-tested for fiber elongation and genetically mapped. One-way analysis of variance detected 22 non-overlapping quantitative trail loci (QTLs) distributed over 15 different chromosomes. The percentage of variance explained by individual loci ranged from 8% to 28%. Although the G. barbadense parent has lower fiber elongation than the G. hirsutum parent, the G. barbadense allele contributed to increased fiber elongation at 64% of the QTLs. Two-way analysis of variance detected significant (P<0.001) among-family genotype effects and genotypexfamily interactions in two and eight regions, respectively, suggesting that the phenotypic effects of some introgressed chromosomal segments are dependent upon the presence/absence of other chromosomal segments.