Archaic and modern human distal humeral morphology

The morphology of the proximal ulna has been shown to effectively differentiate archaic or premodern humans (such as Homo heidelbergensis and H. neanderthalensis) from modern humans (H. sapiens). Accordingly, the morphology of adjacent, articulating elements should be able to distinguish these two broad groups as well. Here we test the taxonomic utility of another portion of the elbow, the distal humerus, as a discriminator of archaic and modern humans. Principal components analysis was employed on a suite of log-raw and log-shape distal humeral measures to examine differences between Neandertal and modern human distal humeri. In addition, the morphological affinities of Broken Hill (Kabwe) E.898, an archaic human distal humeral fragment from the middle Pleistocene of Zambia, and five Pliocene and early Pleistocene australopith humeri were assessed. The morphometric analyses effectively differentiated the Neandertals from the other groups, while the Broken Hill humerus appears morphologically similar to modern human distal humeri. Thus, an archaic/modern human dichotomy-as previously reported for proximal ulnar morphology-is not supported with respect to distal humeral morphology. Relative to australopiths and modern humans, Neandertal humeri are characterized by large olecranon fossae and small distodorsal medial and lateral pillars. The seeming disparity in morphological affinities of proximal ulnae (in which all archaic human groups appear distinct from modern humans) and distal humeri (in which Neandertals appear distinct from modern humans, but other archaic humans do not) is probably indicative of a highly variable, possibly transitional population of which our knowledge is hampered by sample-size limitations imposed by the scarcity of middle-to-late Pleistocene premodern human fossils outside of Europe.     

Nonsequence-specific DNA recognition: a structural perspective

Chromosomal proteins that form essential architectural components of chromatin bind and bend DNA with an intrinsic low degree of sequence preference. Comparisons made between two recently determined structures of high mobility group (HMG) protein-DNA complexes and other nonsequence-specific protein-DNA complexes reveal the structural basis of this important mode of DNA binding.     

Adaptive evolution and effective population size in wild house mice

Estimates of the proportion of amino acid substitutions that have been fixed by selection (α) vary widely among taxa, ranging from zero in humans to over 50% in Drosophila. This wide range may reflect differences in the efficacy of selection due to differences in the effective population size (N(e)). However, most comparisons have been made among distantly related organisms that differ not only in N(e) but also in many other aspects of their biology. Here, we estimate α in three closely related lineages of house mice that have a similar ecology but differ widely in N(e): Mus musculus musculus (N(e) ～ 25,000-120,000), M. m. domesticus (N(e) ～ 58,000-200,000), and M. m. castaneus (N(e) ～ 200,000-733,000). Mice were genotyped using a high-density single nucleotide polymorphism array, and the proportions of replacement and silent mutations within subspecies were compared with those fixed between each subspecies and an outgroup, Mus spretus. There was significant evidence of positive selection in M. m. castaneus, the lineage with the largest N(e), with α estimated to be approximately 40%. In contrast, estimates of α for M. m. domesticus (α = 13%) and for M. m. musculus (α = 12 %) were much smaller. Interestingly, the higher estimate of α for M. m. castaneus appears to reflect not only more adaptive fixations but also more effective purifying selection. These results support the hypothesis that differences in N(e) contribute to differences among species in the efficacy of selection.     

The systematics of right whales (Mysticeti: Balaenidae)

Balaenidae (right whales) are large, critically endangered baleen whales represented by four living species. The evolutionary relationships of balaenids are poorly known, with the number of genera, relationships to fossil taxa, and position within Mysticeti in contention. This study employs a comprehensive set of morphological characters to address aspects of balaenid phylogeny. A sister‐group relationship between neobalaenids and balaenids is strongly supported, although this conflicts with molecular evidence, which may be an artifact of long‐branch attraction (LBA). Monophyly of Balaenidae is supported, and three major clades are recognized: (1) extinct genus Balaenula, (2) extant and extinct species of the genus Eubalaena, and (3) extant and extinct species of the genus Balaena plus the extinct taxon, Balaenella. The relationships of these clades to one another, as well as to the early Miocene stem balaenid, Morenocetus parvus, remain unresolved. Pliocene taxa, Balaenula astensis and Balaenula balaenopsis, form a clade that is the sister group to the Japanese Pliocene Balaenula sp. Eubalaena glacialis and Pliocene Eubalaena belgica, are in an unresolved polytomy with a clade including E. japonica and E. australis. Extant and fossil species of Balaena form a monophyletic group that is sister group to the Dutch Pliocene Balaenella, although phylogenetic relationships within Balaena remain unresolved.     

CAF-1-induced oligomerization of histones H3/H4 and mutually exclusive interactions with Asf1 guide H3/H4 transitions among histone chaperones and DNA

Anti-silencing function 1 (Asf1) and Chromatin Assembly Factor 1 (CAF-1) chaperone histones H3/H4 during the assembly of nucleosomes on newly replicated DNA. To understand the mechanism of histone H3/H4 transfer among Asf1, CAF-1 and DNA from a thermodynamic perspective, we developed and employed biophysical approaches using full-length proteins in the budding yeast system. We find that the C-terminal tail of Asf1 enhances the interaction of Asf1 with CAF-1. Surprisingly, although H3/H4 also enhances the interaction of Asf1 with the CAF-1 subunit Cac2, H3/H4 forms a tight complex with CAF-1 exclusive of Asf1, with an affinity weaker than Asf1–H3/H4 or H3/H4–DNA interactions. Unlike Asf1, monomeric CAF-1 binds to multiple H3/H4 dimers, which ultimately promotes the formation of (H3/H4)₂ tetramers on DNA. Thus, transition of H3/H4 from the Asf1-associated dimer to the DNA-associated tetramer is promoted by CAF-1-induced H3/H4 oligomerization.     

Imputation of single-nucleotide polymorphisms in inbred mice using local phylogeny

We present full-genome genotype imputations for 100 classical laboratory mouse strains, using a novel method. Using genotypes at 549,683 SNP loci obtained with the Mouse Diversity Array, we partitioned the genome of 100 mouse strains into 40,647 intervals that exhibit no evidence of historical recombination. For each of these intervals we inferred a local phylogenetic tree. We combined these data with 12 million loci with sequence variations recently discovered by whole-genome sequencing in a common subset of 12 classical laboratory strains. For each phylogenetic tree we identified strains sharing a leaf node with one or more of the sequenced strains. We then imputed high- and medium-confidence genotypes for each of 88 nonsequenced genomes. Among inbred strains, we imputed 92% of SNPs genome-wide, with 71% in high-confidence regions. Our method produced 977 million new genotypes with an estimated per-SNP error rate of 0.083% in high-confidence regions and 0.37% genome-wide. Our analysis identified which of the 88 nonsequenced strains would be the most informative for improving full-genome imputation, as well as which additional strain sequences will reveal more new genetic variants. Imputed sequences and quality scores can be downloaded and visualized online.     

Histone transfer among chaperones

The eukaryotic processes of nucleosome assembly and disassembly govern chromatin dynamics, in which histones exchange in a highly regulated manner to promote genome accessibility for all DNA-dependent processes. This regulation is partly carried out by histone chaperones, which serve multifaceted roles in co-ordinating the interactions of histone proteins with modification enzymes, nucleosome remodellers, other histone chaperones and nucleosomal DNA. The molecular details of the processes by which histone chaperones promote delivery of histones among their many functional partners are still largely undefined, but promise to offer insights into epigenome maintenance. In the present paper, we review recent findings on the histone chaperone interactions that guide the assembly of histones H3 and H4 into chromatin. This evidence supports the concepts of histone post-translational modifications and specific histone chaperone interactions as guiding principles for histone H3/H4 transactions during chromatin assembly.     

NAADP regulates human platelet function

Platelets play a vital role in maintaining haemostasis. Human platelet activation depends on Ca2+ release, leading to cell activation, granule secretion and aggregation. NAADP (nicotinic acid-adenine dinucleotide phosphate) is a Ca2+-releasing second messenger that acts on acidic Ca2+ stores and is used by a number of mammalian systems. In human platelets, NAADP has been shown to release Ca2+ in permeabilized human platelets and contribute to thrombin-mediated platelet activation. In the present study, we have further characterized NAADP-mediated Ca2+ release in human platelets in response to both thrombin and the GPVI (glycoprotein VI)-specific agonist CRP (collagen-related peptide). Using a radioligand-binding assay, we reveal an NAADP-binding site in human platelets, indicative of a platelet NAADP receptor. We also found that NAADP releases loaded 45Ca2+ from intracellular stores and that total platelet Ca2+ release is inhibited by the proton ionophore nigericin. Ned-19, a novel cell-permeant NAADP receptor antagonist, competes for the NAADP-binding site in platelets and can inhibit both thrombin- and CRP-induced Ca2+ release in human platelets. Ned-19 has an inhibitory effect on platelet aggregation, secretion and spreading. In addition, Ned-19 extends the clotting time in whole-blood samples. We conclude that NAADP plays an important role in human platelet function. Furthermore, the development of Ned-19 as an NAADP receptor antagonist provides a potential avenue for platelet-targeted therapy and the regulation of thrombosis.     

Mitigation of radiation-induced dermatitis by activation of aldehyde dehydrogenase 2 using topical alda-1 in mice

Radiation-induced dermatitis is a debilitating clinical problem in cancer patients undergoing cancer radiation therapy. It is also a possible outcome of exposure to high levels of radiation due to accident or hostile activity. We report that activation of aldehyde dehydrogenase 2 (ALDH2) enzymatic activity using the allosteric agonist, Alda-1, significantly reduced 4-hydroxynonenal adducts accumulation, delayed the onset of radiation dermatitis and substantially reduced symptoms in a clinically-relevant model of radiation-induced dermatitis. Importantly, Alda-1 did not radioprotect tumors in mice. Rather, it increased the sensitivity of the tumors to radiation therapy. This is the first report of reactive aldehydes playing a role in the intrinsic radiosensitivity of normal and tumor tissues. Our findings suggest that ALDH2 represents a novel target for the treatment of radiation dermatitis without reducing the benefit of radiotherapy.