Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution, and the need for population specific genotyping arrays and haplotype reference panels. Here we combine low coverage sequencing (0.15X) with a novel method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at 5% false discovery rate. Gene-level mapping resolution was achieved at about a fifth of loci, implicating Unc13c and Pgc1-alpha at loci for the quality of sleep, Adarb2 for home cage activity, Rtkn2 for intensity of reaction to startle, Bmp2 for wound healing, Il15 and Id2 for several T-cell measures and Prkca for bone mineral content. These findings have implications for diverse areas of mammalian biology and demonstrate how GWAS can be extended via low-coverage sequencing to species with highly recombinant outbred populations.

Objective. Few methods exist to measure the progression of osteoarthritis (OA) or to identify people at high risk of developing OA. Striking radiographic changes include deformation of the femoral head and osteophyte growth, which are usually measured semiquantitatively following visual assessment. In this study, an active shape model (ASM) of the proximal femur was used to determine whether morphologic changes to the bone could be quantified and used as a marker of hip OA.Methods. One hundred ten subjects who had no signs of radiographic hip OA at baseline (Kellgren/ Lawrence [K/L] scores 0-1) were selected from the Rotterdam Study cohort of subjects ages >55 years. To measure the progression of OA, subjects were followed up with radiographic assessment after 6 years. At the 6-year followup, 55 subjects had established OA (K/L score 3), and in 12 of these OA subjects, the progression of the disease required a total hip replacement (THR). Age-and sex-matched control subjects had a K/L score of 0 at followup. Using the ASM, subjects were assessed for shape changes in the femoral head and neck before, during, and after the development of radiographic OA.Scores of shape variance, or mode scores, were assigned for 10 modes of variation in each subject, and differences in mode scores were determined.Results. During followup, significant changes in shape of the proximal femur occurred within the OA group from baseline to followup (P < 0.0001 for mode 1 and P ‫؍‬ 0.002 for mode 6) but not within the control group. At baseline (all subjects having K/L scores 0-1), there were significant differences in mode 6 between the OA group and the control group (P ‫؍‬ 0.020), and in modes 3 and 6 between the OA subjects who underwent THR and the remaining OA subjects (P ‫؍‬ 0.012 and P ‫؍‬ 0.019, respectively).Conclusion. Compared with traditional scoring methods, the ASM can be used more precisely to quantify the deforming effect of OA on the proximal femur and to identify, at an earlier stage of disease, those subjects at highest risk of developing radiographic OA or needing a THR. The ASM may therefore be useful as an imaging biomarker in the assessment of patients with hip OA.Osteoarthritis (OA) is one of the most common disorders in the elderly. It is estimated that by age 75 years, 85% of individuals show either clinical or radiologic evidence of OA (1). As OA of the hip progresses, changes in the shape of the femoral head develop, with flattened and irregular features becoming apparent. These changes can be observed on standard radiographs but are hard to quantify. The severity of OA is generally assessed using semiquantitative methods based on visual evaluation of a radiograph; for example, the Kellgren/ Lawrence (K/L) scoring method (2) is used to assess a Supported by the Dutch Arthritis Association.

Abstract. We discovered by using high resolution video microscopy, that membranes become attached selectively to the growing plus ends of microtubules by membrane/microtubule tip attachment complexes (TACs) in interphase-arrested, undiluted, Xenopus egg extracts. Persistent plus end growth of stationary microtubules pushed the membranes into thin tubules and dragged them through the cytoplasm at the ~20 p,m/ min velocity typical of free plus ends. Membrane tubules also remained attached to plus ends when they switched to the shortening phase of dynamic instability at velocities typical of free ends, 50-60 ixm/min. Over time, the membrane tubules contacted and fused with one another along their lengths, forming a polygonal network much like the distribution of ER in cells. Several components of the membrane networks formed by TACs were identified as ER by immunofluorescent staining using antibodies to ER-resident proteins. TAC motility was not inhibited by known inhibitors of microtubule motor activity, including 5 mM AMP-PNP, 250 IxM orthovanadate, and ATP depletion. These results show that membrane/microtubule TACs enable polymerizing ends to push and depolymerizing ends to pull membranes into thin tubular extensions and networks at fast velocities.

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The shape of the lumbar spine in the sagittal plane varies between individuals and as a result of postural changes but it is not known how the shape in different postures is related. Sagittal images of the lumbar spines of 24 male volunteers were acquired using a positional magnetic resonance scanner. The subjects were imaged lying supine, standing and sitting. An active shape model was used to characterize shape in terms of independent modes of variation. Two modes were identified that described the total (mode 1) and distribution (mode 2) of the curvature. The spinal shape was found to be intercorrelated between the three postures for both modes, suggesting that the lumbar spine has an element of shape that is partially maintained despite postural alterations. Mode 1 values indicated that the spine was straightest when standing and curviest when sitting. Mode 2 values indicated that the distribution in the curvature was most even when sitting and least even when lying supine. Systematic differences in the behaviour of the spine, when changing posture, were found that suggest that the shape of the spine may affect its biomechanics.