Genetic comparison of sickle cell anaemia cohorts from Brazil and the United States reveals high levels of divergence

Genetic analysis of admixed populations raises special concerns with regard to study design and data processing, particularly to avoid population stratification biases. The point mutation responsible for sickle cell anaemia codes for a variant hemoglobin, sickle hemoglobin or HbS, whose presence drives the pathophysiology of disease. Here we propose to explore ancestry and population structure in a genome-wide study with particular emphasis on chromosome 11 in two SCA admixed cohorts obtained from urban populations of Brazil (Pernambuco and Sao Paulo) and the United States (Pennsylvania). Ancestry inference showed different proportions of European, African and American backgrounds in the composition of our samples. Brazilians were more admixed, had a lower African background (43% vs. 78% on the genomic level and 44% vs. 76% on chromosome 11) and presented a signature of positive selection and Iberian introgression in the HbS region, driving a high differentiation of this locus between the two cohorts. The genetic structures of the SCA cohorts from Brazil and US differ considerably on the genome-wide, chromosome 11 and HbS mutation locus levels9CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP8367/2011-1; 150398/2013-1; 304455/2012-1; 310938/2014-7; 305218/2017-48367/2011-1; 150398/2013-1; 304455/2012-1; 310938/2014-7; 305218/2017-42008/57441-0; 2014/00984-3; 2012/06438-5; 2015/13152-9; 2008/10596-

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Investigation of genetic factors on the etiology of orofacial clefts typical

Orientador: Vera Lucia Gil da Silva LopesTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: As fendas orofaciais típicas (FOT) são defeitos congênitos prevalentes que possuem múltiplas etiologias. Estudos populacionais apontaram diferentes genes relacionados às FOTs. Entretanto, em muitos casos, a etiologia permanece desconhecida. A investigação individualizada, utilizando em conjunto diferentes ferramentas laboratoriais, é uma abordagem mais complexa que pode contribuir na caracterização etiológica das FOTs. Assim, este estudo teve como objetivo investigar os fatores genéticos envolvidos na etiologia das FOTs em uma casuística composta por 23 indivíduos afetados, incluindo casos sindrômicos e não-sindrômicos, familiais e esporádicos. Participaram do grupo controle 20 indivíduos sem história familial de fenda em três gerações. Todos os indivíduos portadores de FOT foram previamente avaliados por um médico geneticista e por exame de cariótipo em linfócitos, sendo dois casos detectados com aberrações cromossômicas. A análise de alterações no número de cópias de segmentos de DNA (Copy Number Variation, CNVs) por hibridação genômica em arrays (aGH), baseada na comparação com grupo controle, apontou um novo gene de candidato para FOT, o gene TCEB3, e identificou uma duplicação no gene FGFR1. Em um paciente com fenda palatal submucosa e quadro sindrômico, a utilização da técnica de aGH, em conjunto à hibridação in situ fluorescente (FISH) e Multiplex Ligationdependent Probe Amplification (MLPA), possibilitou a caracterização da aberração cromossômica detectada pelo cariótipo. Em todos os portadores de FOT também foi realizado sequenciamento direto dos genes IRF6, FOXE1, GLI2, MSX2, SKI, SATB2, SPRY1, MSX1, FGF8, FGFR1; em um paciente específico, foi avaliado o gene P63. Alterações de sequencia inéditas foram encontradas nos genes FOXE1, MSX1, GLI2 e FGF8, assim como uma inserção no gene P63, cujos efeitos na proteína codificada deverão ser confirmados em estudos futuros. Os resultados deste trabalho exemplificam a diversidade de fatores genéticos envolvidos na etiologia das FOTs e o desenho de estudo utilizado mostrou a eficácia do uso concomitante de diferentes abordagens investigativas neste grupo de defeitos congênitosAbstract: Typical oral cleft (TOC) is a prevalent and heterogeneous group of congenital defects with multiple etiologies, which remain unknown in several cases. Population studies detected several genes related to TOC. An individualized investigation, involving different laboratorial tools at same time, is an approach that can contribute on the etiological characterization of the TOC. The aim of this study was to investigate genetic factors involved on TOC in a sample composed by 23 individuals (syndromic and non-syndromic; familial and sporadic cases). The control group included 20 individuals without TOC in three generations. All patients were previously evaluated by clinical geneticists and performed karyotype test that showed chromosomal aberrations in two cases. Copy number variation (CNV) investigation by genomic hibridization in arrays (aGH), based in a comparative to control group data, detected a new candidate gene to TOC (TCEB3), and identified a duplication affecting FGFR1 gene. In one patient with syndromic form of submucous cleft palate, the use of aGH technique, together with Fluorescent in situ hibridization (FISH) and Multiplex ligation-dependent probe amplification (MLPA), characterized the chromosomal aberration previously detected by karyotype. Direct sequencing of IRF6, FOXE1, GLI2, MSX2, SKI, SATB2, SPRY1, MSX1, FGF8 and FGFR1 genes was performed in all individuals; in a specific case, P63 gene was investigated. New sequence alterations were found in FOXE1, MSX1, GLI2 e FGF8 genes, as well as an insertion in P63 gene, which effects will be verified in futures studies. In conclusion, results here described reflect the diversity of genetic factors involved in the etiology of TOC and the type of study show the efficiency of the use of different techniques in the etiological investigation of this congenital defectDoutoradoCiencias BiomedicasDoutor em Ciências Médica

22q11.2 chromosome region and the Midline defects with Hipertelorism

Orientador: Vera Lucia Gil da Silva LopesDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias MedicasResumo: Os Defeitos de Linha Média Facial com Hipertelorismo (DLMFH) constituem um grupo de anomalias craniofaciais raras e heterogêneas caracterizado por hipertelorismo ocular e fenda nasal mediana e (ou) lateral. Esses defeitos podem ocorrer isoladamente ou associados a dismorfismos com ou sem padrão definido, motivo pelo qual sua incidência não foi estabelecida até o momento. Dentre os fatores que podem participar da sua gênese encontra-se a perda de controle de genes de desenvolvimento envolvidos no processo de formação facial. A microdeleção 22q11.2, região dos genes HIRA/TUPLE1 e TBX1, causa a Síndrome Velocardiofacial e a Seqüência de DiGeorge. Essa deleção também foi descrita em casos esporádicos de anomalias congênitas múltiplas e DLMFH. Esses fatos, corroborados por extensa revisão da literatura, sugerem que os DLMFH possam fazer parte do espectro dessas condições clínicas e estarem associados a alterações na região 22q11.2. Para estudar essa hipótese, 10 indivíduos com DLMFH foram analisados por meio da técnica de FISH, utilizando a sonda comercial 22q11.2 DiGeorge ¿ HIRA/TUPLE1 locus (VysisTM). Não foi encontrada perda de fragmento cromossômico nessa região em nenhum dos indivíduos analisados. Os genes HIRA/TUPLE1 e TBX1 foram estudados por meio de técnicas moleculares. Não foi possível realizar a padronização da amplificação dos exons do gene HIRA/TUPLE1. Alterações de seqüência no gene TBX1, descritas como polimorfismos de nucleotídeo único e uma alteração inédita no exon 9C, 1132G ? A, foram encontradas. Em vista do tamanho amostral e da heterogeneidade clínica e etiológica, o presente trabalho não pode relacionar o envolvimento da região 22q11.2 na patogenia dos DLMFHAbstract: Midline Facial Defects with Hipertelorism (MFDH) is a rare and heterogeneous group of craniofacial disorders characterized by ocular hypertelorism and bifid nose. This group of craniofacial defects occurs isolated or as part of a syndrome. For these reasons, its prevalence is still unknown. Alterations in developmental genes involved in facial process could be implicated in the genesis of this condition. The 22q11.2 microdeletion, localization of the HIRA/TUPLE1 and TBX1 genes, causes Velocardiofacial Syndrome and DiGeorge Syndrome. This deletion was also described in few cases of multiple congenital anomalies and MFDH. These facts suggested that some cases of MFDH may be part of the spectrum of these conditions and associated to alterations in the 22q11.2 region. In order to verify this hypothesis, fluorescent in situ hybridization (FISH) for 22q11.2 region (DiGeorge ¿ HIRA/TUPLE1 locus probe, VysisTM) was performed on metaphase chromosomes and nuclei of 10 individuals with MFDH. The 22q11.2 deletion was not found in any patient. Molecular techniques were applied in the study of HIRA/TUPLE1 and TBX1 genes. The amplification of HIRA/TUPLE1 exons was not possible to be realized. Alterations in the sequence of TBX1 gene, classified as single nucleotide polymorphism and a new alteration in exon 9C, 1132G ? A, were found. In view of the size of the sample and the clinical-genetic heterogeneity, we could not associate the involvement of 22q11.2 region in the genesis of MFDHMestradoCiencias BiomedicasMestre em Ciências Médica

De Novo Double Reciprocal Translocations In Addition To Partial Monosomy At Another Chromosome: A Very Rare Case

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Reciprocal translocations are one of the most common structural rearrangements with a frequency of 1:500 and occur when there is an exchange of distal segments to breakpoints between non-homologous chromosomes. Two or three independent, simple reciprocal or Robertsonian translocations co-exist in the same carrier were classified as complex chromosome rearrangements (CCRs). Structural chromosome rearrangements are considered balanced when there is no apparent gain or loss of chromosome material. In majority of cases, apparently balanced structural chromosome rearrangements (ABCR) are not associated with abnormal phenotypes, although these have been described in 6% of de novo ABCR and 23% of apparently balanced CCR Here we report a patient with de novo two apparently balanced reciprocal translocations and two partial monosomies, one of these involving an independent chromosome characterized by microarray. Structural rearrangement investigations can improve the knowledge about human genome architecture and correlation of genomic imbalances to abnormal phenotype. (C) 2015 Elsevier B.V. All rights reserved.5731166170Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2011/23794-7, 2012/10071-0]CNPq [304455/2012-1