Hot off the presses! Nov 01 Nat Rev Genet

The Nov 01 issue of the Nat Rev Genet is now up on Pubget (About Nat Rev Genet): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

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  - Nat Rev Genet 11(11):741 (2010)
  
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  - Nat Rev Genet 11(11):743 (2010)
  
• Chromatin: Colour-coded classification | PDF (208 KB)
  - Nat Rev Genet 11(11):745 (2010)
  The traditional classification of chromatin into transcriptionally active euchromatin and repressed heterochromatin has been a useful model but is due for an upgrade to accommodate our increasing knowledge of chromatin functional domains. A massive integrative genome-wide analysis of 53 chromatin-associated proteins in Drosophila melanogaster has revealed that chromatin comes in five principal types; these could form a new framework for describing the epigenome.
• Evolution: Drosophila don't make a clean sweep | PDF (250 KB)
  - Nat Rev Genet 11(11):746 (2010)
  Experimental evolution has been informative for understanding the genomic basis of adaptation but has largely focused on asexual systems, such as bacteria and yeast. A recent study describes whole-genome resequencing data from Drosophila melanogaster populations after long-term selection in the laboratory.
• Complex disease: Epigenomics gets personal | PDF (156 KB)
  - Nat Rev Genet 11(11):746 (2010)
  Despite much recent success in identifying variants that are associated with complex diseases, our ability to predict disease risk from genetic information remains limited in most cases. A recent study suggests a new approach to this problem: it shows that we may each have 'personalized' epigenomic signatures that provide information about our risk of disease.
• Stem cells | DNA methylation | Cancer genetics | Evo–devo | PDF (153 KB)
  - Nat Rev Genet 11(11):746 (2010)
  Stem cells Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA Warren, L. et al. Cell Stem Cell 30 Sep 2010 (doi:10.1016/j.
• Statistical genetics: Pleiotropy revisited | PDF (197 KB)
  - Nat Rev Genet 11(11):747 (2010)
  Pleiotropy has a fundamental function in biology, and several theoretical models have been developed to explain its role in organismal complexity and evolution. Like many theories, this one has now been put under empirical scrutiny thanks to large-scale data sets.
• Complex traits: Using genetic architecture to improve predictions | PDF (229 KB)
  - Nat Rev Genet 11(11):748 (2010)
  The future phenotypes of organisms can be predicted using SNP genotypes, and this information has applications in fields such as medicine, forensics and agriculture. The accuracy of genomic predictions depends on various factors, including the genetic architecture of the trait, particularly the number of loci that affect the trait and the distribution of their effects.
• Speciation | Post-transcriptional regulation | Genome instability | Chromatin | PDF (153 KB)
  - Nat Rev Genet 11(11):748 (2010)
  Speciation A test of the snowball theory for the rate of evolution of hybrid incompatibilities Matute, D. R., Butler, I. A., Turissini, D. A. & Coyne, J. A. Science 329, 1518â€"1521 (2010) Hybrid incompatibility “snowballs” between Solanum species Moyle, L. C. & Nakazato, T. Science 329, 1521â€"1523 (2010) Two studies have confirmed the theory that the number of genes involved in postzygotic isolation accumulate faster than at a linear rate in the time after parent species separate. This 'snowball effect' has now been detected by quantitative trait locus studies of sterility in hybrid seeds of Solanum species and by deficiency mapping in two pairs of Drosophila species.
• Gene expression: Genomic space-savers | PDF (156 KB)
  - Nat Rev Genet 11(11):749 (2010)
  Genomes use several strategies to maximize the packaging of genetic information, perhaps the best known being the use of overlapping ORFs. A systematic study of the nature and extent of information packaging devices shows that they are found extensively in genomes as diverse as viruses and plants.
• Epigenetics: Demethylation links cell fate and cancer | PDF (233 KB)
  - Nat Rev Genet 11(11):749 (2010)
  Genome-wide loss of DNA methylation is characteristic of many cancers; however, mutations in DNA methyltransferases (DNMTs) have not been linked with human tumours, so it has been unclear how this hypomethylation arises. New insights have been provided by a study in zebrafish showing that a tumour suppressor acts through a demethylase system to regulate cell fate decisions, and that loss of the normal control of demethylation contributes to tumorigenesis.
• Determining the specificity of protein–DNA interactions
  - Nat Rev Genet 11(11):751 (2010)
  Proteins, such as many transcription factors, that bind to specific DNA sequences are essential for the proper regulation of gene expression. Identifying the specific sequences that each factor binds can help to elucidate regulatory networks within cells and how genetic variation can cause disruption of normal gene expression, which is often associated with disease. Traditional methods for determining the specificity of DNA-binding proteins are slow and laborious, but several new high-throughput methods can provide comprehensive binding information much more rapidly. Combined with in vivo determinations of transcription factor binding locations, this information provides more detailed views of the regulatory circuitry of cells and the effects of variation on gene expression.
• The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation
  - Nat Rev Genet 11(11):761 (2010)
  The Mediator is an evolutionarily conserved, multiprotein complex that is a key regulator of protein-coding genes. In metazoan cells, multiple pathways that are responsible for homeostasis, cell growth and differentiation converge on the Mediator through transcriptional activators and repressors that target one or more of the almost 30 subunits of this complex. Besides interacting directly with RNA polymerase II, Mediator has multiple functions and can interact with and coordinate the action of numerous other co-activators and co-repressors, including those acting at the level of chromatin. These interactions ultimately allow the Mediator to deliver outputs that range from maximal activation of genes to modulation of basal transcription to long-term epigenetic silencing.
• Statistical analysis strategies for association studies involving rare variants
  - Nat Rev Genet 11(11):773 (2010)
  The limitations of genome-wide association (GWA) studies that focus on the phenotypic influence of common genetic variants have motivated human geneticists to consider the contribution of rare variants to phenotypic expression. The increasing availability of high-throughput sequencing technologies has enabled studies of rare variants but these methods will not be sufficient for their success as appropriate analytical methods are also needed. We consider data analysis approaches to testing associations between a phenotype and collections of rare variants in a defined genomic region or set of regions. Ultimately, although a wide variety of analytical approaches exist, more work is needed to refine them and determine their properties and power in different contexts.
• Mechanisms of trinucleotide repeat instability during human development
  - Nat Rev Genet 11(11):786 (2010)
  Trinucleotide expansion underlies several human diseases. Expansion occurs during multiple stages of human development in different cell types, and is sensitive to the gender of the parent who transmits the repeats. Repair and replication models for expansions have been described, but we do not know whether the pathway involved is the same under all conditions and for all repeat tract lengths, which differ among diseases. Currently, researchers rely on bacteria, yeast and mice to study expansion, but these models differ substantially from humans. We need now to connect the dots among human genetics, pathway biochemistry and the appropriate model systems to understand the mechanism of expansion as it occurs in human disease.
• Reconciling the analysis of IBD and IBS in complex trait studies
  - Nat Rev Genet 11(11):800 (2010)
  Identity by descent (IBD) is a fundamental concept in genetics and refers to alleles that are descended from a common ancestor in a base population. Identity by state (IBS) simply refers to alleles that are the same, irrespective of whether they are inherited from a recent ancestor. In modern applications, IBD relationships are estimated from genetic markers in individuals without any known relationship. This can lead to erroneous inference because a consistent base population is not used. We argue that the purpose of most IBD calculations is to predict IBS at unobserved loci. Recognizing this aim leads to better methods to estimating IBD with benefits in mapping genes, estimating genetic variance and predicting inbreeding depression.
• Stress and the epigenetic landscape: a link to the pathobiology of human diseases?
  - Nat Rev Genet 11(11):806 (2010)
  Accumulating evidence points to a major role for chronic stress of cell renewal systems in the pathogenesis of important human diseases, including cancer, atherosclerosis and diabetes. Here we discuss emerging evidence that epigenetic abnormalities may make substantial contributions to these stress-induced pathologies. Although the mechanisms remain to be fully elucidated, we suggest that chronic stress can elicit heritable changes in the chromatin landscape that 'lock' cells in abnormal states, which then lead to disease. We emphasize the need to investigate epigenetic states in disease and links to stress and to consider how the knowledge gained through these studies may foster new means of disease prevention and management.
• Correspondence: Missing heritability and stochastic genome alterations
  - Nat Rev Genet 11(11):812 (2010)
  A recent Viewpoint article (Eichler, E. E. et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nature Rev.