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At each cell division, nanometer-scale components self-organize to build a micron-scale spindle. In mammalian spindles, microtubule bundles called kinetochore-fibers attach to chromosomes and focus into spindle poles. Despite evidence suggesting that poles can set spindle length, their role remains poorly understood. In fact, many species do not have spindle poles. Here, we probe the pole’s contribution to mammalian spindle length, dynamics, and function by inhibiting dynein to generate spindles whose kinetochore-fibers do not focus into poles, yet maintain a metaphase steady-state length. We find that unfocused kinetochore-fibers have a mean length indistinguishable from control, but a broader length distribution, and reduced length coordination between sisters and neighbors. Further, we show that unfocused kinetochore-fibers, like control, can grow back to their steady-state length if acutely shortened by drug treatment or laser ablation: they recover their length by tuning their end dynamics, albeit slower due to their reduced baseline dynamics. Thus, kinetochore-fiber dynamics are regulated by their length, not just pole-focusing forces. Finally, we show that spindles with unfocused kinetochore-fibers can segregate chromosomes but fail to correctly do so. We propose that mammalian spindle length emerges locally from individual k-fibers while spindle poles globally coordinate k-fibers across space and time.

This paper aims to understand the origins of what is seen as a lack of understanding about the seriousness of our current times. The author's view is that this failure is due to a lack of awareness that our human species is destructive, arrogant, self-centred and ignorant of the laws of nature and the wonderful complexity of the environment that it destroys. Possible new values that could support a new civilizational framework are presented. [ABSTRACT FROM AUTHOR]

This review is a follow up to Grün et al. (2006): Direct Dating of Human Fossils. Since that time there has been progress on the experimental side of the geochronological analyses, which are detailed for uranium-series isotope and ESR dating. Also, many new human fossils, including several new species (e.g., H. naledi, H. luzonensis, and H. longi) have been discovered, named and dated. Direct dating of human fossils has contributed to some major revisions in our understanding of human evolution. For example, the enigmatic Homo floresiensis has been dated to >60 ka instead of ∼18 ka as was originally published. This put an end to the heated debate about how H. floresiensis could have survived the arrival of H. sapiens on Flores for several tens of thousands of years. From Africa, results are presented for Swartkrans, Thomas Quarry, Broken Hill (Kabwe), the Rising Star sites Djebel Irhoud, Florisbad and Omo Kibish. In western Asia, human fossils from Mislya, Tabun, Qafzeh and Al Wusta were analysed and in Europe from Payre, Moula Guercy, Lezetxiki, Apidima, El Sidron and Atapuerca (Sima de los Huesos and Gran Dolina). From Asia and Oceania we discuss the results from Denisova, Penghu, Harbin, Liujiang, Liang Bua, Mata Menge, Callao, Ngandong, Sambungmacan, Wajak, Niah and Tabon, while from Australia WLH50 is added to WLH3. We describe the dating procedures for each site. All published data were re-evaluated. The systematic analysis of the U-series isotopic data led to new insights, particularly with respect to detailed U-diffusion processes (provenance of the uranium, leaching, secondary overprints etc.), which altered the interpretation of the ages for some of the sites. For example, we can show that the minimum age of H. luzonensis is 134 ± 14 ka, covering the transition of MIS6 to MIS 5 (younger dates were the result of secondary U-overprints), and that Apidima 1 and 2 have significantly different isotopic characteristics, refuting claims of initial contemporaneous burials. We discuss the implications of the results for our present understanding of human evolution. • Critical assessment of U-series and ESR dating. • Dating the earliest occurrences of Homo sapiens in Africa, the Levant and Europe. • The ages of new human species found since 2000: H. floresiensis, H. luzonensis, H. nadeli, H. longi. • Updated summary of our present understanding of human evolution. [ABSTRACT FROM AUTHOR]

The protein product of the Homo sapiens TP53 gene is a transcription factor (p53) that regulates the expression of genes critical for the response to DNA damage and tumor suppression, including genes involved in cell cycle arrest, apoptosis, DNA repair, metabolism, and a number of other tumorigenesis-related pathways. Differential transcriptional regulation of these genes is believed to alter the balance between two p53-dependent cell fates: cell cycle arrest or apoptosis. A number of previously identified p53 cofactors covalently modify and alter the function of both the p53 protein and histone proteins. Both gain- and loss-of-function mutations in chromatin modifiers have been strongly implicated in cancer development; thus, we sought to identify novel chromatin regulatory proteins that affect p53-dependent transcription and the balance between the expression of pro-cell cycle arrest and proapoptotic genes. We utilized an siRNA library designed against predicted chromatin regulatory proteins, and identified known and novel chromatin-related factors that affect both global p53-dependent transcription and gene-specific regulators of p53 transcriptional activation. The results from this screen will serve as a comprehensive resource for those interested in further characterizing chromatin and epigenetic factors that regulate p53 transcription.

LW domain is the N-terminal domain I of transcription elongation factor TFIIS, which is a component of RNA polymerase II (Pol II) preinitiation complexes (PICs). Here, we report the resonance assignments of TFIIS LW domain from Homo sapiens for further understanding of the relationship between its structure and function. [ABSTRACT FROM AUTHOR]

Since enzymes catalyze almost all chemical reactions that occur in living organisms, it is crucial that genes encoding such activities are correctly identified and functionally characterized. Several studies suggest that the fraction of enzymatic activities in whichmultiple events of independent origin have taken place during evolution is substantial. However, this topic is still poorly explored, and a comprehensive investigation of the occurrence, distribution, and implications of these events has not been done so far. Fundamental questions, such as how analogous enzymes originate, why somany events of independent origin have apparently occurred during evolution, and what are the reasons for the coexistence in the same organism of distinct enzymatic forms catalyzing the same reaction, remain unanswered. Also, several isofunctional enzymes are still not recognized as nonhomologous, evenwith substantial evidence indicating different evolutionary histories. In this work, we begin to investigate the biological significance of the cooccurrence of nonhomologous isofunctional enzymes in human metabolism, characterizing functional analogous enzymes identified in metabolic pathways annotated in the human genome. Our hypothesis is that the coexistence of multiple enzymatic formsmight not be interpreted as functional redundancy. Instead, these enzymatic forms may be implicated in distinct (and probably relevant) biological roles. [ABSTRACT FROM AUTHOR]

The eukaryotic chaperonin, CCT (Chaperonin Containing TCP1 or TriC-TCP-1 Ring Complex) has been subjected to physical and genetic analyses in S. cerevisiae which can be extrapolated to human CCT (hCCT), owing to its structural and functional similarities with yeast CCT (yCCT). Studies on hCCT and its interactome acquire an additional dimension, as it has been implicated in several disease conditions like neurodegeneration and cancer. We attempt to study its stress response role in general, which will be reflected in the aspects of human diseases and yeast physiology, through computational analysis of the interactome. Towards consolidating and analysing the interactome data, we prepared and compared the unique CCT-interacting protein lists for S. cerevisiae and H. sapiens , performed GO term classification and enrichment studies which provide information on the diversity in CCT interactome, in terms of protein classes in the data set. Enrichment with disease-associated proteins and pathways highlight the medical importance of CCT. Different analyses converge, suggesting the significance of WD-repeat proteins, protein kinases and cytoskeletal proteins in the interactome. The prevalence of proteasomal subunits and ribosomal proteins suggest a possible cross-talk between protein-synthesis, folding and degradation machinery. A network of chaperones and chaperonins that function in combination can also be envisaged from the CCT interactome-Hsp70 interactome analysis. [ABSTRACT FROM AUTHOR]

The timing and geographic origin of the common ancestor of modern humans and Neandertals remain controversial. A poor Pleistocene hominin fossil record and the evolutionary complexities introduced by dispersals and regionalisation of lineages have fuelled taxonomic uncertainty, while new ancient genomic data have raised completely new questions. Here, we use maximum likelihood and 3D geometric morphometric methods to predict possible morphologies of the last common ancestor of modern humans and Neandertals from a simplified, fully resolved phylogeny. We describe the fully rendered 3D shapes of the predicted ancestors of humans and Neandertals, and assess their similarity to individual fossils or populations of fossils of Pleistocene age. Our results support models of an Afro-European ancestral population in the Middle Pleistocene ( Homo heidelbergensis sensu lato) and further predict an African origin for this ancestral population. [ABSTRACT FROM AUTHOR]

The African savanna ecosystem of the large mammals and primates was associated with a dramatic decline in relative brain capacity. This reduction happened to be associated with a decline in docosahexaenoic acid (DHA) from the food chain. DHA is required for brain structures and growth. The biochemistry implies that the expansion of the human brain required a plentiful source of preformed DHA. The richest source of DHA is the marine food chain while the savannah environment offers very little of it. Consequently H. sapiens could not have evolved on the savannahs. Recent fossil evidence indicates that the lacustrine and marine food chain was being extensively exploited at the time cerebral expansion took place and suggests the alternative that the transition from the archaic to modern humans took place at the land\\water interface. Contemporary data on tropical lake shore dwellers reaffirms the above view. Lacustrine habitats provide nutritional support for the vascular system, the development of which would have been a prerequisite for cerebral expansion. Both arachidonic acid (AA) and DHA would have been freely available from such habitats providing the double stimulus of preformed acyl components for the developing blood vessels and brain. The w3 docosapentaenoic acid precursor (w3DPA) was the major w3 metabolite in the savanna mammals. Despite this abundance, neither it or the corresponding w6DPA were used for the photoreceptor nor the synapse. A substantial difference between DHA and other fatty acids is required to explain this high specificity. Studies on fluidity and other mechanical features of cell membranes have not revealed a difference of such magnitude between even a-linolenic acid (LNA) and DHA sufficient to explain the exclusive use of DHA. We suggest that the evolution of the large human brain depended on a rich source of DHA from the land\\water interface. We review a number of proposals for the possible influence of DHA on physical properties of the brain that are essential for its function.

Mitotic chromosomes in different organisms adopt various dimensions. What defines these dimensions is scarcely understood. Here, we compare mitotic chromosomes in budding and fission yeasts harboring similarly sized genomes distributed among 16 or 3 chromosomes, respectively. Hi-C analyses and superresolution microscopy reveal that budding yeast chromosomes are characterized by shorter-ranging mitotic chromatin contacts and are thinner compared with the thicker fission yeast chromosomes that contain longer-ranging mitotic contacts. These distinctions persist even after budding yeast chromosomes are fused to form three fission-yeast-length entities, revealing a species-specific organizing principle. Species-specific widths correlate with the known binding site intervals of the chromosomal condensin complex. Unexpectedly, within each species, we find that longer chromosome arms are always thicker and harbor longer-ranging contacts, a trend that we also observe with human chromosomes. Arm length as a chromosome width determinant informs mitotic chromosome formation models. [Display omitted] • Chromosomes in fission yeast are thicker than in budding yeast and thinner than in humans • Chromosome widths correlate with the span of condensin-mediated chromatin contacts • In each organism, longer chromosome arms are always thicker • Longer, thicker arms inform mitotic chromosome architecture models The factors defining chromosome shape remain an unresolved enigma. Here, Kakui et al. compare chromosome dimensions between yeasts and humans. They find that chromosomes are characterized by species-specific widths but also that within each species, longer chromosome arms are always wider. These observations challenge current models of mitotic chromosome formation. [ABSTRACT FROM AUTHOR]

The future of human evolution triggers many discussions, in the intersection of biological, technological, and philosophical enquiry. I will discuss the proposition that the evolution of the human species will rely increasingly in stochastic phenomena in the future, by a manner at which selection will play a minimal role only. This is the direct consequence of our cultural evolution that was intensified after the Enlightenment and combined with the scientific, technological, and medical advances of our civilization, renders the perseverance of our species, as its ultimate goal. This supersedes the goals instructed by biology alone as they apply to all other species. To that end, H. sapiens will be the first and only species that through its logic-based progress, defies the rationale of natural selection as an evolutionary force and forecasts a rather unpredictable future path. • The forces of evolution include selection, genetic drift, gene flow and mutations. • Cultural evolution promotes increasing humanitarianism that eliminates the operation of selection as a force of evolution. • Remaining forces rely on stochastic phenomena. • The evolution of H. sapiens will be a random process, and "metahumans" may have either higher or lower fitness. • "Logic"-based progress defeats the rationale of evolutionary progress in humans. [ABSTRACT FROM AUTHOR]

Evolution of sequences mostly involves independent changes at different sites. However, substitutions at neighboring sites may co-occur as multinucleotide replacement events (MNRs). Here, we compare noncoding sequences of several species of primates, and of three species of Drosophila fruit flies, in a phylogenetic analysis of the replacements that occurred between species at nearby nucleotide sites. Both in primates and in Drosophila, the frequency of single-nucleotide replacements is substantially elevated within 10 nucleotides from other replacements that occurred on the same lineage but not on another lineage. The data imply that dinucleotide replacements (DNRs) affecting sites at distances of up to 10 nucleotides from each other are responsible for 2.3% of single-nucleotide replacements in primate genomes and for 5.6% in Drosophila genomes. Among these DNRs, 26% and 69%, respectively, are in fact parts of replacements of three or more trinucleotide replacements (TNRs). The plurality of MNRs affect nearby nucleotides, so that at least six times as many DNRs affect two adjacent nucleotide sites than sites 10 nucleotides apart. Still, approximately 60% of DNRs, and approximately 90% of TNRs, span distances more than two (or three) nucleotides. MNRs make a major contribution to the observed clustering of substitutions: In the human–chimpanzee comparison, DNRs are responsible for 50% of cases when two nearby replacements are observed on the human lineage, and TNRs are responsible for 83% of cases when three replacements at three immediately adjacent sites are observed on the human lineage. The prevalence of MNRs matches that is observed in data on de novo mutations and is also observed in the regions with the lowest sequence conservation, suggesting that MNRs mainly have mutational origin; however, epistatic selection and/or gene conversion may also play a role. [ABSTRACT FROM PUBLISHER]

Dental development and skeletal growth are central aspects used by anthropologists when investigating the ontogeny of a population or species. The interrelatedness of the two phenomena is often assumed to be high, but the nature of their relationship is obscured by the fact that they are both highly dependent upon chronological age. The exact relationship between the tempo of dental development and skeletal growth is unclear even in modern humans, which limits the ability to extrapolate to archaeological or fossil forms. It is clear that the influence of chronological age on these two aspects of ontogeny must be accounted for before examining their relationship to one another. This study tests whether dental development and skeletal growth are conditionally independent given age using known-age modern human skeletal samples and proportional odds logistic regression. The results suggest that dental development and skeletal growth are moderately correlated and thus not conditionally independent given age. That is, individuals that are dentally advanced relative to their peers also tend to be skeletally advanced. However, this relationship is moderate at best, so dental development does not appear to be a highly reliable proxy for skeletal growth, or vice versa, in modern humans. These findings have implications for the reconstruction of ontogeny and life history of fossil hominin taxa, since the pace of dental development is often used as a life history proxy. Implications of this study suggest that the proposed accelerated dental development in Pleistocene hominins was not necessarily accompanied by faster skeletal growth. Am J Phys Anthropol, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Mutation rate varies between sites in the genome. Part of this variation can be explained by well-recognized short nucleotide contexts, but a large component of this variation remains cryptic. We used data on interspecies divergence and intraspecies polymorphism in Drosophila and Hominidae to analyze variation of the average rate of the 12 possible kinds of single-nucleotide mutations and in the transition/transversion ratio κ at single-nucleotide resolution. Both the average mutation rate and κ vary by a factor of ∼3 between nucleotide sites. The characteristic scale of variation in κ is up to at least ∼30 nucleotides in Drosophila and ∼5 nucleotides in Hominidae. Genome segments with locally elevated mutation rates possess lower values of κ; however, a substantial fraction of variation in κ cannot be directly explained by the local mutation rates. [ABSTRACT FROM PUBLISHER]

Abstract: Genomes are characterized by global and local compositional properties that are interesting in an evolutionary perspective but also provide useful information for the identification of some functional elements. Following previous studies, in this work we investigated compositional properties of non-coding sequences in four eukaryotic genomes (C. elegans, D. melanogaster, M. musculus, H. sapiens). We developed a procedure based on Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA) to identify pentamers that are over-represented in introns (intron vocabulary) and to define a new parameter (LD) that reflects oligonucleotide composition of a given sequence. We analyzed genomic sequences and we found that all non-coding parts of a genome are characterized by similar LD values. Furthermore, we used the new parameter to analyze potentially regulatory regions. We extracted non-redundant sets of promoter sequences for D. melanogaster and H. sapiens and we studied their compositional (G+C content and LD parameter) and conformational (bendability propensity) properties. We found that regions immediately surrounding transcription start sites are distinguishable because of their %G+C, LD and bendability values. [Copyright &y& Elsevier]

Abstract: The remarkable partial adult skeleton (LB1) excavated from Liang Bua cave on the island of Flores, Indonesia, has been attributed to a new species, Homo floresiensis, based upon a unique mosaic of primitive and derived features compared to any other hominin. The announcement precipitated widespread interest, and attention quickly focused on its possible affinities. LB1 is a small-bodied hominin with an endocranial volume of 380–410cm3, a stature of 1m, and an approximate geological age of 18,000 years. The describers [Brown, P., Sutikna, T., Morwood, M.J., Soejono, R.P., Jatmiko, Wayhu Saptomo, E., Awe Due, R., 2004. A new small-bodied hominin from the Late Pleistocene of Flores, Indonesia. Nature 431, 1055–1061] originally proposed that H. floresiensis was the end product of a long period of isolation of H. erectus or early Homo on a small island, a process known as insular dwarfism. More recently Morwood, Brown, and colleagues [Morwood, M.J., Brown, P., Jatmiko, Sutikna, T., Wahyu Saptomo, E., Westaway, K.E., Awe Due, R., Roberts, R.G., Maeda, T., Wasisto, S., Djubiantono, T., 2005. Further evidence for small-bodied hominins from the Late Pleistocene of Flores, Indonesia. Nature 437, 1012–1017] reviewed this assessment in light of new material from the site and concluded that H. floresiensis is not likely to be descended from H. erectus, with the genealogy of the species remaining uncertain. Other interpretations, namely that LB1 is a pygmy or afflicted with microcephaly, have also been put forward. We explore the affinities of LB1 using cranial and postcranial metric and non-metric analyses. LB1 is compared to early Homo, two microcephalic humans, a ‘pygmoid’ excavated from another cave on Flores, H. sapiens (including African pygmies and Andaman Islanders), Australopithecus, and Paranthropus. Based on these comparisons, we conclude that it is unlikely that LB1 is a microcephalic human, and it cannot be attributed to any known species. Its attribution to a new species, Homo floresiensis, is supported. [Copyright &y& Elsevier]

Abstract: The availability of the complete genome sequences of Homo sapiens together with those of taxonomically diverse organisms provides an opportunity to carry out cross-species comparison. Comparisons of protein sequences from different organisms are significant source of information as these could help in answering questions regarding the fraction of proteins that are shared by humans and organisms representing the three domains of life, viz., archaea, bacteria, and eukaryota. In the present study, a comparative analysis of the proteins encoded by intronless genes in humans was undertaken. We identified 1125 human intronless proteins that are solely present in eukaryotic lineage. More than two-thirds of these eukaryotic specific proteins appear to be mammalia specific while a small fraction of proteins are conserved in bilateria and coelomata, indicating that diversification of these proteins occurred after the divergence of the major lineages of the eukaryotic crown group. A large fraction of mammalia specific proteins are enriched in proteins responsible for transport and binding, cell envelope, and housekeeping function particularly translation. Another 228 intronless proteins are observed that do not exhibit homology to any of the proteins in the database. The distribution of human intronless proteins suggests that lineage specific expansion is one of the most important sources of organizational diversity in crown-group eukaryotes. The presence of these eukaryotic as well as human specific intronless proteins provides the foundation for rapid analysis of some of the basic processes involved in human genome. [Copyright &y& Elsevier]

A number of Middle-to-Late Pleistocene sites preserve only, or primarily, deciduous teeth. While many studies of the fossil hominin deciduous dentition have focused on standard metrical variation, non-metric and morphometric variation also promise to shed light on long-standing taxonomic questions. This study examines the taxonomic significance of the crown outline of the upper deciduous second molar (dm2) through principal components and linear discriminant analyses. We test whether the crown shape of the upper dm2 separates Homo neanderthalensis from H. sapiens and explore whether it can be used to correctly assign individuals to taxa. This study builds on previous work by focusing on the crown rather than cervical outline and by including a large sample of geographically diverse recent human populations. Our recent human sample includes 80 individuals representing Asia, Africa, Europe and South America. Our fossil samples include 17 H. neanderthalensis, 5 early H. sapiens, and 12 Upper Paleolithic H. sapiens individuals. In addition, we include two H. erectus specimens in order to evaluate the polarity of observed crown shape differences. Our results show that crown outline shape of the upper dm2 distinguishes H. sapiens and H. neanderthalensis quite well. Individuals classify correctly 96.5 percent of the time. The H. erectus specimen Sangiran 7-13 classified ambiguously, which would be expected if it preserves a primitive crown outline. About half the H. sapiens individuals share this shape. The remaining H. sapiens individuals, including all early and nearly all Upper Paleolithic H. sapiens, have an outline that is derived in an opposite direction from that of H. neanderthalensis. Finally, the H. erectus upper dm2 from Tighenif classified as H. sapiens with a posterior probability of .99, tentatively suggesting dental continuity within Africa back to 700,000 years BP. [ABSTRACT FROM AUTHOR]