Rapid Evolution of BRCA1 and BRCA2 in Humans and Other Primates

The maintenance of chromosomal integrity is an essential task of every living organism and cellular repair mechanisms exist to guard against insults to DNA. Given the importance of this process, it is expected that DNA repair proteins would be evolutionarily conserved, exhibiting very minimal sequence change over time. However, BRCA1, an essential gene involved in DNA repair, has been reported to be evolving rapidly despite the fact that many protein-altering mutations within this gene convey a significantly elevated risk for breast and ovarian cancers. Results: To obtain a deeper understanding of the evolutionary trajectory of BRCA1, we analyzed complete BRCA1 gene sequences from 23 primate species. We show that specific amino acid sites have experienced repeated selection for amino acid replacement over primate evolution. This selection has been focused specifically on humans and our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). After examining BRCA1 polymorphisms in 7 bonobo, 44 chimpanzee, and 44 rhesus macaque (Macaca mulatta) individuals, we find considerable variation within each of these species and evidence for recent selection in chimpanzee populations. Finally, we also sequenced and analyzed BRCA2 from 24 primate species and find that this gene has also evolved under positive selection. Conclusions: While mutations leading to truncated forms of BRCA1 are clearly linked to cancer phenotypes in humans, there is also an underlying selective pressure in favor of amino acid-altering substitutions in this gene. A hypothesis where viruses are the drivers of this natural selection is discussed.National Institutes of Health R01-GM-093086, 8U42OD011197-13National Science Foundation BCS-07115972Burroughs Wellcome FundMolecular Bioscience

Faint dwarfs as a test of DM models: WDM vs. CDM

We use high resolution Hydro$+$N-Body cosmological simulations to compare the assembly and evolution of a small field dwarf (stellar mass ~ 10$^{6-7}$ M$\odot$, total mass 10$^{10}$ M$\odot$ in $\Lambda$ dominated CDM and 2keV WDM cosmologies. We find that star formation (SF) in the WDM model is reduced and delayed by 1-2 Gyr relative to the CDM model, independently of the details of SF and feedback. Independent of the DM model, but proportionally to the SF efficiency, gas outflows lower the central mass density through `dynamical heating', such that all realizations have circular velocities $<$ 20kms at 500$~$pc, in agreement with local kinematic constraints. As a result of dynamical heating, older stars are less centrally concentrated than younger stars, similar to stellar population gradients observed in nearby dwarf galaxies. Introducing an important diagnostic of SF and feedback models, we translate our simulations into artificial color-magnitude diagrams and star formation histories in order to directly compare to available observations. The simulated galaxies formed most of their stars in many $\sim$10 Myr long bursts. The CDM galaxy has a global SFH, HI abundance and Fe/H and alpha-elements distribution well matched to current observations of dwarf galaxies. These results highlight the importance of directly including `baryon physics' in simulations when 1) comparing predictions of galaxy formation models with the kinematics and number density of local dwarf galaxies and 2) differentiating between CDM and non-standard models with different DM or power spectra.Comment: 13 pages including Appendix on Color Magnitude Diagrams. Accepted by MNRAS. Added one plot and details on ChaNGa implementation. Reduced number of citations after editorial reques

An effective Chinese indexing method based on partitioned signature files.

Wong Chi Yin.Thesis (M.Phil.)--Chinese University of Hong Kong, 1998.Includes bibliographical references (leaves 107-114).Abstract also in Chinese.Abstract --- p.iiAcknowledgements --- p.viChapter 1 --- Introduction --- p.1Chapter 1.1 --- Introduction to Chinese IR --- p.1Chapter 1.2 --- Contributions --- p.3Chapter 1.3 --- Organization of this Thesis --- p.5Chapter 2 --- Background --- p.6Chapter 2.1 --- Indexing methods --- p.6Chapter 2.1.1 --- Full-text scanning --- p.7Chapter 2.1.2 --- Inverted files --- p.7Chapter 2.1.3 --- Signature files --- p.9Chapter 2.1.4 --- Clustering --- p.10Chapter 2.2 --- Information Retrieval Models --- p.10Chapter 2.2.1 --- Boolean model --- p.11Chapter 2.2.2 --- Vector space model --- p.11Chapter 2.2.3 --- Probabilistic model --- p.13Chapter 2.2.4 --- Logical model --- p.14Chapter 3 --- Investigation of Segmentation on the Vector Space Retrieval Model --- p.15Chapter 3.1 --- Segmentation of Chinese Texts --- p.16Chapter 3.1.1 --- Character-based segmentation --- p.16Chapter 3.1.2 --- Word-based segmentation --- p.18Chapter 3.1.3 --- N-Gram segmentation --- p.21Chapter 3.2 --- Performance Evaluation of Three Segmentation Approaches --- p.23Chapter 3.2.1 --- Experimental Setup --- p.23Chapter 3.2.2 --- Experimental Results --- p.24Chapter 3.2.3 --- Discussion --- p.29Chapter 4 --- Signature File Background --- p.32Chapter 4.1 --- Superimposed coding --- p.34Chapter 4.2 --- False drop probability --- p.36Chapter 5 --- Partitioned Signature File Based On Chinese Word Length --- p.39Chapter 5.1 --- Fixed Weight Block (FWB) Signature File --- p.41Chapter 5.2 --- Overview of PSFC --- p.45Chapter 5.3 --- Design Considerations --- p.50Chapter 6 --- New Hashing Techniques for Partitioned Signature Files --- p.59Chapter 6.1 --- Direct Division Method --- p.61Chapter 6.2 --- Random Number Assisted Division Method --- p.62Chapter 6.3 --- Frequency-based hashing method --- p.64Chapter 6.4 --- Chinese character-based hashing method --- p.68Chapter 7 --- Experiments and Results --- p.72Chapter 7.1 --- Performance evaluation of partitioned signature file based on Chi- nese word length --- p.74Chapter 7.1.1 --- Retrieval Performance --- p.75Chapter 7.1.2 --- Signature Reduction Ratio --- p.77Chapter 7.1.3 --- Storage Requirement --- p.79Chapter 7.1.4 --- Discussion --- p.81Chapter 7.2 --- Performance evaluation of different dynamic signature generation methods --- p.82Chapter 7.2.1 --- Collision --- p.84Chapter 7.2.2 --- Retrieval Performance --- p.86Chapter 7.2.3 --- Discussion --- p.89Chapter 8 --- Conclusions and Future Work --- p.91Chapter 8.1 --- Conclusions --- p.91Chapter 8.2 --- Future work --- p.95Chapter A --- Notations of Signature Files --- p.96Chapter B --- False Drop Probability --- p.98Chapter C --- Experimental Results --- p.103Bibliography --- p.10

Upper- and mid-mantle interaction between the Samoan plume and the Tonga-Kermadec slabs

Mantle plumes are thought to play a key role in transferring heat from the core\u2013mantle boundary to the lithosphere, where it can significantly influence plate tectonics. On impinging on the lithosphere at spreading ridges or in intra-plate settings, mantle plumes may generate hotspots, large igneous provinces and hence considerable dynamic topography. However, the active role of mantle plumes on subducting slabs remains poorly understood. Here we show that the stagnation at 660 km and fastest trench retreat of the Tonga slab in Southwestern Pacific are consistent with an interaction with the Samoan plume and the Hikurangi plateau. Our findings are based on comparisons between 3D anisotropic tomography images and 3D petrological-thermo-mechanical models, which self-consistently explain several unique features of the Fiji\u2013Tonga region. We identify four possible slip systems of bridgmanite in the lower mantle that reconcile the observed seismic anisotropy beneath the Tonga slab (VSH4VSV) with thermo-mechanical calculations

Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage.

Tissue fibrosis is a major cause of mortality that results from the deposition of matrix proteins by an activated mesenchyme. Macrophages accumulate in fibrosis, but the role of specific subgroups in supporting fibrogenesis has not been investigated in vivo. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis in mice. A novel computational framework for the annotation of scRNA-seq by reference to bulk transcriptomes (SingleR) enabled the subclustering of macrophages and revealed a disease-associated subgroup with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages. These CX3CR1+SiglecF+ transitional macrophages localized to the fibrotic niche and had a profibrotic effect in vivo. Human orthologs of genes expressed by the transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis. Thus, we have identified a pathological subgroup of transitional macrophages that are required for the fibrotic response to injury