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Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution. © 2005 Nature Publishing Group., link_to_OA_fulltext

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.

Do it right, and your investment in information technology can have ail sorts of strategic payoffs. Do it wrong, and you'll be paying, dearly, for nothing. Here's a guide to evaluating IT and measuring its impact.

Competition, consolidation, and couponing have made consumers savvier and brand loyalty shakier. As a result, nurturing the all‐important brand demands a new level of creativity and an increased attention to strategy. Often it means a closer look at logos and package design.

Human exposures to air pollution control (APC) residues released from 6 landfills were modeled and assessed. Following a qualitative risk characterisation, direct and indirect exposures were quantified. Site-specific air dispersion modeling was conducted for PM10, PCDDs/PCDFs, Pb, Cd, As and CrVI concentrations at the closest residential points of exposure for 4 landfill sites accepting, in total, 75% w/w of the APC residues disposed of in 2000–2001 (UK). Inhalation risks, assessed by reference to air quality standards at residential exposure points, were assessed as insignificant. Preliminary modeling suggested that indirect exposures from PCDDs/PCDFs at the 95th percentile level for the site where APC deposition rates were highest could potentially exceed the tolerable daily soil intake (TDSI) but this warrants further study given the model limitations. These results offer an initial screen of the significance of potential risks from APC disposal, which is of value in addressing concerns about the uncertainty of potential risks to human health from bulk APC disposal at strategic locations. Keywords: Air pollution control residues, Risk, Air quality impact, Landfill, Health

The soil nematodes Caenorhabditis briggsae and Caenorhabditis elegans diverged from a common ancestor roughly 100 million years ago and yet are almost indistinguishable by eye. They have the same chromosome number and genome sizes, and they occupy the same ecological niche. To explore the basis for this striking conservation of structure and function, we have sequenced the C. briggsae genome to a high-quality draft stage and compared it to the finished C. elegans sequence. We predict approximately 19,500 protein-coding genes in the C. briggsae genome, roughly the same as in C. elegans. Of these, 12,200 have clear C. elegans orthologs, a further 6,500 have one or more clearly detectable C. elegans homologs, and approximately 800 C. briggsae genes have no detectable matches in C. elegans. Almost all of the noncoding RNAs (ncRNAs) known are shared between the two species. The two genomes exhibit extensive colinearity, and the rate of divergence appears to be higher in the chromosomal arms than in the centers. Operons, a distinctive feature of C. elegans, are highly conserved in C. briggsae, with the arrangement of genes being preserved in 96% of cases. The difference in size between the C. briggsae (estimated at approximately 104 Mbp) and C. elegans (100.3 Mbp) genomes is almost entirely due to repetitive sequence, which accounts for 22.4% of the C. briggsae genome in contrast to 16.5% of the C. elegans genome. Few, if any, repeat families are shared, suggesting that most were acquired after the two species diverged or are undergoing rapid evolution. Coclustering the C. elegans and C. briggsae proteins reveals 2,169 protein families of two or more members. Most of these are shared between the two species, but some appear to be expanding or contracting, and there seem to be as many as several hundred novel C. briggsae gene families. The C. briggsae draft sequence will greatly improve the annotation of the C. elegans genome. Based on similarity to C. briggsae, we found strong evidence for 1,300 new C. elegans genes. In addition, comparisons of the two genomes will help to understand the evolutionary forces that mold nematode genomes., With the Caenorhabditis briggsae genome now in hand, C. elegans biologists have a powerful new research tool to refine their knowledge of gene function in C. elegans and to study the path of genome evolution

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

The finished sequence of human chromosome 20 comprises 59,187,298 base pairs (bp) and represents 99.4% of the euchromatic DNA. A single contig of 26 megabases (Mb) spans the entire short arm, and five contigs separated by gaps totalling 320 kb span the long arm of this metacentric chromosome. An additional 234,339 bp of sequence has been determined within the pericentromeric region of the long arm. We annotated 727 genes and 168 pseudogenes in the sequence. About 64% of these genes have a 5' and a 3' untranslated region and a complete open reading frame. Comparative analysis of the sequence of chromosome 20 to whole-genome shotgun-sequence data of two other vertebrates, the mouse Mus musculus and the puffer fish Tetraodon nigroviridis, provides an independent measure of the efficiency of gene annotation, and indicates that this analysis may account for more than 95% of all coding exons and almost all genes.

Craig Ahlstrom has never met Peter Magowan. But he wants his job.

We describe a map of 1.42 million single nucleotide polymorphisms (SNPs) distributed throughout the human genome, providing an average density on available sequence of one SNP every 1.9 kilobases. These SNPs were primarily discovered by two projects: The SNP Consortium and the analysis of clone overlaps by the International Human Genome Sequencing Consortium. The map integrates all publicly available SNPs with described genes and other genomic features. We estimate that 60,000 SNPs fall within exon (coding and untranslated regions), and 85% of exons are within 5 kb of the nearest SNP. Nucleotide diversity varies greatly across the genome, in a manner broadly consistent with a standard population genetic model of human history. This high-density SNP map provides a public resource for defining haplotype variation across the genome, and should help to identify biomedically important genes for diagnosis and therapy.

The optimum population of the world is the one that is most likely to make the option of a good quality of life available to everyone everywhere, both now and in the future. Establishing a consensus about the size of such a population would be an important step towards achieving it. Estimates of an optimum involve three main steps. First, estimate the maximum (carrying capacity) assuming a specified lifestyle. The main criteria are the maintenance of biodiversity, the availability of freshwater, and the availability of land--for agriculture, forestry and artificial systems but above all for the conversion of energy. (In applying the criteria, there are always two questions to ask: 'What is the maximum amount of consumption that the biosphere can stand?' and 'What is an adequate share of such consumption per person?') Second, convert the maximum (two to three billion) into an optimum by applying a far wider range of criteria, including personal liberty, mobility, recreation and political representation. Third, consider just two criteria (economies of scale and technological innovation) in order to ensure that the optimum (one to two billion) has not fallen below the minimum (half to one billion). The estimates are so low because of the need for a huge increase in median per capita consumption if everyone is to have the option of an adequate material standard of living. Opinion-formers are likely not to take much notice of such estimates, but it is probable that minds will be concentrated by an energy shock some time during the next decade. Achieving an optimum world population will not solve the world's major problems, but it would make them solvable.

(1999). David Pimentel on the ecology of increasing disease: Population growth and environmental degradation. Medicine, Conflict and Survival: Vol. 15, No. 3, pp. 291-294.

Citrobacter rodentium is a natural mouse pathogen that causes attaching and effacing (A/E) lesions. It shares a common virulence strategy with the clinically significant human A/E pathogens enteropathogenic E. coli (EPEC) and enterohaemorrhagic E. coli (EHEC) and is widely used to model this route of pathogenesis. We previously reported the complete genome sequence of C. rodentium ICC168, where we found that the genome displayed many characteristics of a newly evolved pathogen. In this study, through PFGE, sequencing of isolates showing variation, whole genome transcriptome analysis and examination of the mobile genetic elements, we found that, consistent with our previous hypothesis, the genome of C. rodentium is unstable as a result of repeat-mediated, large-scale genome recombination and because of active transposition of mobile genetic elements such as the prophages. We sequenced an additional C. rodentium strain, EX-33, to reveal that the reference strain ICC168 is representative of the species and that most of the inactivating mutations were common to both isolates and likely to have occurred early on in the evolution of this pathogen. We draw parallels with the evolution of other bacterial pathogens and conclude that C. rodentium is a recently evolved pathogen that may have emerged alongside the development of inbred mice as a model for human disease., Author Summary The pathogenic bacterium Citrobacter rodentium naturally infects mice using a mechanism similar to those employed by certain strains of E. coli that cause severe gastro-intestinal infections in humans. As such it is an important model organism for human disease research. We previously sequenced the genome of C. rodentium strain ICC168 and found that it had many features in common with other bacterial pathogens that have recently adapted to live in a new environment and colonise new hosts. In this study, we sequenced the genome of an additional strain of C. rodentium that was independently isolated on a different continent, and found that the two strains were remarkably similar. In addition, we investigated several C. rodentium isolates and showed that the genome is unstable, existing in multiple conformations within a single population due to genomic inversions, recombination between repetitive sequences, and horizontally acquired DNA that is mobile within the genome. We conclude that C. rodentium recently evolved to become a pathogen of mice, possibly concurrently with the development of mouse models for human diseases, and that it is still adapting to its new environment.

The mission? To sensibly go where many have gone before--into the realm of information technology, where applications often outnumber sound business reasons to use them. If you've never been, don't believe everything you hear. Mainframes may be useful after all, and even widespread technologies don't hold all the answers.

Background: The origins of the recombination hotspots that are a common feature of both allelic and non-allelic homologous recombination in the human genome are poorly understood. We have investigated, by comparative sequencing, the evolution of two hotspots of non-allelic homologous recombination on the Y chromosome that lie within paralogous sequences known to sponsor deletions resulting in male infertility. Results: These recombination hotspots are characterized by signatures of concerted evolution, which indicate that gene conversion between paralogs has been predominant in shaping their recent evolution. By contrast, the paralogous sequences that surround the hotspots exhibit little evidence of gene conversion. A second feature of these rearrangement hotspots is the extreme interspecific sequence divergence (around 2.5%) that places them among the most divergent orthologous sequences between humans and chimpanzees. Conclusions: Several hominid-specific gene conversion events have rendered these hotspots better substrates for chromosomal rearrangements in humans than in chimpanzees or gorillas. Monte Carlo simulations of sequence evolution suggest that extreme sequence divergence is a direct consequence of gene conversion between paralogs. We propose that the coincidence of signatures of concerted evolution and recurrent breakpoints of chromosomal rearrangement (mapped at the sequence level) may enable the identification of putative rearrangement hotspots from analysis of comparative sequences from great apes.

A combination of approaches was used to close 8 of the 11 gaps in the original sequence of human chromosome 22, and to generate a total 1.018 Mb of new sequence., Background Although the human genome sequence was declared complete in 2004, the sequence was interrupted by 341 gaps of which 308 lay in an estimated approximately 28 Mb of euchromatin. While these gaps constitute only approximately 1% of the sequence, knowledge of the full complement of human genes and regulatory elements is incomplete without their sequences. Results We have used a combination of conventional chromosome walking (aided by the availability of end sequences) in fosmid and bacterial artificial chromosome (BAC) libraries, whole chromosome shotgun sequencing, comparative genome analysis and long PCR to finish 8 of the 11 gaps in the initial chromosome 22 sequence. In addition, we have patched four regions of the initial sequence where the original clones were found to be deleted, or contained a deletion allele of a known gene, with a further 126 kb of new sequence. Over 1.018 Mb of new sequence has been generated to extend into and close the gaps, and we have annotated 16 new or extended gene structures and one pseudogene. Conclusion Thus, we have made significant progress to completing the sequence of the euchromatic regions of human chromosome 22 using a combination of detailed approaches. Our experience suggests that substantial work remains to close the outstanding gaps in the human genome sequence.