Using the Neandertal and Denisova Genetic Data to Understand the Common \u3cem\u3eMAPT\u3c/em\u3e 17q21 Inversion in Modern Humans

The polymorphic inversion on 17q21, that includes the MAPT gene, represents a unique locus in the human genome characterized by a large region with strong linkage disequilibrium. Two distinct haplotypes, H1 and H2, exist in modern humans, and H1 has been unequivocally related to several neurodegenerative disorders. Recent data indicates that recurrent inversions of this genomic region have occurred through primate evolution, with the H2 haplotype being the ancestral state. Neandertals harbored the H1 haplotype, however until now no data was available for the Denisova hominin. Neandertals and Denisovans are sister groups that share a common ancestor with modern humans. We analyzed the MAPT sequence and assessed the differences between modern humans, Neandertals, Denisovans, and great apes. Our analysis indicated that the Denisova hominin carried the H1 haplotype and the Neandertal and Denisova common ancestor probably shared the same subhaplotype (H1j). We also found 68 intronic variants within the MAPT gene, 23 exclusive to Denisova hominin, 6 limited to Neandertals and 24 exclusive to present-day humans. Our results reinforce previous data suggesting that the 17q21 inversion arose within the modern human lineage. The data also indicates that archaic hominins that coexisted in Eurasia probably shared the same MAPT subhaplotype, hat can be found in almost 2% of chromosomes from European ancestry

Hyper, a Hydrogen Peroxide Sensor, Indicates the Sensitivity of the Arabidopsis Root Elongation Zone to Aluminum Treatment

Emerging evidence indicates that some reactive oxygen species (ROS), such as the superoxide anion radical and hydrogen peroxide (H2O2), are central regulators of plant responses to biotic and abiotic stresses. Thus, the cellular levels of ROS are thought to be tightly regulated by an efficient and elaborate pro- and antioxidant system that modulates the production and scavenging of ROS. Until recently, studies of ROS in plant cells have been limited to biochemical assays and the use of fluorescent probes; however, the irreversible oxidation of these fluorescent probes makes it impossible to visualize dynamic changes in ROS levels. In this work, we describe the use of Hyper, a recently developed live cell probe for H2O2 measurements in living cells, to monitor oxidative stress in Arabidopsis roots subjected to aluminum treatment. Hyper consists of a circularly permuted YFP (cpYFP) inserted into the regulatory domain of the Escherichia coli hydrogen peroxide-binding protein (OxyR), and is a H2O2-specific ratiometric, and therefore quantitative, probe that can be expressed in plant and animal cells. Now we demonstrate that H2O2 levels drop sharply in the elongation zone of roots treated with aluminum. This response could contribute to root growth arrest and provides evidence that H2O2 is involved in early Al sensing

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems

Search for a Light Charged Higgs Boson Decaying to a W Boson and a CP-Odd Higgs Boson in Final States with eμμ or μμμ in Proton-Proton Collisions at √s=13 TeV

A search for a light charged Higgs boson (H+) decaying to a W boson and a CP-odd Higgs boson (A) in final states with eμμ or μμμ is performed using data from pp collisions at √s=13  TeV, recorded by the CMS detector at the LHC and corresponding to an integrated luminosity of 35.9  fb−1. In this search, it is assumed that the H+ boson is produced in decays of top quarks, and the A boson decays to two oppositely charged muons. The presence of signals for H+ boson masses between 100 and 160 GeV and A boson masses between 15 and 75 GeV is investigated. No evidence for the production of the H+ boson is found. Upper limits at 95% confidence level are obtained on the combined branching fraction for the decay chain, t→bH+→bW+A→bW+μ+μ−, of 1.9×10−6 to 8.6×10−6, depending on the masses of the H+ and A bosons. These are the first limits for these decay modes of the H+ and A bosons.Peer reviewe

Search for dark matter particles produced in association with a Higgs boson in proton-proton collisions at √s = 13 TeV

© 2020, The Author(s). A search for dark matter (DM) particles is performed using events with a Higgs boson candidate and large missing transverse momentum. The analysis is based on proton- proton collision data at a center-of-mass energy of 13 TeV collected by the CMS experiment at the LHC in 2016, corresponding to an integrated luminosity of 35.9 fb−1. The search is performed in five Higgs boson decay channels: h → b b ¯ , γγ, τ+τ−, W+W−, and ZZ. The results from the individual channels are combined to maximize the sensitivity of the analysis. No significant excess over the expected standard model background is observed in any of the five channels or in their combination. Limits are set on DM production in the context of two simplified models. The results are also interpreted in terms of a spin-independent DM-nucleon scattering cross section and compared to those from direct-detection DM experiments. This is the first search for DM particles produced in association with a Higgs boson decaying to a pair of W or Z bosons, and the first statistical combination based on five Higgs boson decay channels. [Figure not available: see fulltext.].SCOAP

Almost 20 years of Neanderthal palaeogenetics: Adaptation, admixture, diversity, demography and extinction

Nearly two decades since the first retrieval of Neanderthal DNA, recent advances in next-generation sequencing technologies have allowed the generation of high-coverage genomes from two archaic hominins, a Neanderthal and a Denisovan, as well as a complete mitochondrial genome from remains which probably represent early members of the Neanderthal lineage. This genomic information, coupled with diversity exome data from several Neanderthal specimens is shedding new light on evolutionary processes such as the genetic basis of Neanderthal and modern human-specific adaptations—including morphological and behavioural traits—as well as the extent and nature of the admixture events between them. An emerging picture is that Neanderthals had a long-term small population size, lived in small and isolated groups and probably practised inbreeding at times. Deleterious genetic effects associated with these demographic factors could have played a role in their extinction. The analysis of DNA from further remains making use of new large-scale hybridization-capture-based methods as well as of new approaches to discriminate contaminant DNA sequences will provide genetic information in spatial and temporal scales that could help clarify the Neanderthal's—and our very own—evolutionary history.© 2014 The Author(s) Published by the Royal Society. All rights reserved.Peer Reviewe

Population Genomic Analysis of Ancient and Modern Genomes Yields New Insights into the Genetic Ancestry of the Tyrolean Iceman and the Genetic Structure of Europe

Sikora, Martin et al.Genome sequencing of the 5,300-year-old mummy of the Tyrolean Iceman, found in 1991 on a glacier near the border of Italy and Austria, has yielded new insights into his origin and relationship to modern European populations. A key finding of that study was an apparent recent common ancestry with individuals from Sardinia, based largely on the Y chromosome haplogroup and common autosomal SNP variation. Here, we compiled and analyzed genomic datasets from both modern and ancient Europeans, including genome sequence data from over 400 Sardinians and two ancient Thracians from Bulgaria, to investigate this result in greater detail and determine its implications for the genetic structure of Neolithic Europe. Using whole-genome sequencing data, we confirm that the Iceman is, indeed, most closely related to Sardinians. Furthermore, we show that this relationship extends to other individuals from cultural contexts associated with the spread of agriculture during the Neolithic transition, in contrast to individuals from a hunter-gatherer context. We hypothesize that this genetic affinity of ancient samples from different parts of Europe with Sardinians represents a common genetic component that was geographically widespread across Europe during the Neolithic, likely related to migrations and population expansions associated with the spread of agriculture. © 2014 Sikora et al.This project was supported by NIH grant 2R01HG003229. This work was also partially supported by an Erwin Schrödinger Fellowship of the Austrian Science Fund (FWF) to MS (J3375-B19).Peer reviewe

Adressing Neandertal evolutionary genetics at three different resolution levels : admixture with modern humans, demography and social structure

Almost 20 years of Neandertal paleogenetics studies have significantly increased our knowledge about their evolutionary history. The analysis of DNA recovered from Neandertal remains to date, suggest that although they were a distinct hominin population to modern humans, a certain degree of gene flow occurred between the two of them. Furthermore, recent evidence suggests that archaic introgressed material could have been biologically relevant for modern humans to adapt to new environments. Moreover, insights from a wide geographic and temporally different sampling of Neandertal mitochondrial sequences and from a high-coverage genome, suggest that Neandertals probably had a low effective population, which was possibly decreasing towards the end of their evolutionary time. This thesis focus to address the evolutionary genetic history of Neandertals at three different levels of resolution from: analyzing further aspects of their relatedness to modern humans, better characterizing their population history and identify the genetic basis for some of their distinctive morphological features, to describing their genetic structure within a social group. Insights from these three lines of research intend to reconstruct key aspects of their population history and its implications towards their eventual demise.Casi veinte años de estudios de paleogenética Neandertal han incrementado significativamente nuestro conocimiento sobre su historia evolutiva. El análisis de secuencias genéticas recuperadas a partir de fósiles Neandertales, sugiere que a pesar de que éstos era un grupo de homínidos diferentes a los humanos modernos, cierta grado de introgresión genética ocurrió de Neandertales hacia humanos modernos. Más aún, estudios recientes sugieren que el material genético introducido a éstos pudo haber sido relevante biológicamente para adaptarse a nuevos ambientes. Por otro lado, inferencias a partir de datos genéticos mitocondriales provenientes de muestras de diferentes zonas geográficas y origen temporal, a la par con la secuencia de un genoma completo de alta calidad sugieren que los Neandertales tenían un tamaño efectivo de población reducido y que probablemente estaba disminuyendo hacia el final de su tiempo. La tesis aquí presentada, se enfoca a abordar la historia evolutiva Neandertal a tres niveles de resolución diferentes, analizando datos genéticos provenientes de fósiles. Primero, se analizan otros posibles eventos de introgresión genética con humanos modernos, no descritos hasta la fecha. Posteriormente, se caracteriza a detalle su demografía e identifica cambios específicos para su linaje evolutivo que podrían estar relacionados con las bases genéticas de algunos de sus rasgos morfológicos más distintivos. Finalmente, se describe la estructura genética y dinámica de un grupo social Neandertal. Las perspectivas de estas tres líneas de investigación pretenden no sólo reconstruir aspectos claves de su historia evolutiva, sino también entender las consecuencias que ésta pudo haber tenido con su eventual extinción

Patterns of coding variation in the complete exomes of three Neandertals

We present the DNA sequence of 17,367 protein-coding genes in two Neandertals from Spain and Croatia and analyze them together with the genome sequence recently determined from a Neandertal from southern Siberia. Comparisons with present-day humans from Africa, Europe, and Asia reveal that genetic diversity among Neandertals was remarkably low, and that they carried a higher proportion of amino acid-changing (nonsynonymous) alleles inferred to alter protein structure or function than present-day humans. Thus, Neandertals across Eurasia had a smaller long-term effective population than present-day humans. We also identify amino acid substitutions in Neandertals and present-day humans that may underlie phenotypic differences between the two groups. We find that genes involved in skeletal morphology have changed more in the lineage leading to Neandertals than in the ancestral lineage common to archaic and modern humans, whereas genes involved in behavior and pigmentation have changed more on the modern human lineage.We thank David Reich and Montgomery Slatkin for comments on the manuscript, Oscar Lao for clarifying the ancestry of one present-day individual, Cesare de Filippo for help with the principal components analysis plots, Agilent Technologies for the capture arrays, and the Presidential Innovation Fund of the Max Planck Society for support. C.L.-F. and F.A.S.-Q. are supported by the Ministerio de Economía y Competitividad (Grant BFU2012-34157). Castellano, Sergi et al.Peer Reviewe