Quality assessment of the human genome sequence

As the final sequencing of the human genome has now been completed, we present the results of the largest examination of the quality of the finished DNA sequence. The completed study covers the major contributing sequencing centres and is based on a rigorous combination of laboratory experiments and computational analysis.     

IRS-2 pathways integrate female reproduction and energy homeostasis

Severe dietary restriction, catabolic states and even short-term caloric deprivation impair fertility in mammals. Likewise, obesity is associated with infertile conditions such as polycystic ovary syndrome. The reproductive status of lower organisms such as Caenorhabditis elegans is also modulated by availability of nutrients. Thus, fertility requires the integration of reproductive and metabolic signals. Here we show that deletion of insulin receptor substrate-2 (IRS-2), a component of the insulin/insulin-like growth factor-1 signalling cascade, causes female infertility. Mice lacking IRS-2 have small, anovulatory ovaries with reduced numbers of follicles. Plasma concentrations of luteinizing hormone, prolactin and sex steroids are low in these animals. Pituitaries are decreased in size and contain reduced numbers of gonadotrophs. Females lacking IRS-2 have increased food intake and obesity, despite elevated levels of leptin. Our findings indicate that insulin, together with leptin and other neuropeptides, may modulate hypothalamic control of appetite and reproductive endocrinology. Coupled with findings on the role of insulin-signalling pathways in the regulation of fertility, metabolism and longevity in C. elegans and Drosophila, we have identified an evolutionarily conserved mechanism in mammals that regulates both reproduction and energy homeostasis.     

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.     

Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects

Mutations in genes encoding ribosomal proteins cause the Minute phenotype in Drosophila and mice, and Diamond-Blackfan syndrome in humans. Here we report two mouse dark skin (Dsk) loci caused by mutations in Rps19 (ribosomal protein S19) and Rps20 (ribosomal protein S20). We identify a common pathophysiologic program in which p53 stabilization stimulates Kit ligand expression, and, consequently, epidermal melanocytosis via a paracrine mechanism. Accumulation of p53 also causes reduced body size and erythrocyte count. These results provide a mechanistic explanation for the diverse collection of phenotypes that accompany reduced dosage of genes encoding ribosomal proteins, and have implications for understanding normal human variation and human disease.     

A new multipoint method for genome-wide association studies by imputation of genotypes

Genome-wide association studies are set to become the method of choice for uncovering the genetic basis of human diseases. A central challenge in this area is the development of powerful multipoint methods that can detect causal variants that have not been directly genotyped. We propose a coherent analysis framework that treats the problem as one involving missing or uncertain genotypes. Central to our approach is a model-based imputation method for inferring genotypes at observed or unobserved SNPs, leading to improved power over existing methods for multipoint association mapping. Using real genome-wide association study data, we show that our approach (i) is accurate and well calibrated, (ii) provides detailed views of associated regions that facilitate follow-up studies and (iii) can be used to validate and correct data at genotyped markers. A notable future use of our method will be to boost power by combining data from genome-wide scans that use different SNP sets.     

Isoquinolines, beta-carbolines and alcohol drinking: involvement of opioid and dopaminergic mechanisms

Two classes of amine-aldehyde adducts, the tetrahydroisoquinoline (TIQ) and beta-carboline (THBC) compounds, have been implicated in the mechanism in the brain underlying the addictive drinking of alcohol. One part of this review focuses on the large amount of evidence unequivocally demonstrating not only the corporeal synthesis of the TIQs and THBCs but their sequestration in brain tissue as well. Experimental studies published recently have revealed that exposure to alcohol enhances markedly the endogenous formation of condensation products. Apart from their multiple neuropharmacological actions, certain adducts when delivered directly into the brain of either the rat or monkey, to circumvent the brain's blood-barrier system, can evoke an intense and dose-dependent increase in the voluntary drinking of solutions of alcohol even in noxious concentrations. That the abnormal intake of alcohol is related functionally to opioid receptors in the brain is likely on the basis of several distinct lines of evidence which include: the attenuation of alcohol drinking by opioid receptor antagonists; binding of a TIQ to opiate receptors in the brain; and marked differences in enkephalin values in animals genetically predisposed to the ingestion of alcohol. Finally, it is proposed that the dopaminergic reward pathways which traverse the meso-limbic-forebrain systems of the brain more than likely constitute an integrative anatomical substrate for the adduct-opioid cascade of neuronal events which promote and sustain the aberrant drinking of alcohol.     

The phylogenetic history of immunodeficiency viruses

Knowledge of the phylogenetic history of the human immunodeficiency viruses (HIV-1 and HIV-2) is important for our understanding of the epidemiology of AIDS, the disease caused by these viruses. Reconstruction of the evolutionary tree is hampered, however, by two problems. One is the high variation in nucleotide sequence between the known HIV isolates which can create formidable difficulties in identifying homologous genomic sites that may be used in a molecular phylogenetic reconstruction. Another impediment has been the lack of unequivocal time calibration points: there is only a sparse 'fossil record' for HIV and limited historical epidemiological data. We have largely overcome these difficulties by: (1) a thorough optimal-sequence alignment analysis; (2) the inclusion of sequences of an early (1976) HIV-1 isolate, a recent (1986) HIV-2 isolate and two simian immunodeficiency viruses (SIV) along with five other HIV-1 isolates; and (3) the reconstruction of a minimum-length evolutionary tree based on the envelope-gene variable positions. We conclude that HIV-1 may have evolved from its common ancestor with HIV-2 as recently as 40 years ago.     

Feeding in infancy: short- and long-term effects on cardiovascular function.

Cardiovascular responses of adult organisms to feeding are well characterized and, in general, are understood as acute adaptations required for processing and distributing nutrients. Research over the past several years has shown that infants also have important cardiovascular responses to nutrient intake and that these are regulated by changes in autonomic activity to the heart and vasculature. Recent studies have provided results that suggest these responses in infancy may make an important contribution to the long-term development of cardiovascular function, in particular, adult blood pressure (BP). The purpose of this presentation will be to review the evidence that has led to this conclusion, offer ideas about how this potential early-life shaping of subsequent cardiovascular function may come about, and suggest further studies that will be required in order to characterize the mechanisms responsible for these effects.