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1.
Am J Bot ; 108(9): 1808-1815, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34590302

RESUMO

PREMISE: Plant domestication can be detected when transport, use, and manipulation of propagules impact reproductive functionality, especially in species with self-incompatible breeding systems. METHODS: Evidence for human-caused founder effect in the Four Corners potato (Solanum jamesii Torr.) was examined by conducting 526 controlled matings between archaeological and non-archaeological populations from field-collected tubers grown in a greenhouse. Specimens from 24 major herbaria and collection records from >160 populations were examined to determine which produced fruits. RESULTS: Archaeological populations did not produce any fruits when self-crossed or outcrossed between individuals from the same source. A weak ability to self- or outcross within populations was observed in non-archaeological populations. Outcrossing between archaeological and non-archaeological populations, however, produced fully formed, seed-containing fruits, especially with a non-archaeological pollen source. Fruit formation was observed in 51 of 162 occurrences, with minimal evidence of constraint by monsoonal drought, lack of pollinators, or spatial separation of suitable partners. Some archaeological populations (especially those along ancient trade routes) had records of fruit production (Chaco Canyon), while others (those in northern Arizona, western Colorado, and southern Utah) did not. CONCLUSIONS: The present study suggests that archaeological populations could have different origins at different times-some descending directly from large gene pools to the south and others derived from gardens already established around occupations. The latter experienced a chain of founder events, which presumably would further reduce genetic diversity and mating capability. Consequently, some archaeological populations lack the genetic ability to sexually reproduce, likely as the result of human-caused founder effect.


Assuntos
Solanum , Efeito Fundador , Geografia , Humanos , Melhoramento Vegetal , Polinização , Reprodução , Solanum/genética
2.
Sci Rep ; 11(1): 17184, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433859

RESUMO

Malignant cells leave their initial tumor of growth and disperse to other tissues to form metastases. Dispersals also occur in nature when individuals in a population migrate from their area of origin to colonize other habitats. In cancer, phylogenetic biogeography is concerned with the source and trajectory of cell movements. We examine the suitability of primary features of organismal biogeography, including genetic diversification, dispersal, extinction, vicariance, and founder effects, to describe and reconstruct clone migration events among tumors. We used computer-simulated data to compare fits of seven biogeographic models and evaluate models' performance in clone migration reconstruction. Models considering founder effects and dispersals were often better fit for the clone phylogenetic patterns, especially for polyclonal seeding and reseeding of metastases. However, simpler biogeographic models produced more accurate estimates of cell migration histories. Analyses of empirical datasets of basal-like breast cancer had model fits consistent with the patterns seen in the analysis of computer-simulated datasets. Our analyses reveal the powers and pitfalls of biogeographic models for modeling and inferring clone migration histories using tumor genome variation data. We conclude that the principles of molecular evolution and organismal biogeography are useful in these endeavors but that the available models and methods need to be applied judiciously.


Assuntos
Neoplasias da Mama/genética , Efeito Fundador , Migração Humana , Modelos Genéticos , Filogenia , Neoplasias da Mama/epidemiologia , Evolução Molecular , Feminino , Frequência do Gene , Humanos , Masculino , Polimorfismo Genético
3.
Nat Commun ; 12(1): 4306, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262034

RESUMO

We lack a thorough understanding of the origin and maintenance of standing genetic variation that enables rapid evolutionary responses of natural populations. Whole genome sequencing of a resurrected Daphnia population shows that standing genetic variation in over 500 genes follows an evolutionary trajectory that parallels the pronounced and rapid adaptive evolution of multiple traits in response to predator-driven natural selection and its subsequent relaxation. Genetic variation carried by only five founding individuals from the regional genotype pool is shown to suffice at enabling the observed evolution. Our results provide insight on how natural populations can acquire the genomic variation, through colonization by a few regional genotypes, that fuels rapid evolution in response to strong selection pressures. While these evolutionary responses in our study population involved hundreds of genes, we observed no evidence of genetic erosion.


Assuntos
Adaptação Fisiológica/genética , Daphnia/fisiologia , Efeito Fundador , Variação Genética , Animais , Evolução Biológica , Daphnia/genética , Frequência do Gene , Genética Populacional , Genoma/genética , Genótipo , Fenótipo , Seleção Genética
4.
Eur J Med Genet ; 64(9): 104291, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34303877

RESUMO

Aicardi-Goutieres Syndrome (AGS) is a heterogeneous genetic syndrome, manifesting early as encephalopathy and is associated with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, thrombocytopenia and intracranial calcification. The most severe neonatal type, AGS1, is caused by biallelic disease-causing variants in TREX1. In this study, we describe four patients with TREX1-related AGS1 whose phenotype overlaps with intra-uterine infections and neonatal lupus. Exome sequencing identified a previously reported TREX1 variant, c.223dup (NM_016381.5; p. Glu75GlyfsTer82) in all the four patients belonging to the Indian subcontinent. The functional consequence of the disease-causing variant was predicted by using a new combination of bioinformatics softwares. The recurrence of this pathogenic variant indicates a possible founder effect in TREX1 for AGS1 in this population. The phenotypic variability in those with this founder mutation can mimic intrauterine infections and neonatal lupus, thereby leading to misdiagnosis warranting a targeted genetic testing approach to be a part of the diagnostic workup to obtain a definite, early and cost-effective diagnosis in patients from Indian subcontinent with early onset encephalopathy.


Assuntos
Doenças Autoimunes do Sistema Nervoso/genética , Exodesoxirribonucleases/genética , Malformações do Sistema Nervoso/genética , Fenótipo , Fosfoproteínas/genética , Doenças Autoimunes do Sistema Nervoso/epidemiologia , Doenças Autoimunes do Sistema Nervoso/patologia , Exodesoxirribonucleases/química , Feminino , Efeito Fundador , Frequência do Gene , Humanos , Índia , Lactente , Masculino , Mutação , Malformações do Sistema Nervoso/epidemiologia , Malformações do Sistema Nervoso/patologia , Fosfoproteínas/química , Domínios Proteicos
5.
Eur J Endocrinol ; 185(4): 453-462, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34292171

RESUMO

Aims: LMNA-linked familial partial lipodystrophy type 2 (FPLD2) leads to insulin resistance-associated metabolic complications and cardiovascular diseases. We aimed to characterise the disease phenotype in a cohort of patients carrying an LMNA founder variant. Methods: We collected clinical and biological data from patients carrying the monoallelic or biallelic LMNA p.(Thr655Asnfs*49) variant (n = 65 and 13, respectively) and 19 non-affected relative controls followed-up in Reunion Island Lipodystrophy Competence Centre, France. Results: Two-thirds of patients with FPLD2 (n = 51) and one-third of controls (n = 6) displayed lipodystrophy and/or lean or android morphotype (P = 0.02). Although age and BMI were not statistically different between the two groups, the insulin resistance index (median HOMA-IR: 3.7 vs 1.5, P = 0.001), and the prevalence of diabetes, dyslipidaemia, and non-alcoholic fatty liver disease were much higher in patients with FPLD2 (51.3 vs 15.8%, 83.3 vs 42.1%, and 83.1 vs 33.3% (all P ≤ 0.01), respectively). Atherosclerosis tended to be more frequent in patients with FPLD2 (P = 0.07). Compared to heterozygous, homozygous patients displayed more severe lipoatrophy and metabolic alterations (lower BMI, fat mass, leptin and adiponectin, and higher triglycerides P ≤ 0.03) and tended to develop diabetes more frequently, and earlier (P = 0.09). Dilated cardiomyopathy and/or rhythm/conduction disturbances were the hallmark of the disease in homozygous patients, leading to death in four cases. Conclusions: The level of expression of the LMNA 'Reunionese' variant determines the severity of both lipoatrophy and metabolic complications. It also modulates the cardiac phenotype, from atherosclerosis to severe cardiomyopathy, highlighting the need for careful cardiac follow-up in affected patients.


Assuntos
Cardiomiopatias/genética , Lamina Tipo A/genética , Lipodistrofia Parcial Familiar/genética , Doenças Metabólicas/genética , Adulto , Cardiomiopatias/epidemiologia , Estudos de Casos e Controles , Feminino , Efeito Fundador , Frequência do Gene , Heterozigoto , Homozigoto , Humanos , Laminopatias/complicações , Laminopatias/epidemiologia , Laminopatias/genética , Lipodistrofia Parcial Familiar/complicações , Lipodistrofia Parcial Familiar/epidemiologia , Masculino , Doenças Metabólicas/epidemiologia , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Reunião/epidemiologia , Adulto Jovem
6.
PLoS One ; 16(7): e0255169, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34297786

RESUMO

Since the first case of COVID-19 in December 2019 in Wuhan, China, SARS-CoV-2 has spread worldwide and within a year and a half has caused 3.56 million deaths globally. With dramatically increasing infection numbers, and the arrival of new variants with increased infectivity, tracking the evolution of its genome is crucial for effectively controlling the pandemic and informing vaccine platform development. Our study explores evolution of SARS-CoV-2 in a representative cohort of sequences covering the entire genome in the United States, through all of 2020 and early 2021. Strikingly, we detected many accumulating Single Nucleotide Variations (SNVs) encoding amino acid changes in the SARS-CoV-2 genome, with a pattern indicative of RNA editing enzymes as major mutators of SARS-CoV-2 genomes. We report three major variants through October of 2020. These revealed 14 key mutations that were found in various combinations among 14 distinct predominant signatures. These signatures likely represent evolutionary lineages of SARS-CoV-2 in the U.S. and reveal clues to its evolution such as a mutational burst in the summer of 2020 likely leading to a homegrown new variant, and a trend towards higher mutational load among viral isolates, but with occasional mutation loss. The last quartile of 2020 revealed a concerning accumulation of mostly novel low frequency replacement mutations in the Spike protein, and a hypermutable glutamine residue near the putative furin cleavage site. Finally, end of the year data and 2021 revealed the gradual increase to prevalence of known variants of concern, particularly B.1.1.7, that have acquired additional Spike mutations. Overall, our results suggest that predominant viral genomes are dynamically evolving over time, with periods of mutational bursts and unabated mutation accumulation. This high level of existing variation, even at low frequencies and especially in the Spike-encoding region may become problematic when super-spreader events, akin to serial Founder Events in evolution, drive these rare mutations to prominence.


Assuntos
COVID-19 , Evolução Molecular , Efeito Fundador , Genoma Viral , Mutação , Pandemias , SARS-CoV-2/genética , COVID-19/epidemiologia , COVID-19/genética , Humanos , Estados Unidos
7.
Biomed Res Int ; 2021: 1515641, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34235214

RESUMO

Background: Metabolic disorder alkaptonuria is an autosomal recessive disorder caused by mutations in the HGD gene, and a deficiency HGD enzyme activity results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. Methods: We clinically evaluated 18 alkaptonuria patients (age range, 3 to 60 years) from four unrelated families. Furthermore, 11 out of 18 alkaptonuria patients and 7 unaffected members were enrolled for molecular investigations by utilizing Sanger sequencing to identify variants of the 14 exons of HGD gene. Results: We found that the seven patients from the 4 unrelated families carried a recurrent pathogenic missense variant (c.365C>T, p. Ala122Val) in exon 6 of HGD gene. The variant was fully segregated with the disease in affected family members while the other unaffected family members were heterozygous carriers for this variant. Additionally, the clinical features were fully predicted with alkaptonuria disorder. Conclusion: In this study, we confirmed that the most common variants in Jordanian AKU patients was c.365C>T, p. Ala122Val in exon 6 of HGD gene. Additionally, we correlated the clinical and genetic features of AKU patients at various ages (3-60 years).


Assuntos
Alcaptonúria/genética , Saúde da Família , Efeito Fundador , Genes Recessivos , Homogentisato 1,2-Dioxigenase/genética , Ocronose/genética , Adolescente , Adulto , Criança , Pré-Escolar , Éxons , Feminino , Variação Genética , Heterozigoto , Ácido Homogentísico/metabolismo , Humanos , Jordânia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Oligonucleotídeos , Linhagem , Análise de Sequência de DNA , Adulto Jovem
8.
Stem Cell Res ; 53: 102364, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34087993

RESUMO

Women who inherit heterozygous mutations in the BRCA2 gene have an increased risk of developing cancer, mainly breast and ovarian tumors. A particular BRCA2 mutation (c.156_157insAlu) is exclusively found in families of Portuguese ancestry and is present in approximately 30% of all Portuguese families with hereditary breast and ovarian cancers. We report the generation and characterization of the first iPSC line from a female donor harboring the Portuguese BRCA2 founder mutation. Skin fibroblasts were reprogrammed using a non-integrative Sendai virus. These iPSCs are a valuable tool to study the origin of BRCA2-associated cancer in its earliest phases.


Assuntos
Neoplasias da Mama , Células-Tronco Pluripotentes Induzidas , Neoplasias Ovarianas , Proteína BRCA2/genética , Feminino , Efeito Fundador , Genes BRCA2 , Predisposição Genética para Doença , Humanos , Mutação , Portugal
9.
Genes (Basel) ; 12(5)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064542

RESUMO

Diastrophic dysplasia (DTD) is a rare osteochondrodysplasia characterized by short-limbed short stature and joint dysplasia. DTD is caused by mutations in SLC26A2 and is particularly common in the Finnish population. However, the disease incidence in Finland and clinical features in affected individuals have not been recently explored. This registry-based study aimed to investigate the current incidence of DTD in Finland, characterize the national cohort of pediatric subjects with DTD and review the disease-related literature. Subjects with SLC26A2-related skeletal dysplasia, born between 2000 and 2020, were identified from the Skeletal dysplasia registry and from hospital patient registry and their clinical and molecular data were reviewed. Fourteen subjects were identified. Twelve of them were phenotypically classified as DTD and two, as recessive multiple epiphyseal dysplasia (rMED). From the subjects with available genetic data, 75% (9/12) were homozygous for the Finnish founder mutation c.-26+2T>C. Two subjects with rMED phenotype were compound heterozygous for p.Arg279Trp and p.Thr512Lys variants. The variable phenotypes in our cohort highlight the wide spectrum of clinical features, ranging from a very severe form of DTD to milder forms of DTD and rMED. The incidence of DTD in Finland has significantly decreased over the past decades, most likely due to increased prenatal diagnostics.


Assuntos
Nanismo/patologia , Fenótipo , Transportadores de Sulfato/genética , Adolescente , Criança , Nanismo/epidemiologia , Nanismo/genética , Feminino , Finlândia , Efeito Fundador , Genes Recessivos , Heterozigoto , Homozigoto , Humanos , Masculino , Mutação , Adulto Jovem
11.
Ital J Pediatr ; 47(1): 126, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078422

RESUMO

BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome Type 1 is a rare autosomal recessive syndrome. The disorder is caused by mutations in the AIRE (AutoImmune Regulator) gene. According to the classic criteria, clinical diagnosis requires the presence of at least two of three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Furthermore, patients are often affected by other endocrine or non-endocrine associated autoimmune conditions. The enrichment of the non-classical triad seems to occur differently in different cohorts. Screenings of the population revealed that homozygous AIRE mutations c.769C > T, c.415C > T and c.254A > G have a founder effect in Finnish, Sardinian and Iranian Jew populations respectively. CASE PRESENTATION: We report here the clinical and genetic characteristics of two new Serbian APECED siblings, one male and one female, actual age of 27 and 24 respectively, born from non-consanguineous parents. Addison's disease was diagnosed in the male at the age of 3.5 and hypoparathyroidism at the age of 4. The female developed hypoparathyroidism at 4 years of age. She presented diffuse alopecia, madarosis, onychomycosis, teeth enamel dysplasia. She further developed Addison's disease at the age of 11 and Hashimoto's thyroiditis at the age of 13.5. She had menarche at the age of 14 but developed autoimmune oophoritis and premature ovarian failure at the age of 16. A treatment with hydrocortisone, fludrocortisone and alfacalcidiol was established for both siblings; L-T4 (levo-thyroxine) for thyroid dysfunction and levonorgestrel and etinilestradiol for POF were also administered to the female. Genetic screening revealed a homozygous c.769C > T (R257X (p.Arg257X)) AIRE mutation. We additionally reviewed the literature on 11 previously published Serbian patients and evaluated the frequency of their main diseases in comparison to Finnish, Sardinian, Turkish, Indian and North/South American cohorts. CONCLUSION: A founder effect was discovered for the R257X genotype detected in the DNA of 10 homozygous and 2 heterozygous patients. Of note, all Serbian APECED patients were affected by adrenal insufficiency and 10 out of 13 patients presented CMC.


Assuntos
Efeito Fundador , Genótipo , Mutação , Poliendocrinopatias Autoimunes/genética , Irmãos , Fatores de Transcrição/genética , Adulto , Feminino , Humanos , Masculino , Sérvia , Adulto Jovem
12.
Anim Genet ; 52(5): 725-729, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34157133

RESUMO

In this article, we analyzed pedigree information on males from 12 bovine breeds born in France between 2015 and 2019. We report an overall small number of paternal lineages with, for example, a minimal number of ancestors accounting for 95% of the Y-chromosome pool of their breed ranging from only 2 to 15 individuals. Then, we mined whole-genome sequence data from 811 sires (2 ≤ n ≤ 510 per breed) and built a median-joining network using 1411 SNPs. Most branches were breed-specific and in agreement with the geographic and genetic relatedness of these populations. The within-breed haplotype diversity was lower than expected based on genealogical information, which supports the existence of major male founder effects predating pedigree recording. In addition, we observed de novo mutation events among the descendants of the same ancestors, which are of interest to define paternal sub-lineages. Our results pave the way to future studies on the estimation of the effects of Y-chromosome haplotypes on male reproductive performances and on the conservation of Y-chromosome diversity.


Assuntos
Bovinos/genética , Cromossomo Y/genética , Animais , Cruzamento , Efeito Fundador , França , Haplótipos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma/veterinária
13.
Hum Biol ; 92(3): 153-166, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34057328

RESUMO

Geneticists have argued that the linear decay in within-population genetic diversity with increasing geographic distance from East Africa is best explained by a phylogenetic process of repeated founder effects, growth, and isolation. However, this serial founder effect (SFE) process has not yet been adequately vetted against other evolutionary processes that may also affect geospatial patterns of diversity. Additionally, studies of the SFE process have been largely based on a limited 52-population sample. In this modestly updated article, originally published in Human Biology in 2016 (vol. 88, no. 3, pp. 219-231), we assess the effects of founder effect, admixture, and localized gene flow processes on patterns of global and regional diversity using a published data set of 645 autosomal microsatellite genotypes from 5,415 individuals in 248 widespread populations. We used a formal tree-fitting approach to explore the role of founder effects. The approach involved fitting global and regional population trees to extant patterns of gene diversity and then systematically examining the deviations in fit. We also informally tested the SFE process using linear models of gene diversity versus waypoint geographic distances from Africa. We tested the role of localized gene flow using partial Mantel correlograms of gene diversity versus geographic distance controlling for the confounding effects of treelike genetic structure. We corroborate previous findings that global patterns of diversity, both within and between populations, are the product of an out-of-Africa SFE process. Within regions, however, diversity within populations is uncorrelated with geographic distance from Africa. Here, patterns of diversity have been largely shaped by recent interregional admixture and secondary range expansions. Our detailed analyses of the pattern of diversity within and between populations reveal that the signatures of different evolutionary processes dominate at different geographic scales. These findings have important implications for recent publications on the biology of race. Our new foreword situates these findings in a long line of anthropological research that categorically rejects racial interpretations of analyses of human diversity.


Assuntos
Efeito Fundador , Fluxo Gênico , África , Variação Genética/genética , Genética Populacional , Humanos , Repetições de Microssatélites , Filogenia
14.
Mol Biol Rep ; 48(4): 3841-3844, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33948853

RESUMO

Primary hyperoxaluria type-III is a disorder of glyoxylate metabolism, caused by pathogenic variants in the HOGA1 gene. To date more than 50 disease-associated pathogenic sequence variants are identified in the gene. A few of the variants are population specific and are considered to have a founder effect in respective populations. The most prevalent variant, c.700+5G>T, identified frequently in Caucasian (allele frequency 0.63) and European (0.35) populations. Two variants, c.860G>T (p.Gly287Val) and c.944_946delAGG (p.Glu315del), account for 95% of the allele count in patients of Ashkenazi Jews ancestry. A possible mutational hot-spot at c.834 position is frequently found mutated in Chinese patients. This observed ethnic associations of HOGA1 alleles span a spectrum ranging from recurrence limited to an ethnic group to a possible founder-effect.


Assuntos
Hiperoxalúria Primária/genética , Oxo-Ácido-Liases/genética , Polimorfismo Genético , Grupos Étnicos/genética , Efeito Fundador , Frequência do Gene , Humanos , Hiperoxalúria Primária/etnologia
15.
J Intern Med ; 290(2): 404-415, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33955087

RESUMO

AIM: To investigate whether genotyping could be used as a cost-effective screening step, preceding next-generation sequencing (NGS), in molecular diagnosis of familial hypercholesterolaemia (FH) in Swedish patients. METHODS AND RESULTS: Three hundred patients of Swedish origin with clinical suspicion of heterozygous FH were analysed using a specific array genotyping panel embedding 112 FH-causing mutations in the LDLR, APOB and PCSK9 genes. The mutations had been selected from previous reports on FH patients in Scandinavia and Finland. Mutation-negative cases were further analysed by NGS. In 181 patients with probable or definite FH using the Dutch lipid clinics network (DLCN) criteria (score ≥ 6), a causative mutation was identified in 116 (64%). Of these, 94 (81%) were detected by genotyping. Ten mutations accounted for more than 50% of the positive cases, with APOB c.10580G>A being the most common. Mutations in LDLR predominated, with (c.2311+1_2312-1)(2514)del (FH Helsinki) and c.259T>G having the highest frequency. Two novel LDLR mutations were identified. In patients with DLCN score < 6, mutation detection rate was significantly higher at younger age. CONCLUSION: A limited number of mutations explain a major fraction of FH cases in Sweden. Combination of selective genotyping and NGS facilitates the clinical challenge of cost-effective genetic screening in suspected FH. The frequency of APOB c.10580G>A was higher than previously reported in Sweden. The lack of demonstrable mutations in the LDLR, APOB and PCSK9 genes in ~1/3 of patients with probable FH strongly suggests that additional genetic mechanisms are to be found in phenotypic FH.


Assuntos
Efeito Fundador , Testes Genéticos , Genótipo , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Apolipoproteína B-100/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Suécia
16.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799598

RESUMO

We sought to develop a cell-based cytotoxicity assay using human hepatocytes, which reflect the effects of drug-metabolizing enzymes on cytotoxicity. In this study, we generated luminescent human hepatoblastoma HepG2 cells using the mouse artificial chromosome vector, in which click beetle luciferase alone or luciferase and major drug-metabolizing enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) are expressed, and monitored the time-dependent changes of CYP-mediated cytotoxicity expression by bioluminescence measurement. Real-time bioluminescence measurement revealed that compared with CYP-non-expressing cells, the luminescence intensity of CYP-expressing cells rapidly decreased when the cells were treated with low concentrations of aflatoxin B1 or primaquine, which exhibits cytotoxicity in the presence of CYP3A4 or CYP2D6, respectively. Using kinetics data obtained by the real-time bioluminescence measurement, we estimated the time-dependent changes of 50% inhibitory concentration (IC50) values in the aflatoxin B1- and primaquine-treated cell lines. The first IC50 value was detected much earlier and at a lower concentration in primaquine-treated CYP-expressing HepG2 cells than in primaquine-treated CYP-non-expressing cells, and the decrease of IC50 values was much faster in the former than the latter. Thus, we successfully monitored time- and concentration-dependent dynamic changes of CYP-mediated cytotoxicity expression in CYP-expressing luminescent HepG2 cells by means of real-time bioluminescence measurement.


Assuntos
Aflatoxina B1/toxicidade , Efeito Fundador , Medições Luminescentes/métodos , Primaquina/toxicidade , Imagem com Lapso de Tempo/métodos , Xenobióticos/toxicidade , Animais , Linhagem Celular Tumoral , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Células Hep G2 , Humanos , Concentração Inibidora 50 , Luciferases/genética , Luciferases/metabolismo , Luminescência , Camundongos
17.
Mol Ecol ; 30(11): 2495-2510, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33826187

RESUMO

When populations colonize new areas, both strong selection and strong drift can be experienced due to novel environments and small founding populations, respectively. Empirical studies have predominantly focused on the phenotype when assessing the role of selection, and limited neutral-loci when assessing founder-induced loss of diversity. Consequently, the extent to which processes interact to influence evolutionary trajectories is difficult to assess. Genomic-level approaches provide the opportunity to simultaneously consider these processes. Here, we examine the roles of selection and drift in shaping genomic diversity and divergence in historically documented sequential island colonizations by the silvereye (Zosterops lateralis). We provide the first empirical demonstration of the rapid appearance of highly diverged genomic regions following population founding, the position of which are highly idiosyncratic. As these regions rarely contained loci putatively under selection, it is most likely that these differences arise via the stochastic nature of the founding process. However, selection is required to explain rapid evolution of larger body size in insular silvereyes. Reconciling our genomic data with these phenotypic patterns suggests there may be many genomic routes to the island phenotype, which vary across populations. Finally, we show that accelerated divergence associated with multiple founding steps is the product of genome-wide rather than localized differences, and that diversity erodes due to loss of rare alleles. However, even multiple founder events do not result in divergence and diversity levels seen in evolutionary older subspecies, and therefore do not provide a shortcut to speciation as proposed by founder-effect speciation models.


Assuntos
Passeriformes , Animais , Efeito Fundador , Variação Genética , Genoma/genética , Passeriformes/genética , Fenótipo , Seleção Genética
18.
Genes (Basel) ; 12(3)2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802939

RESUMO

Gotland sheep, a breed native to Gotland, Sweden (an island in the Baltic Sea), split from the Gute sheep breed approximately 100 years ago, and since, has probably been crossed with other breeds. This breed has recently gained popularity, due to its pelt quality. This study estimates the shared ancestors and identifies recent selection signatures in Gotland sheep using 600 K single nucleotide polymorphism (SNP) genotype data. Admixture analysis shows that the Gotland sheep is a distinct breed, but also has shared ancestral genomic components with Gute (~50%), Karakul (~30%), Romanov (~20%), and Fjällnäs (~10%) sheep breeds. Two complementary methods were applied to detect selection signatures: A Bayesian population differentiation FST and an integrated haplotype homozygosity score (iHS). Our results find that seven significant SNPs (q-value < 0.05) using the FST analysis and 55 significant SNPs (p-value < 0.0001) using the iHS analysis. Of the candidate genes that contain significant markers, or are in proximity to them, we identify several belongings to the keratin genes, RXFP2, ADCY1, ENOX1, USF2, COX7A1, ARHGAP28, CRYBB2, CAPNS1, FMO3, and GREB1. These genes are involved in wool quality, polled and horned phenotypes, fertility, twining rate, meat quality, and growth traits. In summary, our results provide shared founders of Gotland sheep and insight into genomic regions maintained under selection after the breed was formed. These results contribute to the detection of candidate genes and QTLs underlying economic traits in sheep.


Assuntos
Técnicas de Genotipagem/veterinária , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Carneiro Doméstico/classificação , Animais , Teorema de Bayes , Cruzamento , Efeito Fundador , Genótipo , Seleção Genética , Ovinos , Carneiro Doméstico/genética , Suécia
19.
Am J Hum Genet ; 108(5): 764-785, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33811808

RESUMO

Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent manner. The expansion of repeat length across generations is a well-established process that results in human disorders mainly affecting the central nervous system. At least 50 disorders associated with expansion loci have been described to date, with half recognized only in the last ten years, as prior methodological difficulties limited their identification. These limitations still apply to the current widely used molecular diagnostic methods (exome or gene panels) and thus result in missed diagnosis detrimental to affected individuals and their families, especially for disorders that are very rare and/or clinically not recognizable. Most of these disorders have been identified through family-driven approaches and many others likely remain to be identified. The recent development of long-read technologies provides a unique opportunity to systematically investigate the contribution of tandem repeats and repeat expansions to the genetic architecture of human disorders. In this review, we summarize the current and most recent knowledge about the genetics of repeat expansion disorders and the diversity of their pathophysiological mechanisms and outline the perspectives of developing personalized treatments in the future.


Assuntos
Pesquisa Biomédica/tendências , Expansão das Repetições de Trinucleotídeos , Antecipação Genética , Efeito Fundador , Genes Dominantes , Genes Recessivos , Genoma Humano/genética , Humanos , Fatores de Tempo , Expansão das Repetições de Trinucleotídeos/genética
20.
Sci Rep ; 11(1): 7696, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33833316

RESUMO

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of inherited retinal degenerations. The ortholog of Drosophila eyes shut/spacemaker, EYS on chromosome 6q12 is a major genetic cause of recessive RP worldwide, with prevalence of 5 to 30%. In this study, by using targeted NGS, MLPA and Sanger sequencing we uncovered the EYS gene as one of the most common genetic cause of autosomal recessive RP in northern Sweden accounting for at least 16%. The most frequent pathogenic variant was c.8648_8655del that in some patients was identified in cis with c.1155T>A, indicating Finnish ancestry. We also showed that two novel EYS variants, c.2992_2992+6delinsTG and c.3877+1G>A caused exon skipping in human embryonic kidney cells, HEK293T and in retinal pigment epithelium cells, ARPE-19 demonstrating that in vitro minigene assay is a straightforward tool for the analysis of intronic variants. We conclude, that whenever it is possible, functional testing is of great value for classification of intronic EYS variants and the following molecular testing of family members, their genetic counselling, and inclusion of RP patients to future treatment studies.


Assuntos
Proteínas do Olho/genética , Retinite Pigmentosa/classificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Coortes , Feminino , Efeito Fundador , Genes Recessivos , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Splicing de RNA , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/metabolismo , Retinite Pigmentosa/genética , Suécia , Adulto Jovem
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