Biology subjects

Jin, B.

Publications and source records attributed to Jin, B..

3 recordsLinked to original sources

bioRxiv2019

Single-cell whole-genome sequencing reveals mutational landscapes of DNA mismatch repair deficiency in mouse primary fibroblasts

DNA Mismatch repair (MMR) deficiency is a major cause of hereditary non-polyposis colorectal cancer, and is also associated with increased risk of several other cancers. This is generally ascribed to the role of MMR in avoiding mutations by correcting DNA replication errors. In MMR knockout mice very high frequencies of somatic mutations, up until 100-fold of background, have been reported. However, these results have been obtained using bacterial reporter transgenes, which are not representative for the genome overall, and mutational patterns of MMR deficiency remain largely unknown. To fill this knowledge gap, we performed single-cell whole-genome sequencing of lung fibroblasts of Msh2-/- and wild-type mice. We observed a 4-fold increase of somatic single nucleotide variants (SNVs) in the fibroblasts of Msh2-/- mice compared to those of wild-type mice. The SNV signature of Msh2 deficiency was found to be driven by C>T and T>C transitions. By comparing it to human cancer signatures, we not only confirmed the inferred MMR-deficiency-related etiology of several cancer signatures but also suggested that MMR deficiency is likely the cause of a cancer signature with its etiology previously unknown. We also observed a 7-fold increase of somatic small insertions and deletions (INDELs) in the Msh2-/- mice. An elevated INDEL frequency has also been found in human MMR-related cancers. INDELs and SNVs distributed differently across genomic features in the Msh2-/- and control cells, with evidence of selection pressure and repair preference. These results provide insights into the landscape of somatic mutations in normal somatic cells caused by MMR deficiency.\n\nSignificanceOur results show that MMR deficiency in the mouse is associated with a much lower elevation of somatic mutation rates than previously reported and provides the first MMR whole-genome mutational landscapes in normal somatic cells in vivo.

genomics↗

bioRxiv2019

3D computational models explain muscle activation patterns and energetic functions of internal structures in fish swimming

How muscles are used is a key to understanding the internal driving of fish swimming. However, the underlying mechanisms of some features of the muscle activation patterns and their differential appearance on different species are still obscure. In this study, we explain the muscle activation patterns by using 3D computational fluid dynamics models coupled to the motion of fish with prescribed deformation and examining the torque and power required along the fish body with two primary swimming modes. We find that the torque required by the hydrodynamic forces and body inertia exhibits a wave pattern that travels faster than the curvature wave in both anguilliform and carangiform swimmers, which can explain the traveling wave speeds of the muscle activations. Most interestingly, intermittent negative power (i.e., power delivered by the fluid to the body) on the posterior part, along with a timely transfer of torque and energy by tendons, explains the decrease of the duration of muscle activation towards the tail. The torque contribution from the body elasticity further solves the mystery of the wave speed increase or the reverse of the wave direction of the muscle activation on the posterior part of a carangiform swimmer. For anguilliform swimmers, the absence of the changes mentioned above in the muscle activation on the posterior part is in line with our torque prediction and the absence of long tendons from experimental observations. These results provide novel insights into the function of muscles and tendons as an integrative part of the internal driving system, especially from an energy perspective, and highlight the differences in the internal driving systems between the two primary swimming modes. Author summaryFor undulatory swimming, fish form posteriorly traveling waves of body bending by activating their muscles sequentially along the body. However, experimental observations have showed that the muscle activation wave does not simply match the bending wave. Researchers have previously computed the torque required for muscles along the body based on classic hydrodynamic theories and explained the higher wave speed of the muscle activation compared to the curvature wave. However, the origins of other features of the muscle activation pattern and their variation among different species are still obscure after decades of research. In this study, we use 3D computational fluid dynamics models to compute the spatiotemporal distributions of both the torque and power required for eel-like and mackerel-like swimming. By examining both the torque and power patterns and considering the energy transfer, storage, and release by tendons and body viscoelasticity, we can explain not only the features and variations in the muscle activation patterns as observed from fish experiments but also how tendons and body elasticity save energy. We provide a mechanical picture in which the body shape, body movement, muscles, tendons, and body elasticity of a mackerel (or similar) orchestrate to make swimming efficient.

biophysics↗

bioRxiv2019

Mutation of the ATPase domain of MutS homolog-5 (MSH5) reveals a requirement for a functional MutSγ complex for all crossovers in mammalian meiosis

During meiosis, induction of DNA double strand breaks (DSB) leads to recombination between homologous chromosomes, resulting in crossovers (CO) and non-crossovers (NCO). Only 10% DSBs resolve as COs, mostly through a class I pathway dependent on MutS{gamma} (MSH4/ MSH5). Class II CO events represent a minor proportion of the total CO count and also arise from DSBs, but are not thought to involve MutS{gamma}. However, loading of MutS{gamma} occurs very early in prophase I at a frequency that far exceeds the final number of class I COs found in late prophase I. Moreover, loss of MutS{gamma} in mouse results in apoptosis before CO formation, preventing analysis of its CO function. We generated a mutation in the ATP binding domain of Msh5 (Msh5GA). While this mutation was not expected to affect MutS{gamma} complex formation, MutS{gamma} foci do not accumulate during prophase I. Nevertheless, while some spermatocytes from Msh5-/- animals progress into pachynema, most spermatocytes from Msh5GA/GA mice progress to late pachynema and beyond. Some spermatocytes from Msh5GA/GA mice complete prophase I entirely, allowing for the first time an assessment of MSH5 function in CO formation. At pachynema, Msh5GA/GA spermatocytes show persistent DSBs, incomplete homolog pairing, and fail to accumulate MutL{gamma} (MLH1/MLH3). Unexpectedly, Msh5GA/GA diakinesis-staged spermatocytes have no chiasmata at all from any CO pathway, indicating that a functional MutS{gamma} complex in early prophase I is a pre-requisite for all COs. ARTICLE SUMMARYMSH4/MSH5 are critical components of the class I crossover (CO) machinery, which is responsible for >90% of the COs that arise in mammalian meiosis. We generated a point mutation in the ATP binding motif of Msh5, and found that mutant spermatocytes lose all COs, not just those arising from the class I pathway.

genetics↗