The segregation of a translocation t(1;4) in two male carriers heterozygous for the translocation

Summary We examined the meiotic segregation pattern of a t(1;4)(p36.2;q31.3) reciprocal translocation in two male cousins heterozygous for the translocation. The wife of subject 1 had four recognized spontaneous abortions and two carrier daughters, and the wife of subject 2 had three recognized spontaneous abortions and no liveborn children. The results showed that subject 1 had an imbalance rate of 54% and subject 2 had an imbalance rate of 61% with respect to the translocation. This was not statistically different (P = 0.3174) and the 95% confidence intervals overlapped for each segregation type. The sex ratio of X- and Y-bearing sperm was not statistically different than the expected 50%. The rate of structural abnormalities was 11.3% in subject 1 and 17.8% in subject 2. Both of these values were above the range of control subjects in our lab, but only subject 2's value fell outside the 95% confidence interval for the control population.     

The ethics of risk displacement in research and public policy

We identify three distinct ethical problems that can arise with risk displacement. Risk displacement is the shifting of extant risk from one or more individuals to other individual(s) such that the reduction of risk to the first group is causally implicated in increasing risk to the second group. These problems are: concentration of risk in inequitable ways; transfer of risk to already vulnerable or disadvantaged populations; and exercise of undue influence over potential research participants. The first two arise in both public policy and research initiatives, whereas the third is a special concern that only applies to research initiatives. We argue that when one or more of these is of high magnitude, then the study or policy intervention may be ethically wrong. Finally, we conclude that although some risk displacement is ethically permissible, researchers and policymakers still have ethical reasons to reduce the magnitude of these problems.     

Cloned mouse ribonucleotide reductase subunit M1 cDNA reveals amino acid sequence homology with Escherichia coli and herpesvirus ribonucleotide reductases

We have isolated and sequenced overlapping cDNA clones containing the entire coding region of mouse ribonucleotide reductase subunit M1. The coding region comprises 2.4 kilobases and predicts a polypeptide of 792 amino acids (Mr 90,234) which shows striking homology with ribonucleotide reductases from Escherichia coli and the herpesviruses, Epstein-Barr virus and herpes simplex virus. The homologies reveal three domains: an N-terminal domain common to the mammalian and bacterial enzymes, a C-terminal domain common to the mammalian and viral ribonucleotide reductases, and a central domain common to all three. We speculate on the functional basis of this conservation.     

Tyrosine phosphorylation of myosin heavy chain during skeletal muscle differentiation: an integrated bioinformatics approach

Background  

Previously it has been shown that insulin-mediated tyrosine phosphorylation of myosin heavy chain is concomitant with enhanced association of C-terminal SRC kinase during skeletal muscle differentiation. We sought to identify putative site(s) for this phosphorylation event.     

Paralemmin-1, a modulator of filopodia induction is required for spine maturation

Dendritic filopodia are thought to participate in neuronal contact formation and development of dendritic spines; however, molecules that regulate filopodia extension and their maturation to spines remain largely unknown. Here we identify paralemmin-1 as a regulator of filopodia induction and spine maturation. Paralemmin-1 localizes to dendritic membranes, and its ability to induce filopodia and recruit synaptic elements to contact sites requires protein acylation. Effects of paralemmin-1 on synapse maturation are modulated by alternative splicing that regulates spine formation and recruitment of AMPA-type glutamate receptors. Paralemmin-1 enrichment at the plasma membrane is subject to rapid changes in neuronal excitability, and this process controls neuronal activity-driven effects on protrusion expansion. Knockdown of paralemmin-1 in developing neurons reduces the number of filopodia and spines formed and diminishes the effects of Shank1b on the transformation of existing filopodia into spines. Our study identifies a key role for paralemmin-1 in spine maturation through modulation of filopodia induction.     

Nr-CAM and neurofascin interactions regulate ankyrin G and sodium channel clustering at the node of Ranvier.

Voltage-dependent sodium (Na(+)) channels are highly concentrated at nodes of Ranvier in myelinated axons and play a key role in promoting rapid and efficient conduction of action potentials by saltatory conduction. The molecular mechanisms that direct their localization to the node are not well understood but are believed to involve contact-dependent signals from myelinating Schwann cells and interactions of Na(+) channels with the cytoskeletal protein, ankyrin G. Two cell adhesion molecules (CAMs) expressed at the axon surface, Nr-CAM and neurofascin, are also linked to ankyrin G and accumulate at early stages of node formation, suggesting that they mediate contact-dependent Schwann cell signals to initiate node development. To examine the potential role of Nr-CAM in this process, we treated myelinating cocultures of DRG (dorsal root ganglion) neurons and Schwann cells with an Nr-CAM-Fc (Nr-Fc) fusion protein. Nr-Fc had no effect on initial axon-Schwann cell interactions, including Schwann cell proliferation, or on the extent of myelination, but it strikingly and specifically inhibited Na(+) channel and ankyrin G accumulation at the node. Nr-Fc bound directly to neurons and clustered and coprecipitated neurofascin expressed on axons. These results provide the first evidence that neurofascin plays a major role in the formation of nodes, possibly via interactions with Nr-CAM.     

Genome scan meta-analysis of schizophrenia and bipolar disorder,part I: Methods and power analysis

This is the first of three articles on a meta-analysis of genome scans of schizophrenia (SCZ) and bipolar disorder (BPD) that uses the rank-based genome scan meta-analysis (GSMA) method. Here we used simulation to determine the power of GSMA to detect linkage and to identify thresholds of significance. We simulated replicates resembling the SCZ data set (20 scans; 1,208 pedigrees) and two BPD data sets using very narrow (9 scans; 347 pedigrees) and narrow (14 scans; 512 pedigrees) diagnoses. Samples were approximated by sets of affected sibling pairs with incomplete parental data. Genotypes were simulated and nonparametric linkage (NPL) scores computed for 20 180-cM chromosomes, each containing six 30-cM bins, with three markers/bin (or two, for some scans). Genomes contained 0, 1, 5, or 10 linked loci, and we assumed relative risk to siblings (lambda(sibs)) values of 1.15, 1.2, 1.3, or 1.4. For each replicate, bins were ranked within-study by maximum NPL scores, and the ranks were averaged (R(avg)) across scans. Analyses were repeated with weighted ranks ((sqrt)N[genotyped cases] for each scan). Two P values were determined for each R(avg): P(AvgRnk) (the pointwise probability) and P(ord) (the probability, given the bin's place in the order of average ranks). GSMA detected linkage with power comparable to or greater than the underlying NPL scores. Weighting for sample size increased power. When no genomewide significant P values were observed, the presence of linkage could be inferred from the number of bins with nominally significant P(AvgRnk), P(ord), or (most powerfully) both. The results suggest that GSMA can detect linkage across multiple genome scans.     

Oligodendrocytes assist in the maintenance of sodium channel clusters independent of the myelin sheath

To ensure rapid and efficient impulse conduction, myelinated axons establish and maintain specific protein domains. For instance, sodium (Na+) channels accumulate in the node of Ranvier; potassium (K+) channels aggregate in the juxtaparanode and neurexin/caspr/paranodin clusters in the paranode. Our understanding of the mechanisms that control the initial clustering of these proteins is limited and less is known about domain maintenance. Correlative data indicate that myelin formation and/or mature myelin-forming cells mediate formation of all three domains. Here, we test whether myelin is required for maintaining Na+ channel domains in the nodal gap by employing two demyelinating murine models: (1) cuprizone ingestion, which induces complete demyelination through oligodendrocyte toxicity; and (2) ceramide galactosyltransferase deficient mice, which undergo spontaneous adult-onset demyelination without oligodendrocyte death. Our data indicate that the myelin sheath is essential for long-term maintenance of sodium channel domains; however, oligodendrocytes, independent of myelin, provide a partial protective influence on the maintenance of nodal Na+ channel clusters. Thus, we propose that multiple mechanisms regulate the maintenance of nodal protein organization. Finally, we present evidence that following the loss of Na+ channel clusters the chronological progression of expression and reclustering of Na+ channel isoforms during the course of CNS remyelination recapitulates development.     

A genetic linkage map of the vervet monkey (Chlorocebus aethiops sabaeus)

The spectacular progress in genomics increasingly highlights the importance of comparative biology in biomedical research. In particular, nonhuman primates, as model systems, provide a crucial intermediate between humans and mice. The close similarities between humans and other primates are stimulating primate studies in virtually every area of biomedical research, including development, anatomy, physiology, immunology, and behavior. The vervet monkey (Chlorocebus aethiops sabaeus) is an important model for studying human diseases and complex traits, especially behavior. We have developed a vervet genetic linkage map to enable mapping complex traits in this model organism and facilitate comparative genomic analysis between vervet and other primates. Here we report construction of an initial genetic map built with about 360 human orthologous short tandem repeats (STRs) that were genotyped in 434 members of an extended vervet pedigree. The map includes 226 markers mapped in a unique order with a resolution of 9.8 Kosambi centimorgans (cM) in the vervet monkey genome, and with a total length (including all 360 markers) of 2726 cM. At least one complex and 11 simple rearrangements in marker order distinguish vervet chromosomes from human homologs. While inversions and insertions can explain a similar number of changes in marker order between vervet and rhesus homologs, mostly inversions are observed when vervet chromosome organization is compared to that in human and chimpanzee. Our results support the notion that large inversions played a less prominent role in the evolution within the group of the Old World monkeys compared to the human and chimpanzee lineages. Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users.     

The effect of linkage disequilibrium on linkage analysis of incomplete pedigrees

Dense SNP maps can be highly informative for linkage studies. But when parental genotypes are missing, multipoint linkage scores can be inflated in regions with substantial marker-marker linkage disequilibrium (LD). Such regions were observed in the Affymetrix SNP genotypes for the Genetic Analysis Workshop 14 (GAW14) Collaborative Study on the Genetics of Alcoholism (COGA) dataset, providing an opportunity to test a novel simulation strategy for studying this problem. First, an inheritance vector (with or without linkage present) is simulated for each replicate, i.e., locations of recombinations and transmission of parental chromosomes are determined for each meiosis. Then, two sets of founder haplotypes are superimposed onto the inheritance vector: one set that is inferred from the actual data and which contains the pattern of LD; and one set created by randomly selecting parental alleles based on the known allele frequencies, with no correlation (LD) between markers. Applying this strategy to a map of 176 SNPs (66 Mb of chromosome 7) for 100 replicates of 116 sibling pairs, significant inflation of multipoint linkage scores was observed in regions of high LD when parental genotypes were set to missing, with no linkage present. Similar inflation was observed in analyses of the COGA data for these affected sib pairs with parental genotypes set to missing, but not after reducing the marker map until r2 between any pair of markers was 相似文献