Early gas stripping as the origin of the darkest galaxies in the Universe

The known galaxies most dominated by dark matter (Draco, Ursa Minor and Andromeda IX) are satellites of the Milky Way and the Andromeda galaxies. They are members of a class of faint galaxies, devoid of gas, known as dwarf spheroidals, and have by far the highest ratio of dark to luminous matter. None of the models proposed to unravel their origin can simultaneously explain their exceptional dark matter content and their proximity to a much larger galaxy. Here we report simulations showing that the progenitors of these galaxies were probably gas-dominated dwarf galaxies that became satellites of a larger galaxy earlier than the other dwarf spheroidals. We find that a combination of tidal shocks and ram pressure swept away the entire gas content of such progenitors about ten billion years ago because heating by the cosmic ultraviolet background kept the gas loosely bound: a tiny stellar component embedded in a relatively massive dark halo survived until today. All luminous galaxies should be surrounded by a few extremely dark-matter-dominated dwarf spheroidal satellites, and these should have the shortest orbital periods among dwarf spheroidals because they were accreted early.     

Structural definition of a conserved neutralization epitope on HIV-1 gp120

The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 A resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.     

The architecture of human kin detection

Evolved mechanisms for assessing genetic relatedness have been found in many species, but their existence in humans has been a matter of controversy. Here we report three converging lines of evidence, drawn from siblings, that support the hypothesis that kin detection mechanisms exist in humans. These operate by computing, for each familiar individual, a unitary regulatory variable (the kinship index) that corresponds to a pairwise estimate of genetic relatedness between self and other. The cues that the system uses were identified by quantitatively matching individual exposure to potential cues of relatedness to variation in three outputs relevant to the system's evolved functions: sibling altruism, aversion to personally engaging in sibling incest, and moral opposition to third party sibling incest. As predicted, the kin detection system uses two distinct, ancestrally valid cues to compute relatedness: the familiar other's perinatal association with the individual's biological mother, and duration of sibling coresidence.     

Lanthanide contraction and magnetism in the heavy rare earth elements

The heavy rare earth elements crystallize into hexagonally close packed (h.c.p.) structures and share a common outer electronic configuration, differing only in the number of 4f electrons they have. These chemically inert 4f electrons set up localized magnetic moments, which are coupled via an indirect exchange interaction involving the conduction electrons. This leads to the formation of a wide variety of magnetic structures, the periodicities of which are often incommensurate with the underlying crystal lattice. Such incommensurate ordering is associated with a 'webbed' topology of the momentum space surface separating the occupied and unoccupied electron states (the Fermi surface). The shape of this surface-and hence the magnetic structure-for the heavy rare earth elements is known to depend on the ratio of the interplanar spacing c and the interatomic, intraplanar spacing a of the h.c.p. lattice. A theoretical understanding of this problem is, however, far from complete. Here, using gadolinium as a prototype for all the heavy rare earth elements, we generate a unified magnetic phase diagram, which unequivocally links the magnetic structures of the heavy rare earths to their lattice parameters. In addition to verifying the importance of the c/a ratio, we find that the atomic unit cell volume plays a separate, distinct role in determining the magnetic properties: we show that the trend from ferromagnetism to incommensurate ordering as atomic number increases is connected to the concomitant decrease in unit cell volume. This volume decrease occurs because of the so-called lanthanide contraction, where the addition of electrons to the poorly shielding 4f orbitals leads to an increase in effective nuclear charge and, correspondingly, a decrease in ionic radii.     

Multimodal fast optical interrogation of neural circuitry

Our understanding of the cellular implementation of systems-level neural processes like action, thought and emotion has been limited by the availability of tools to interrogate specific classes of neural cells within intact, living brain tissue. Here we identify and develop an archaeal light-driven chloride pump (NpHR) from Natronomonas pharaonis for temporally precise optical inhibition of neural activity. NpHR allows either knockout of single action potentials, or sustained blockade of spiking. NpHR is compatible with ChR2, the previous optical excitation technology we have described, in that the two opposing probes operate at similar light powers but with well-separated action spectra. NpHR, like ChR2, functions in mammals without exogenous cofactors, and the two probes can be integrated with calcium imaging in mammalian brain tissue for bidirectional optical modulation and readout of neural activity. Likewise, NpHR and ChR2 can be targeted together to Caenorhabditis elegans muscle and cholinergic motor neurons to control locomotion bidirectionally. NpHR and ChR2 form a complete system for multimodal, high-speed, genetically targeted, all-optical interrogation of living neural circuits.     

A second generation human haplotype map of over 3.1 million SNPs

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.     

Genome-wide detection and characterization of positive selection in human populations

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.     

Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia

Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.