A Devonian tetrapod-like fish and the evolution of the tetrapod body plan

The relationship of limbed vertebrates (tetrapods) to lobe-finned fish (sarcopterygians) is well established, but the origin of major tetrapod features has remained obscure for lack of fossils that document the sequence of evolutionary changes. Here we report the discovery of a well-preserved species of fossil sarcopterygian fish from the Late Devonian of Arctic Canada that represents an intermediate between fish with fins and tetrapods with limbs, and provides unique insights into how and in what order important tetrapod characters arose. Although the body scales, fin rays, lower jaw and palate are comparable to those in more primitive sarcopterygians, the new species also has a shortened skull roof, a modified ear region, a mobile neck, a functional wrist joint, and other features that presage tetrapod conditions. The morphological features and geological setting of this new animal are suggestive of life in shallow-water, marginal and subaerial habitats.     

Palaeoceanography: methane release in the Early Jurassic period

Dramatic global warming, triggered by release of methane from clathrates, has been postulated to have occurred during the early Toarcian age in the Early Jurassic period. Kemp et al. claim that this methane was released at three points, as recorded by three sharp excursions of delta13C(org) of up to 3 per thousand magnitude. But they discount another explanation for the excursions: namely that some, perhaps all, of the rapid excursions could be a local signature of a euxinic basin caused by recycling of isotopically light carbon from the lower water column. This idea has been proposed previously (see ref. 3, for example) and is supported by the lack evidence for negative delta13C excursions in coeval belemnite rostra. Kemp et al. dismiss this alternative, claiming that each abrupt shift would have required the recycling of about double the amount of organic carbon that is currently present in the modern ocean; however, their measurements are not from an ocean but from a restricted, epicontinental seaway and so would not require whole-ocean mixing to achieve the excursions.     

Sexual reproduction selects for robustness and negative epistasis in artificial gene networks

The mutational deterministic hypothesis for the origin and maintenance of sexual reproduction posits that sex enhances the ability of natural selection to purge deleterious mutations after recombination brings them together into single genomes. This explanation requires negative epistasis, a type of genetic interaction where mutations are more harmful in combination than expected from their separate effects. The conceptual appeal of the mutational deterministic hypothesis has been offset by our inability to identify the mechanistic and evolutionary bases of negative epistasis. Here we show that negative epistasis can evolve as a consequence of sexual reproduction itself. Using an artificial gene network model, we find that recombination between gene networks imposes selection for genetic robustness, and that negative epistasis evolves as a by-product of this selection. Our results suggest that sexual reproduction selects for conditions that favour its own maintenance, a case of evolution forging its own path.     

Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53

Aurora kinase A (also called STK15 and BTAK) is overexpressed in many human cancers. Ectopic overexpression of aurora kinase A in mammalian cells induces centrosome amplification, chromosome instability and oncogenic transformation, a phenotype characteristic of loss-of-function mutations of p53. Here we show that aurora kinase A phosphorylates p53 at Ser315, leading to its ubiquitination by Mdm2 and proteolysis. p53 is not degraded in the presence of inactive aurora kinase A or ubiquitination-defective Mdm2. Destabilization of p53 by aurora kinase A is abrogated in the presence of mutant Mdm2 that is unable to bind p53 and after repression of Mdm2 by RNA interference. Silencing of aurora kinase A results in less phosphorylation of p53 at Ser315, greater stability of p53 and cell-cycle arrest at G2-M. Cells depleted of aurora kinase A are more sensitive to cisplatin-induced apoptosis, and elevated expression of aurora kinase A abolishes this response. In a sample of bladder tumors with wild-type p53, elevated expression of aurora kinase A was correlated with low p53 concentration. We conclude that aurora kinase A is a key regulatory component of the p53 pathway and that overexpression of aurora kinase A leads to increased degradation of p53, causing downregulation of checkpoint-response pathways and facilitating oncogenic transformation of cells.     

Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation

Dandy-Walker malformation (DWM; OMIM #220200) is a common but poorly understood congenital cerebellar malformation in humans. Through physical mapping of 3q2 interstitial deletions in several individuals with DWM, we defined the first critical region associated with DWM, encompassing two adjacent Zinc finger in cerebellum genes, ZIC1 and ZIC4. Mice with a heterozygous deletion of these two linked genes have a phenotype that closely resembles DWM, providing a mouse model for this malformation.     

Assessing the impact of population stratification on genetic association studies

Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and case-cohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies.     

The knockout mouse project

Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.     

Mutations in a new member of the chromodomain gene family cause CHARGE syndrome

CHARGE syndrome is a common cause of congenital anomalies affecting several tissues in a nonrandom fashion. We report a 2.3-Mb de novo overlapping microdeletion on chromosome 8q12 identified by array comparative genomic hybridization in two individuals with CHARGE syndrome. Sequence analysis of genes located in this region detected mutations in the gene CHD7 in 10 of 17 individuals with CHARGE syndrome without microdeletions, accounting for the disease in most affected individuals.