Diffusion and distal linkages govern interchromosomal dynamics during meiotic prophase.

SignificanceEssential for sexual reproduction, meiosis is a specialized cell division required for the production of haploid gametes. Critical to this process are the pairing, recombination, and segregation of homologous chromosomes (homologs). While pairing and recombination are linked, it is not known how many linkages are sufficient to hold homologs in proximity. Here, we reveal that random diffusion and the placement of a small number of linkages are sufficient to establish the apparent "pairing" of homologs. We also show that colocalization between any two loci is more dynamic than anticipated. Our study provides observations of live interchromosomal dynamics during meiosis and illustrates the power of combining single-cell measurements with theoretical polymer modeling.

Rad21l1 cohesin subunit is dispensable for spermatogenesis but not oogenesis in zebrafish.

During meiosis I, ring-shaped cohesin complexes play important roles in aiding the proper segregation of homologous chromosomes. RAD21L is a meiosis-specific vertebrate cohesin that is required for spermatogenesis in mice but is dispensable for oogenesis in young animals. The role of this cohesin in other vertebrate models has not been explored. Here, we tested if the zebrafish homolog Rad21l1 is required for meiotic chromosome dynamics during spermatogenesis and oogenesis. We found that Rad21l1 localizes to unsynapsed chromosome axes. It is also found between the axes of the mature tripartite synaptonemal complex (SC) in both sexes. We knocked out rad21l1 and found that nearly all rad21l1-/- mutants develop as fertile males, suggesting that the mutation causes a defect in juvenile oogenesis, since insufficient oocyte production triggers female to male sex reversal in zebrafish. Sex reversal was partially suppressed by mutation of the checkpoint gene tp53, suggesting that the rad21l1 mutation activates Tp53-mediated apoptosis or arrest in females. This response, however, is not linked to a defect in repairing Spo11-induced double-strand breaks since deletion of spo11 does not suppress the sex reversal phenotype. Compared to tp53 single mutant controls, rad21l1-/- tp53-/- double mutant females produce poor quality eggs that often die or develop into malformed embryos. Overall, these results indicate that the absence of rad21l1-/- females is due to a checkpoint-mediated response and highlight a role for a meiotic-specific cohesin subunit in oogenesis but not spermatogenesis.

Ligand additivity relationships enable efficient exploration of transition metal chemical space.

To accelerate the exploration of chemical space, it is necessary to identify the compounds that will provide the most additional information or value. A large-scale analysis of mononuclear octahedral transition metal complexes deposited in an experimental database confirms an under-representation of lower-symmetry complexes. From a set of around 1000 previously studied Fe(II) complexes, we show that the theoretical space of synthetically accessible complexes formed from the relatively small number of unique ligands is significantly (∼816k) larger. For the properties of these complexes, we validate the concept of ligand additivity by inferring heteroleptic properties from a stoichiometric combination of homoleptic complexes. An improved interpolation scheme that incorporates information about cis and trans isomer effects predicts the adiabatic spin-splitting energy to around 2 kcal/mol and the HOMO level to less than 0.2 eV. We demonstrate a multi-stage strategy to discover leads from the 816k Fe(II) complexes within a targeted property region. We carry out a coarse interpolation from homoleptic complexes that we refine over a subspace of ligands based on the likelihood of generating complexes with targeted properties. We validate our approach on nine new binary and ternary complexes predicted to be in a targeted zone of discovery, suggesting opportunities for efficient transition metal complex discovery.

Mechanistic Insights into Co and Fe Quaterpyridine-Based CO2 Reduction Catalysts: Metal-Ligand Orbital Interaction as the Key Driving Force for Distinct Pathways.

Both [CoII(qpy)(H2O)2]2+ and [FeII(qpy)(H2O)2]2+ (with qpy = 2,2':6',2″:6'',2‴-quaterpyridine) are efficient homogeneous electrocatalysts and photoelectrocatalysts for the reduction of CO2 to CO. The Co catalyst is more efficient in the electrochemical reduction, while the Fe catalyst is an excellent photoelectrocatalyst ( ACS Catal. 2018, 8, 3411-3417). This work uses density functional theory to shed light on the contrasting catalytic pathways. While both catalysts experience primarily ligand-based reductions, the second reduction in the Co catalyst is delocalized onto the metal via a metal-ligand bonding interaction, causing a spin transition and a distorted ligand framework. This orbital interaction explains the experimentally observed mild reduction potential and slow kinetics of the second reduction. The decreased hardness and doubly occupied dz2-orbital facilitate a σ-bond with the CO2-π* in an η1-κC binding mode. CO2 binding is only possible after two reductions resulting in an EEC mechanism (E = electron transfer, C = chemical reaction), and the second protonation is rate-limiting. In contrast, the Fe catalyst maintains a Lewis acidic metal center throughout the reduction process because the metal orbitals do not strongly mix with the qpy-π* orbitals. This allows binding of the activated CO2 in an η2-binding mode. This interaction stabilizes the activated CO2 via a π-type interaction of a Fe-t2g orbital and the CO2-π* and a dative bond of the oxygen lone pair. This facilitates CO2 binding to a singly reduced catalyst resulting in an ECE mechanism. The barrier for CO2 addition and the second protonation are higher than those for the Co catalyst and rate-limiting.

Large-scale comparison of 3d and 4d transition metal complexes illuminates the reduced effect of exchange on second-row spin-state energetics.

Density functional theory (DFT) is widely used in transition-metal chemistry, yet essential properties such as spin-state energetics in transition-metal complexes (TMCs) are well known to be sensitive to the choice of the exchange-correlation functional. Increasing the amount of exchange in a functional typically shifts the preferred ground state in first-row TMCs from low-spin to high-spin by penalizing delocalization error, but the effect on properties of second-row complexes is less well known. We compare the exchange sensitivity of adiabatic spin-splitting energies in pairs of mononuclear 3d and 4d mid-row octahedral transition-metal complexes. We analyze hundreds of complexes assembled from four metals in two oxidation states with ten small monodentate ligands that span a wide range of field strengths expected to favor a variety of ground states. We observe consistently lower but proportional sensitivity to exchange fraction among 4d TMCs with respect to their isovalent 3d TMC counterparts, leading to the largest difference in sensitivities for the strongest field ligands. The combined effect of reduced exchange sensitivities and the greater low-spin bias of most 4d TMCs means that while over one-third of 3d TMCs change ground states over a modest variation (ca. 0.0-0.3) in exchange fraction, almost no 4d TMCs do. Differences in delocalization, as judged through changes in the metal-ligand bond lengths between spin states, do not explain the distinct behavior of 4d TMCs. Instead, evaluation of potential energy curves in 3d and 4d TMCs reveals that higher exchange sensitivities in 3d TMCs are likely due to the opposing effect of exchange on the low-spin and high-spin states, whereas the effect on both spin states is more comparable in 4d TMCs.

Nucleation and Growth Kinetics from LaMer Burst Data.

In LaMer burst nucleation, the individual nucleation events happen en masse, quasi-simultaneously, and at nearly identical homogeneous conditions. These properties make LaMer burst nucleation important for applications that require monodispersed particles and also for theoretical analyses. Sugimoto and co-workers predicted that the number of nuclei generated during a LaMer burst depends only on the solute supply rate and the growth rate, independent of the nucleation kinetics. Some experiments confirm that solute supply kinetics control the number of nuclei, but flaws in the original theoretical analysis raise questions about the predicted roles of growth and nucleation kinetics. We provide a rigorous analysis of the coupled equations that govern concentrations of nuclei and solutes. Our analysis confirms that the number of nuclei is largely determined by the solute supply and growth rates, but our predicted relationship differs from that of Sugimoto et al. Moreover, we find that additional nucleus size dependent corrections should emerge in systems with slow growth kinetics. Finally, we show how the nucleation kinetics determine the particle size distribution. We suggest that measured particle size distributions might therefore provide ways to test theoretical models of homogeneous nucleation kinetics.

Detection of multi-reference character imbalances enables a transfer learning approach for virtual high throughput screening with coupled cluster accuracy at DFT cost.

Appropriately identifying and treating molecules and materials with significant multi-reference (MR) character is crucial for achieving high data fidelity in virtual high-throughput screening (VHTS). Despite development of numerous MR diagnostics, the extent to which a single value of such a diagnostic indicates the MR effect on a chemical property prediction is not well established. We evaluate MR diagnostics for over 10 000 transition-metal complexes (TMCs) and compare to those for organic molecules. We observe that only some MR diagnostics are transferable from one chemical space to another. By studying the influence of MR character on chemical properties (i.e., MR effect) that involve multiple potential energy surfaces (i.e., adiabatic spin splitting, ΔE H-L, and ionization potential, IP), we show that differences in MR character are more important than the cumulative degree of MR character in predicting the magnitude of an MR effect. Motivated by this observation, we build transfer learning models to predict CCSD(T)-level adiabatic ΔE H-L and IP from lower levels of theory. By combining these models with uncertainty quantification and multi-level modeling, we introduce a multi-pronged strategy that accelerates data acquisition by at least a factor of three while achieving coupled cluster accuracy (i.e., to within 1 kcal mol-1 MAE) for robust VHTS.

The Nucleoporin Nup2 Contains a Meiotic-Autonomous Region that Promotes the Dynamic Chromosome Events of Meiosis.

Meiosis is a specialized cellular program required to create haploid gametes from diploid parent cells. Homologous chromosomes pair, synapse, and recombine in a dynamic environment that accommodates gross chromosome reorganization and significant chromosome motion, which are critical for normal chromosome segregation. In Saccharomyces cerevisiae, Ndj1 is a meiotic telomere-associated protein required for physically attaching telomeres to proteins embedded in the nuclear envelope. In this study, we identified additional proteins that act at the nuclear periphery from meiotic cell extracts, including Nup2, a nonessential nucleoporin with a known role in tethering interstitial chromosomal loci to the nuclear pore complex. We found that deleting NUP2 affects meiotic progression and spore viability, and gives increased levels of recombination intermediates and products. We identified a previously uncharacterized 125 aa region of Nup2 that is necessary and sufficient for its meiotic function, thus behaving as a meiotic autonomous region (MAR). Nup2-MAR forms distinct foci on spread meiotic chromosomes, with a subset overlapping with Ndj1 foci. Localization of Nup2-MAR to meiotic chromosomes does not require Ndj1, nor does Ndj1 localization require Nup2, suggesting these proteins function in different pathways, and their interaction is weak or indirect. Instead, several severe synthetic phenotypes are associated with the nup2Δ ndj1Δ double mutant, including delayed turnover of recombination joint molecules, and a failure to undergo nuclear divisions without also arresting the meiotic program. These data suggest Nup2 and Ndj1 support partially overlapping functions that promote two different levels of meiotic chromosome organization necessary to withstand a dynamic stage of the eukaryotic life cycle.

A Computational Approach to Estimating Nondisjunction Frequency in Saccharomyces cerevisiae.

Errors segregating homologous chromosomes during meiosis result in aneuploid gametes and are the largest contributing factor to birth defects and spontaneous abortions in humans. Saccharomyces cerevisiae has long served as a model organism for studying the gene network supporting normal chromosome segregation. Measuring homolog nondisjunction frequencies is laborious, and involves dissecting thousands of tetrads to detect missegregation of individually marked chromosomes. Here we describe a computational method (TetFit) to estimate the relative contributions of meiosis I nondisjunction and random-spore death to spore inviability in wild type and mutant strains. These values are based on finding the best-fit distribution of 4, 3, 2, 1, and 0 viable-spore tetrads to an observed distribution. Using TetFit, we found that meiosis I nondisjunction is an intrinsic component of spore inviability in wild-type strains. We show proof-of-principle that the calculated average meiosis I nondisjunction frequency determined by TetFit closely matches empirically determined values in mutant strains. Using these published data sets, TetFit uncovered two classes of mutants: Class A mutants skew toward increased nondisjunction death, and include those with known defects in establishing pairing, recombination, and/or synapsis of homologous chromosomes. Class B mutants skew toward random spore death, and include those with defects in sister-chromatid cohesion and centromere function. Epistasis analysis using TetFit is facilitated by the low numbers of tetrads (as few as 200) required to compare the contributions to spore death in different mutant backgrounds. TetFit analysis does not require any special strain construction, and can be applied to previously observed tetrad distributions.