Center for Academic Research and Training in Anthropogeny

La Jolla, United States

Center for Academic Research and Training in Anthropogeny

La Jolla, United States
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Hrvoj-Mihic B.,University of California at San Diego | Marchetto M.C.N.,Salk Institute for Biological Studies | Gage F.H.,Salk Institute for Biological Studies | Gage F.H.,Center for Academic Research and Training in Anthropogeny | And 4 more authors.
Biological Psychiatry | Year: 2014

Recent applications of genomic tools on the analysis of alterations unique to our species coupled with a growing number of neuroanatomical studies across primates provide an unprecedented opportunity to compile different levels of human brain evolution into a complex whole. Applications of induced pluripotent stem cell (iPSC) technology, capable of reprogramming somatic tissue of different species and generating species-specific neuronal phenotypes, for the first time offer an opportunity to test specific evolutionary hypotheses in a field of inquiry that has been long plagued by the limited availability of research specimens. In this review, we will focus specifically on the experimental role of iPSC technology as applied to the analysis of neocortical pyramidal neurons. Pyramidal neurons emerge as particularly suitable for testing evolutionary scenarios, since they form the most common morphological class of neurons in the cortex, display morphological variations across different cortical areas and cortical layers that appear species-specific, and express unique molecular signatures. Human and nonhuman primate iPSC-derived neurons may represent a unique biological resource to elucidate the phenotypic differences between humans and other hominids. As the typical morphology of pyramidal neurons tends to be compromised in neurological disorders, application of iPSC technology to the analysis of pyramidal neurons could not only bring new insights into human adaptation but also offer opportunities to link biomedical research with studies of the origins of the human species. © 2014 Society of Biological Psychiatry.

News Article | February 3, 2016

Zika emergency The World Health Organization (WHO) has declared a global public-health emergency over the cluster of birth-defect cases linked to the outbreak of Zika virus in Brazil and the Americas. The mosquito-borne virus has been linked to a condition called microcephaly, in which babies are born with abnormally small heads and brains, in children born to infected mothers. WHO experts say that the link is strongly suspected, if not yet scientifically proven. According to the Pan American Health Organisation, the disease is now present in 26 countries and territories in the Americas. The WHO says that restrictions on travel and trade are not necessary. See pages 5 and 13 for more. Scandal memoirs Haruko Obokata, the researcher at the centre of a stem-cell scandal, released a memoir on 28 January. Obokata’s claims that embryonic-like stem cells could be created by stressing mature mouse cells in a process called stimulus-triggered acquisition of pluripotency (STAP) fell apart, and two Nature papers were retracted in July 2014. In the book, Obokata attempts to shift responsibility for part of the scandal to a former mentor. Fifty thousand copies of the book were released initially. According to publisher Kodansha, many stores have sold out. Ocean-floor drilling mission digs deep An expedition in the Indian Ocean that aimed to create the deepest hole ever drilled into the ocean crust ended on 27 January, having reached 789 metres below the sea floor. Project scientists had hoped that drilling with the JOIDES Resolution ship would reach at least 1.3 kilometres, but say they are happy with the depth achieved. They intend to return and try to deepen the hole to reach the boundary between Earth’s crust and mantle. The two-month expedition was sidetracked in part by a team member requiring medical evacuation to Mauritius in the middle of drilling. Embryo editing In a world first, the UK Human Fertilisation and Embryology Authority has given scientists permission to edit the genomes of human embryos for research. The decision, announced on 1 February, allows developmental biologist Kathy Niakan at the Francis Crick Institute in London to use the genome-editing technique CRISPR–Cas9 in healthy human embryos. Niakan’s team plans to alter genes that are active in the first few days after fertilization. After seven days, the experiments will end and the embryos will be destroyed. See page 18 for more. Ancestry error Software problems have forced researchers to go back on claims that humans across the whole of Africa carry DNA inherited from Eurasian immigrants. The authors issued a note explaining the mistake in an October 2015 Science paper on the genome of a 4,500-year-old man from Ethiopia (M. Gallego Llorente et al. Science 350, 820–822; 2015). The paper had confirmed findings that although the first humans began to leave Africa 100,000 years ago, a group returned some 3,000 years ago. But its conclusion that the backflow reached West and Central Africa was wrong. The authors say that they used incompatible software packages to compare genetic variants, causing the error. See for more. Uranium glut The world’s civilian research reactors are taking too long to eliminate the use of highly enriched uranium, says a 28 January report from the US National Academies of Science, Engineering, and Medicine. Despite calls to phase out weapons-grade uranium, which is enriched to 90% or greater in the uranium-235 isotope, 74 reactors continue to use it. As an interim step to phasing it out completely — a process likely to take two decades — the report recommends blending the fuel to 45% enrichment or less. Diagnostics deal Global health-care company Abbott is to buy diagnostics firm Alere for US$5.8 billion. The buyout, announced on 1 February, will bolster Abbott’s diagnostics portfolio. Alere, in Waltham, Massachusetts, has annual sales of $2.5 billion and makes a range of point-of-care tests that can be used in remote locations to detect infections including HIV, tuberculosis, malaria and dengue. If the deal is approved, the firm will become an Abbott subsidiary, and Alere shareholders will get $56 per share. Fish flip-flop Despite the decision last November by the US Food and Drug Administration (FDA) to approve genetically modified salmon for human consumption, Americans will not be eating the fish any time soon. On 29 January, the FDA banned imports of fast-growing salmon produced in Panama and Canada by AquaBounty Technologies of Maynard, Massachusetts. The move is in response to the US budget bill passed last December, which bans sales of the fish until the FDA decides whether it should be labelled as genetically modified. The agency may take several years to finalize this rule. EU car tests The European Commission has unveiled tougher vehicle standards for car manufacturers in the wake of the Volkswagen emissions scandal. The proposed rules, announced on 27 January, will include increased independence of vehicle-emissions testing, spot checks on cars already on the market, and more powers for European authorities in an area that has been mainly the responsibility of individual governments. Volkswagen is still dealing with the aftermath of the revelation that it fitted some vehicles with devices that were designed to fool emissions tests. The company faces legal action from governments and consumers. Pipeline policy Pipelines and other natural-resource projects in Canada will soon be subject to more-robust environmental and public-review processes. The new assessment, announced on 27 January, will analyse greenhouse-gas emissions from construction and processing, and will include a broader public-consultation process, emphasizing the rights of indigenous peoples. The announcement is part of a broader effort by Prime Minister Justin Trudeau to bolster action on climate change. Last November, the United States denied Canadian energy-infrastructure company TransCanada a construction permit for a major pipeline that would have carried oil from the tar sands of Alberta to US refineries. Misconduct penalty Plant biologist Olivier Voinnet of the Swiss Federal Institute of Technology in Zurich has been stripped of an award and given a three-year ban on receiving funds from the Swiss National Science Foundation. Voinnet made his name studying gene silencing in plants, but charges of image manipulation and other issues have led to a slew of retractions and corrections of his published work (see Nature; 2015). On 28 January, Europe’s life-sciences organization EMBO told its members that Voinnet had agreed to return the EMBO Gold Medal he won in 2009. Trachea film A documentary has rekindled controversy surrounding surgeon Paolo Macchiarini, who is famed for performing artificial-trachea transplants. Concerns raised in the documentary, aired last month by SVT, Sweden’s public broadcaster, have prompted the Karolinska Institute in Stockholm, where Macchiarini is a visiting professor, to investigate — five months after it cleared him of separate accusations of scientific misconduct. Footage in the film suggests that one patient who received the risky procedure and later died was in broadly good health before the operation, contradicting the surgeon’s statements that he attempted the surgery only on people facing life-threatening illness. The documentary also illuminated a mismatch between the actual performance of a prosthetic trachea and its description in a paper co-authored by Macchiarini. See for more. More than 600 journals have signed up to the ARRIVE guidelines, which are designed to improve the reporting of animal experiments. Released in 2010, they list details that should be in such reports, including strains and sexes of animals, calculations and adverse reactions. More journals than ever signed up in 2015, says the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research, which produced the guidelines. Some have questioned whether ARRIVE can be enforced. 5 February The evolutionary origins of the genus Homo are debated at the Salk institute in La Jolla, California, in a seminar hosted by the Center for Academic Research and Training in Anthropogeny. 7–11 February Researchers looking at the cancer genome gather in Banff, Canada.

Babb P.L.,University of Pennsylvania | Fernandez-Duque E.,University of Pennsylvania | Fernandez-Duque E.,CONICET | Baiduc C.A.,University of Pennsylvania | And 4 more authors.
American Journal of Physical Anthropology | Year: 2011

Owl monkeys (Aotus spp.) inhabit much of South America yet represent an enigmatic evolutionary branch among primates. While morphological, cytogenetic, and immunological evidence suggest that owl monkey populations have undergone isolation and diversification since their emergence in the New World, problems with adjacent species ranges, and sample provenance have complicated efforts to characterize genetic variation within the genus. As a result, the phylogeographic history of owl monkey species and subspecies remains unclear, and the extent of genetic diversity at the population level is unknown. To explore these issues, we analyzed mitochondrial DNA (mt DNA) variation in a population of wild Azara's owl monkeys (Aotus azarai azarai) living in the Gran Chaco region of Argentina. We sequenced the complete mitochondrial genome from one individual (16,585 base pairs (bp)) and analyzed 1,099 bp of the hypervariable control region (CR) and 696 bp of the cytochrome oxidase II (COII) gene in 117 others. In addition, we sequenced the mitochondrial genome (16,472 bp) of one Nancy Ma's owl monkey (A. nancymaae). Based on the whole mtDNA and COII data, we observed an ancient phylogeographic discontinuity among Aotus species living north, south, and west of the Amazon River that began more than eight million years ago. Our population analyses identified three major CR lineages and detected a high level of haplotypic diversity within A. a. azarai. These data point to a recent expansion of Azara's owl monkeys into the Argentinean Chaco. Overall, we provide a detailed view of owl monkey mtDNA variation at genus, species, and population levels. Copyright © 2011 Wiley-Liss, Inc.

Chailangkarn T.,University of California at San Diego | Chailangkarn T.,Center for Academic Research and Training in Anthropogeny | Chailangkarn T.,National Center for Genetic Engineering and Biotechnology | Trujillo C.A.,University of California at San Diego | And 35 more authors.
Nature | Year: 2016

Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1, 2, 3, 4, 5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain. © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Comins J.A.,University of California at San Diego | Comins J.A.,Center for Academic Research and Training in Anthropogeny | Gentner T.Q.,University of California at San Diego | Gentner T.Q.,Kavli Institute for Brain and Mind
Animal Cognition | Year: 2014

The sequential patterning of complex acoustic elements is a salient feature of bird song and other forms of vocal communication. For European starlings (Sturnus vulgaris), a songbird species, individual vocal recognition is improved when the temporal organization of song components (called motifs) follows the normal patterns of each singer. This sensitivity to natural motif sequences may underlie observations that starlings can also learn more complex, unnatural motif patterns. Alternatively, it has been proposed that the apparent acquisition of abstract motif patterning rules instead reflects idiosyncrasies of the training conditions used in prior experiments. That is, that motif patterns are learned not by recognizing differences in temporal structures between patterns, but by identifying serendipitous features (e.g., acoustical cues) in the small sets of training and testing stimuli used. Here, we investigate this possibility, by asking whether starlings can learn to discriminate between two arbitrary motif patterns, when unique examples of each pattern are presented on every trial. Our results demonstrate that abstract motif patterning rules can be acquired from trial-unique stimuli and suggest that such training leads to better pattern generalization compared with training with much smaller stimulus subsets. © 2014 Springer-Verlag Berlin Heidelberg.

Franks T.M.,Salk Institute for Biological Studies | Benner C.,Salk Institute for Biological Studies | Narvaiza I.,Salk Institute for Biological Studies | Marchetto M.C.N.,Salk Institute for Biological Studies | And 5 more authors.
Genes and Development | Year: 2016

Nuclear pore complexes (NPCs) emerged as nuclear transport channels in eukaryotic cells ~1.5 billion years ago. While the primary role of NPCs is to regulate nucleo-cytoplasmic transport, recent research suggests that certain NPC proteins have additionally acquired the role of affecting gene expression at the nuclear periphery and in the nucleoplasm in metazoans. Here we identify a widely expressed variant of the transmembrane nucleoporin (Nup) Pom121 (named sPom121, for “soluble Pom121”) that arose by genomic rearrangement before the divergence of hominoids. sPom121 lacks the nuclear membrane-anchoring domain and thus does not localize to the NPC. Instead, sPom121 colocalizes and interacts with nucleoplasmic Nup98, a previously identified transcriptional regulator, at gene promoters to control transcription of its target genes in human cells. Interestingly, sPom121 transcripts appear independently in several mammalian species, suggesting convergent innovation of Nup-mediated transcription regulation during mammalian evolution. Our findings implicate alternate transcription initiation as a mechanism to increase the functional diversity of NPC components. © 2016 Franks et al.

Wang X.,Center for Academic Research and Training in Anthropogeny | Chow R.,University of California at San Diego | Deng L.,University of California at San Diego | Anderson D.,Yerkes National Primate Research Center | And 8 more authors.
Glycobiology | Year: 2011

Siglecs (Sialic acid-binding Immunoglobulin Superfamily Lectins) are cell surface signaling receptors of the I-type lectin group that recognize sialic acid-bearing glycans. CD33-related-Siglecs are a subset with expression primarily in cells of hematopoietic origin and functional relevance to immune reactions. Earlier we reported a human-specific gene conversion event that markedly changed the coding region for the extracellular domain of Siglec-11, associated with human-specific expression in microglia (Hayakawa T, Angata T, Lewis AL, Mikkelsen TS, Varki NM, Varki A. 2005. A human-specific gene in microglia. Science. 309:1693). Analyzing human gene microarrays to define new patterns of expression, we observed high levels of SIGLEC11 transcript in the ovary and adrenal cortex. Thus, we examined human and chimpanzee tissues using a well-characterized anti-Siglec-11 mouse monoclonal antibody. Although adrenal expression was variable and confined to infiltrating macrophages in capillaries, ovarian expression of Siglec-11 in both humans and chimpanzees was on fibroblasts, the first example of Siglec expression on mesenchyme-derived stromal cells. Cytokines from such ovarian stromal fibroblasts play important roles in follicle development and ovulation. Stable transfection of SIGLEC11 into a primary human ovarian stromal fibroblast cell line altered the secretion of growth-regulated oncogene , interleukin (IL)-10, IL-7, transforming growth factor 1 and tumor necrosis factor-, cytokines involved in ovarian physiology. Probing for Siglec-11 ligands revealed distinct and strong mast cell expression in human ovaries, contrasting to diffuse stromal ligands in chimpanzee ovaries. Interestingly, there was a trend of increased Siglec-11 expression in post-menopausal ovaries compared with pre-menopausal ones. Siglec-11 expression was also found on human ovarian stromal tumors and in polycystic ovarian syndrome, a human-specific disease. These results indicate potential roles for Siglec-11 in ovarian physiology and human evolution. © 2011 The Author.

Nuttle X.,University of Washington | Giannuzzi G.,University of Lausanne | Duyzend M.H.,University of Washington | Schraiber J.G.,University of Washington | And 31 more authors.
Nature | Year: 2016

Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. Here we reconstruct the evolutionary history of the locus and identify bolA family member 2 (BOLA2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95-kilobase-pair segment containing BOLA2 duplicated across the critical region approximately 282 thousand years ago (ka), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carried one or more copies of the duplication, which nearly fixed early in the human lineage-a pattern unlikely to have arisen so rapidly in the absence of selection (P < 0.0097). We show that the duplication of BOLA2 led to a novel, human-specific in-frame fusion transcript and that BOLA2 copy number correlates with both RNA expression (r = 0.36) and protein level (r = 0.65), with the greatest expression difference between human and chimpanzee in experimentally derived stem cells. Analyses of 152 patients carrying a chromosome 16p11.2 rearrangement show that more than 96% of breakpoints occur within the H. sapiens-specific duplication. In summary, the duplicative transposition of BOLA2 at the root of the H. sapiens lineage about 282 ka simultaneously increased copy number of a gene associated with iron homeostasis and predisposed our species to recurrent rearrangements associated with disease. © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

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