Synaptonemal complex assembly in C. elegans is dispensable for loading strand-exchange proteins but critical for proper completion of recombination

Here we probe the relationships between assembly of the synaptonemal complex (SC) and progression of recombination between homologous chromosomes during Caenorhabditis elegans meiosis. We identify SYP-2 as a structural component of the SC central region and show that central region assembly depends on proper morphogenesis of chromosome axes. We find that the SC central region is dispensable for initiation of recombination and for loading of DNA strand-exchange protein RAD-51, despite the fact that extensive RAD-51 loading normally occurs in the context of assembled SC. Further, persistence of RAD-51 foci and absence of crossover products in meiotic mutants suggests that SC central region components and recombination proteins MSH-4 and MSH-5 are required to promote conversion of resected double-strand breaks into stable post-strand exchange intermediates. Our data also suggest that early prophase barriers to utilization of sister chromatids as repair templates do not depend on central region assembly.     

The Cdc14 phosphatase and the FEAR network control meiotic spindle disassembly and chromosome segregation

During meiosis, DNA replication is followed by two consecutive rounds of chromosome segregation. Cells lacking the protein phosphatase CDC14 or its regulators, SPO12 and SLK19, undergo only a single meiotic division, with some chromosomes segregating reductionally and others equationally. We find that this abnormal chromosome behavior is due to an uncoupling of meiotic events. Anaphase I spindle disassembly is delayed in cdc14-1, slk19Delta, or spo12Delta mutants, but the chromosome segregation cycle continues, so that both meiotic chromosome segregation phases take place on the persisting meiosis I spindle. Our results show that Cdc14, Slk19, and Spo12 are not only required for meiosis I spindle disassembly but also play a pivotal role in establishing two consecutive chromosome segregation phases, a key feature of the meiotic cell cycle.     

The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum

Myostatin, also known as growth and differentiation factor 8, is a member of the transforming growth factor beta superfamily that negatively regulates skeletal muscle mass (1). Recent experiments have shown that myostatin activity is detected in serum by a reporter gene assay only after activation by acid, suggesting that native myostatin circulates as a latent complex (2). We have used a monoclonal myostatin antibody, JA16, to isolate the native myostatin complex from normal mouse and human serum. Analysis by mass spectrometry and Western blot shows that circulating myostatin is bound to at least two major proteins, the myostatin propeptide and the follistatin-related gene (FLRG). The myostatin propeptide is known to bind and inhibit myostatin in vitro (3). Here we show that this interaction is relevant in vivo, with a majority (>70%) of myostatin in serum bound to its propeptide. Studies with recombinant V5-His-tagged FLRG protein confirm a direct interaction between mature myostatin and FLRG. Functional studies show that FLRG inhibits myostatin activity in a reporter gene assay. These experiments suggest that the myostatin propeptide and FLRG are major negative regulators of myostatin in vivo.     

Characterization of a low-sulfated chondroitin sulfate from the body of Viviparus ater (mollusca gastropoda). Modification of its structure by lead pollution

A chondroitin sulfate was purified from the body of Viviparus ater (Mollusca gastropoda) and analyzed for molecular mass, constituent disaccharides, and structure by 1H NMR and 1H 2D NMR. A quite unique glycosaminoglycan species was isolated having a high molecular mass (greater than 45,000) and low charge density, about 0.60, due to the presence of 42% non-sulfated disaccharide, 5% 6-sulfated disaccharide, 48% 4-sulfated disaccharide, and 5% 4,6-disulfated disaccharide. Specimens of Mollusca were also submitted to lead exposure for different times, and the effect on chondroitin sulfate structure was studied. After 96 h treatment a strong decrease in chondroitin sulfate content was observed with a significant modification of its structure producing a more desulfated polymer, in particular in position 4 of the galactosamine unit. Simultaneously, the amount of unsaturated non-sulfated disaccharide increased with an overall decrease of the charge density.     

Seasonal effects on some serum and muscle enzymes of catfish (Ictalurus melas) and common carp (Cyprinus carpio)1

Serum and muscle activities of enzymes (LDH, ALD, CK and ICDH) in intensively farmed catfish (Ictalurus melas) and common carp (Cyprinus carpio) were determined bimonthly between July 1 and November 2. Catfish serum enzymes showed no significant differences under different environmental conditions (exception = CK; values increased slighfly in the last sample). In carp serum, a remarkable increase of LDH and ALD occurred during the cold season. Muscle enzyme activity decreased in both species with decreasing water temperature and reduced metabolic activity.     

Widespread allele-specific topological domains in the human genome are not confined to imprinted gene clusters

Neural networks such as variational autoencoders (VAE) perform dimensionality reduction for the visualization and analysis of genomic data, but are limited in their interpretability: it is unknown which data features are represented by each embedding dimension. We present siVAE, a VAE that is interpretable by design, thereby enhancing downstream analysis tasks. Through interpretation, siVAE also identifies gene modules and hubs without explicit gene network inference. We use siVAE to identify gene modules whose connectivity is associated with diverse phenotypes such as iPSC neuronal differentiation efficiency and dementia, showcasing the wide applicability of interpretable generative models for genomic data analysis.

     

The Apolipoprotein E/CI/CII Gene Cluster and Late-Onset Alzheimer Disease

The chromosome 19 apolipoprotein E/CI/CII gene cluster was examined for evidence of linkage to a familial Alzheimer disease (FAD) locus. The family groups studied were Volga German (VG), early-onset non-VG (ENVG; mean age at onset <60 years), and late-onset families. A genetic association was observed between apolipoprotein E (ApoE) allele ε4 and FAD in late-onset families; the ε4 allele frequency was .51 in affected subjects, .37 in at-risk subjects, .11 in spouses, and .19 in unrelated controls. The differences between the ε4 frequencies in affected subjects versus controls and in at-risk subjects versus controls were highly significant (standard normal deviate [Z_SND]) = 7.37, P < 10⁻⁹; and Z_SND = 4.07, P < .00005, respectively). No association between the ε4 allele and FAD was observed in the ENVG or VG groups. A statistically significant allelic association between ε4 and AD was also observed in a group of unrelated subjects; the ε4 frequency was .26 in affected subjects, versus .19 in controls (Z_SND = 2.20, P < .03). Evidence of linkage of ApoE and ApoCII to FAD was examined by maximum-likelihood methods, using three models and assuming autosomal dominant inheritance: (1) age-dependent penetrance, (2) extremely low (1%) penetrance, and (3) age-dependent penetrance corrected for sporadic Alzheimer disease (AD). For ApoCII in late-onset families, results for close linkage were negative, and only small positive lod-score-statistic (Z) values were obtained (model 1, maximum Z [Z_max] = 0.61, recombination fraction [θ] = .30; model 2, Z_max = 0.47, θ = .20). For ApoE in late-onset kindreds, positive Z values were obtained when either allele frequencies from controls (model 1, Z_max = 2.02, θ = .15; model 2, Z_max = 3.42, θ = .05) or allele frequencies from the families (model 1, Z_max = 1.43, θ = .15; model 2, Z_max = 1.70, θ = .05) were used. When linkage disequilibrium was incorporated into the analysis, the Z values increased (model 1, Z_max = 3.17, θ = .23; model 3, Z_max = 1.85, θ = .20). For the ENVG group, results for ApoE and ApoCII were uniformly negative. Affected-pedigree-member analysis gave significant results for the late-onset kindreds, for ApoE (Z_SND = 3.003, P = .003) and ApoCII (Z_SND = 2.319, P = .016), when control allele frequencies were used but not when allele frequencies were derived from the families.     

Partial deficiency of red cell 6-phosphogluconate dehydrogenase: A family study

Summary A family with partial deficiency of erythrocytic 6PGD is described. Biochemical and electrophoretic analysis suggest that the partial deficiency is due to a silent PGD ⁰ allele.Chromosomal analysis and assay of closely linked markers do not reveal a grossly detectable deletion.Abbreviations used in this paper G6PD glucose-6-phosphate dehydrogenase - GSSGR glutathione reductase - PK pyruvate kinase - GSH glutathione - PGM phosphoglucomutase