Fine mapping of regulatory loci for mammalian gene expression using radiation hybrids

We mapped regulatory loci for nearly all protein-coding genes in mammals using comparative genomic hybridization and expression array measurements from a panel of mouse-hamster radiation hybrid cell lines. The large number of breaks in the mouse chromosomes and the dense genotyping of the panel allowed extremely sharp mapping of loci. As the regulatory loci result from extra gene dosage, we call them copy number expression quantitative trait loci, or ceQTLs. The -2log10P support interval for the ceQTLs was <150 kb, containing an average of <2-3 genes. We identified 29,769 trans ceQTLs with -log10P > 4, including 13 hotspots each regulating >100 genes in trans. Further, this work identifies 2,761 trans ceQTLs harboring no known genes, and provides evidence for a mode of gene expression autoregulation specific to the X chromosome.     

Cattle movements and bovine tuberculosis in Great Britain

For 20 years, bovine tuberculosis (BTB) has been spreading in Great Britain (England, Wales and Scotland) and is now endemic in the southwest and parts of central England and in southwest Wales, and occurs sporadically elsewhere. Although its transmission pathways remain poorly understood, the disease's distribution was previously modelled statistically by using environmental variables and measures of their seasonality. Movements of infected animals have long been considered a critical factor in the spread of livestock diseases, as reflected in strict import/export regulations, the extensive movement restrictions imposed during the 2001 foot-and-mouth disease outbreak, the tracing procedures after a new case of BTB has been confirmed and the Government's recently published strategic framework for the sustainable control on BTB. Since January 2001 it has been mandatory for stock-keepers in Great Britain to notify the British Cattle Movement Service of all cattle births, movements and deaths. Here we show that movements as recorded in the Cattle Tracing System data archive, and particularly those from areas where BTB is reported, consistently outperform environmental, topographic and other anthropogenic variables as the main predictor of disease occurrence. Simulation distribution models for 2002 and 2003, incorporating all predictor categories, are presented and used to project distributions for 2004 and 2005.     

The DNA sequence of the human X chromosome

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.     

An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis

Using advanced gene targeting methods, generating mouse models of cancer that accurately reproduce the genetic alterations present in human tumors is now relatively straightforward. The challenge is to determine to what extent such models faithfully mimic human disease with respect to the underlying molecular mechanisms that accompany tumor progression. Here we describe a method for comparing mouse models of cancer with human tumors using gene-expression profiling. We applied this method to the analysis of a model of Kras2-mediated lung cancer and found a good relationship to human lung adenocarcinoma, thereby validating the model. Furthermore, we found that whereas a gene-expression signature of KRAS2 activation was not identifiable when analyzing human tumors with known KRAS2 mutation status alone, integrating mouse and human data uncovered a gene-expression signature of KRAS2 mutation in human lung cancer. We confirmed the importance of this signature by gene-expression analysis of short hairpin RNA-mediated inhibition of oncogenic Kras2. These experiments identified both a pattern of gene expression indicative of KRAS2 mutation and potential effectors of oncogenic KRAS2 activity in human cancer. This approach provides a strategy for using genomic analysis of animal models to probe human disease.     

A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility

Multiple sclerosis is a common disease with proven heritability, but, despite large-scale attempts, no underlying risk genes have been identified. Traditional linkage scans have so far identified only one risk haplotype for multiple sclerosis (at HLA on chromosome 6), which explains only a fraction of the increased risk to siblings. Association scans such as admixture mapping have much more power, in principle, to find the weak factors that must explain most of the disease risk. We describe here the first high-powered admixture scan, focusing on 605 African American cases and 1,043 African American controls, and report a locus on chromosome 1 that is significantly associated with multiple sclerosis.     

Evolutionary instability of ectomycorrhizal symbioses in basidiomycetes

Mycorrhizae, the symbiotic associations of plant roots and fungal hyphae, are classic examples of mutualisms. In these ecologically important associations, the fungi derive photosynthetic sugars from their plant hosts, which in turn benefit from fungus-mediated uptake of mineral nutrients. Early views on the evolution of symbioses suggested that all long-term, intimate associations tend to evolve toward mutualism. Following this principle, it has been suggested that mycorrhizal symbioses are the stable derivatives of ancestral antagonistic interactions involving plant parasitic fungi. Alternatively, mutualisms have been interpreted as inherently unstable reciprocal parasitisms, which can be disrupted by conflicts of interest among the partners. To determine the number of origins of mycorrhizae, and to assess their evolutionary stability, it is necessary to understand the phylogenetic relationships of the taxa involved. Here we present a broad phylogenetic analysis of mycorrhizal and free-living homobasidiomycetes (mushroom-forming fungi). Our results indicate that mycorrhizal symbionts with diverse plant hosts have evolved repeatedly from saprotrophic precursors, but also that there have been multiple reversals to a free-living condition. These findings suggest that mycorrhizae are unstable, evolutionarily dynamic associations.     

Natural occurrence of 2-5A in interferon-treated EMC virus-infected L cells.

Until now the interferon-mediated 2'-5' adenine oligonucleotide inhibitors (2-5A) of cell-free protein synthesis have not been detected in intact cells. Here we report their natural occurrence in interferon-treated, EMC virus-infected mouse L cells in amounts consistent with the idea that they play a part in the inhibition of virus growth.     

Alkaloid studies XXV. The structure of the Aspidosperma alkaloids cylindrocarpine and cylindrocarpidine

Zusammenfassung Die Strukturaufklärung von Cylindrocarpin (II) und Cylindrocarpidin (IV) zeigt, dass diese zwei Alkaloide die ersten Mitglieder der Aspidosperminfamilie (I) sind, in denen eine sauerstoffhaltige Seitenkette anstatt der gewöhnlichen C-5-Äthylgruppe vorliegt.

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Paper XXIV,T. Nakano, C. Djerassi, R. A. Corral, andO. O. Orazi, J. org. Chem., in press.

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Postdoctorate research fellow, 1958–1960.