The mouse X chromosome is enriched for multicopy testis genes showing postmeiotic expression

According to the prevailing view, mammalian X chromosomes are enriched in spermatogenesis genes expressed before meiosis and deficient in spermatogenesis genes expressed after meiosis. The paucity of postmeiotic genes on the X chromosome has been interpreted as a consequence of meiotic sex chromosome inactivation (MSCI)--the complete silencing of genes on the XY bivalent at meiotic prophase. Recent studies have concluded that MSCI-initiated silencing persists beyond meiosis and that most genes on the X chromosome remain repressed in round spermatids. Here, we report that 33 multicopy gene families, representing approximately 273 mouse X-linked genes, are expressed in the testis and that this expression is predominantly in postmeiotic cells. RNA FISH and microarray analysis show that the maintenance of X chromosome postmeiotic repression is incomplete. Furthermore, X-linked multicopy genes exhibit a similar degree of expression as autosomal genes. Thus, not only is the mouse X chromosome enriched for spermatogenesis genes functioning before meiosis, but in addition, approximately 18% of mouse X-linked genes are expressed in postmeiotic cells.     

Host recognition by the tobacco hornworm is mediated by a host plant compound

It is generally believed that animals make decisions about the selection of mates, kin or food on the basis of pre-constructed recognition templates. These templates can be innate or acquired through experience. An example of an acquired template is the feeding preference exhibited by larvae of the moth, Manduca sexta. Naive hatchlings will feed and grow successfully on many different plants or artificial diets, but once they have fed on a natural host they become specialist feeders. Here we show that the induced feeding preference of M. sexta involves the formation of a template to a steroidal glycoside, indioside D, that is present in solanaceous foliage. This compound is both necessary and sufficient to maintain the induced feeding preference. The induction of host plant specificity is at least partly due to a tuning of taste receptors to indioside D. The taste receptors of larvae fed on host plants show an enhanced response to indioside D as compared with other plant compounds tested.     

Preferences of transmembrane helices for cooperative amplification of Gαs and Gαq signaling of the thyrotropin receptor

The majority of constitutively activating mutations (CAMs) of the thyroid-stimulating hormone receptor display a partially activated receptor. Thus, full receptor activation requires a multiplex activation process. To define impacts of different transmembrane helices (TMHs) on cooperative signal transduction, we combined single CAMs in particular TMHs to double mutations and measured second messenger accumulation of the G_αs and the G_αq pathway. We observed a synergistic increase for basal activity of the G_αs pathway, for all characterized double mutants except for two combinations. Each double mutation, containing CAMs in TMH2, 6 and 7 showed the highest constitutive activities, suggesting that these helices contribute most to G_αs-mediated signaling. No single CAM revealed constitutive activity for the G_αq pathway. The double mutations with CAMs from TMH1, 2, 3 and 6 also exhibited increase for basal G_αq signaling. Our results suggest that TMH2, 6, 7 show selective preferences towards G_αs signaling, and TMH1, 2, 3, 6 for G_αq signaling.     

Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. Here we describe methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P.?falciparum genome.     

Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease

Integration of genome-wide expression profiling with linkage analysis is a new approach to identifying genes underlying complex traits. We applied this approach to the regulation of gene expression in the BXH/HXB panel of rat recombinant inbred strains, one of the largest available rodent recombinant inbred panels and a leading resource for genetic analysis of the highly prevalent metabolic syndrome. In two tissues important to the pathogenesis of the metabolic syndrome, we mapped cis- and trans-regulatory control elements for expression of thousands of genes across the genome. Many of the most highly linked expression quantitative trait loci are regulated in cis, are inherited essentially as monogenic traits and are good candidate genes for previously mapped physiological quantitative trait loci in the rat. By comparative mapping we generated a data set of 73 candidate genes for hypertension that merit testing in human populations. Mining of this publicly available data set is expected to lead to new insights into the genes and regulatory pathways underlying the extensive range of metabolic and cardiovascular disease phenotypes that segregate in these recombinant inbred strains.     

Occludin binds to the SH3-hinge-GuK unit of zonula occludens protein 1: potential mechanism of tight junction regulation

The interaction between tight junction proteins occludin and zona occludens protein 1 (ZO-1) was clarified. The sequence cc1 within the hinge region of ZO-1, connecting its SH3 and GuK domains, was identified as a new association site for the occludin C-terminus, core binding area GLRSSKRNLRKSR (mouse ZO-1^606-618). Occludin also bound to the sequence H2 within GuK, core area HKLRKNNH (ZO-1^759-766). In occludin, the binding core was ELSRLDKELDDYREESEEY (mouse occludin^455-473). Helicity of the sequences was suggested by circular dichroism. Because basic residues in ZO-1, acidic residues in occludin (underlined), coiled-coil helix-forming leucine heptad motifs (bold) in occludin and, probably, in cc1 were essential, we conclude that interactions were both helical and ionic. Moreover, the GuK domain bound other GuK molecules, suggesting oligomerization of ZO-1. Generally, the assumption is supported that the SH3-hinge-GuK region represents a functional and regulatory unit in ZO-1 forming a multiprotein tight junction complex with occludin.Received 12 January 2004; received after revision 23 February 2004; accepted 31 March 2004     

Analysing the 1811-1812 New Madrid earthquakes with recent instrumentally recorded aftershocks

Although dynamic stress changes associated with the passage of seismic waves are thought to trigger earthquakes at great distances, more than 60 per cent of all aftershocks appear to be triggered by static stress changes within two rupture lengths of a mainshock. The observed distribution of aftershocks may thus be used to infer details of mainshock rupture geometry. Aftershocks following large mid-continental earthquakes, where background stressing rates are low, are known to persist for centuries, and models based on rate-and-state friction laws provide theoretical support for this inference. Most past studies of the New Madrid earthquake sequence have indeed assumed ongoing microseismicity to be a continuing aftershock sequence. Here we use instrumentally recorded aftershock locations and models of elastic stress change to develop a kinematically consistent rupture scenario for three of the four largest earthquakes of the 1811-1812 New Madrid sequence. Our results suggest that these three events occurred on two contiguous faults, producing lobes of increased stress near fault intersections and end points, in areas where present-day microearthquakes have been hitherto interpreted as evidence of primary mainshock rupture. We infer that the remaining New Madrid mainshock may have occurred more than 200 km north of this region in the Wabash Valley of southern Indiana and Illinois--an area that contains abundant modern microseismicity, and where substantial liquefaction was documented by historic accounts. Our results suggest that future large mid-plate earthquake sequences may extend over a much broader region than previously suspected.