Stratified Whole Genome Linkage Analysis of Chiari Type I Malformation Implicates Known Klippel-Feil Syndrome Genes as Putative Disease Candidates

Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of “CTD-negative” families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3–5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.     

Feature-level exploration of a published Affymetrix GeneChip control dataset

A comment on Preferred analysis methods for Affymetrix GeneChips revealed by a wholly defined control dataset by SE Choe, M Boutros, AM Michelson, GM Church and MS Halfon. Genome Biology 2005, 6:R16.     

Competitive interactions between two successful molluscan invaders of freshwaters: an experimental study

The New Zealand mud snail Potamopyrgus antipodarum (Hydrobiidae) and the pulmonate Physella acuta (Physidae) have invaded freshwaters in many parts of the world and become established. They co-exist in many streams, lakes and ponds in New Zealand, often at high densities. In the present study the effects of intraspecific- and interspecific interactions between the two species on growth and reproductive output were examined in laboratory mesocosms. In 30-day experiments, growth of Potamopyrgus antipodarum was lower in high density treatments than controls providing evidence for competition at higher densities of both snail species. No competitive effect was obtained for Physella acuta when controls were compared with high-density treatments, but growth was reduced at high densities of conspecifics. Numbers of juveniles released by Potamopyrgus antipodarum in 40 day trials declined at high snail densities and were lowest at high densities of conspecifics. Egg production by Physella acuta was also reduced at high snail densities. However, when the two species were kept together at equal densities (total snail density twice that of controls), egg production by Physella acuta was significantly higher than in all other treatments, suggesting facilitation by the congenor. Lastly, in a 10-day experiment, Physella acuta grew faster in water conditioned by Potamopyrgus antipodarum than in Physa-conditioned water, whereas Potamopyrgus antipodarum showed no growth response to Physella-conditioned water. Overall, our results indicate that growth and reproductive output of both snail species are influenced more by the density of conspecifics than the presence and density of the other species. The successful co-existence of the two species in New Zealand freshwaters therefore may be a reflection, at least in part, of few competitive interactions between them.     

Urine dopamine in starving obese subjects

In seven obese female subjects undergoing a period of therapeutic starvation, the excretion of sodium, potassium and dopamine and plasma levels of renin and aldosterone were measured. Sodium excretion increased during starvation and was maximal on the 2nd day. The urinary excretion of dopamine was significantly higher on day 4 and it remained elevated till the end of the study. Plasma renin activity and plasma aldosterone levels were also higher on the 4th-6th days of starvation. These findings suggest that dopamine may not play a significant role in the natriuresis of starvation.     

Cooperative interactions in nerve membrane potential and in photosynthesis, evidenced by non-linear Arrhenius plots and critical exponents

The resting membrane potential of Aplysia nerve and the rate of photosynthesis by intact Chlorella cells have temperature dependences characterized by curved Arrhenius plots, for which the logarithm of the activation energy is a linear function of temperature. Ferromagnetic and ferroelectric systems show similar curves, which suggests that the above two biological systems are governed by cooperative interactions between adjacent molecular sites. Critical exponent analysis suggests the same conclusion.