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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.

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.

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 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.

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]

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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

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]

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]

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]