RESUMO
Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%-18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity.
Assuntos
Consanguinidade , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/genética , Homozigoto , Fenótipo , Polimorfismo de Nucleotídeo Único , Bancos de Espécimes Biológicos , Genoma Humano , Predisposição Genética para Doença , Reino UnidoRESUMO
Reinventing potato from a clonally propagated tetraploid into a seed-propagated diploid, hybrid potato, is an important innovation in agriculture. Due to deleterious mutations, it has remained a challenge to develop highly homozygous inbred lines, a prerequisite to breed hybrid potato. Here, we employed genome design to develop a generation of pure and fertile potato lines and thereby the uniform, vigorous F1s. The metrics we applied in genome design included the percentage of genome homozygosity and the number of deleterious mutations in the starting material, the number of segregation distortions in the S1 population, the haplotype information to infer the break of tight linkage between beneficial and deleterious alleles, and the genome complementarity of the parental lines. This study transforms potato breeding from a slow, non-accumulative mode into a fast-iterative one, thereby potentiating a broad spectrum of benefits to farmers and consumers.
Assuntos
Genoma de Planta , Hibridização Genética , Solanum tuberosum/genética , Cruzamentos Genéticos , Diploide , Fertilidade/genética , Genes de Plantas , Variação Genética , Genética Populacional , Heterozigoto , Homozigoto , Vigor Híbrido/genética , Mutação/genética , Linhagem , Melhoramento Vegetal , Análise de Componente Principal , Seleção GenéticaRESUMO
Only five species of the once-diverse Rhinocerotidae remain, making the reconstruction of their evolutionary history a challenge to biologists since Darwin. We sequenced genomes from five rhinoceros species (three extinct and two living), which we compared to existing data from the remaining three living species and a range of outgroups. We identify an early divergence between extant African and Eurasian lineages, resolving a key debate regarding the phylogeny of extant rhinoceroses. This early Miocene (â¼16 million years ago [mya]) split post-dates the land bridge formation between the Afro-Arabian and Eurasian landmasses. Our analyses also show that while rhinoceros genomes in general exhibit low levels of genome-wide diversity, heterozygosity is lowest and inbreeding is highest in the modern species. These results suggest that while low genetic diversity is a long-term feature of the family, it has been particularly exacerbated recently, likely reflecting recent anthropogenic-driven population declines.
Assuntos
Evolução Molecular , Genoma , Perissodáctilos/genética , Animais , Demografia , Fluxo Gênico , Variação Genética , Geografia , Heterozigoto , Homozigoto , Especificidade de Hospedeiro , Cadeias de Markov , Mutação/genética , Filogenia , Especificidade da Espécie , Fatores de TempoRESUMO
Searching for factors to improve knockin efficiency for therapeutic applications, biotechnology, and generation of non-human primate models of disease, we found that the strand exchange protein RAD51 can significantly increase Cas9-mediated homozygous knockin in mouse embryos through an interhomolog repair (IHR) mechanism. IHR is a hallmark of meiosis but only occurs at low frequencies in somatic cells, and its occurrence in zygotes is controversial. Using multiple approaches, we provide evidence for an endogenous IHR mechanism in the early embryo that can be enhanced by RAD51. This process can be harnessed to generate homozygotes from wild-type zygotes using exogenous donors and to convert heterozygous alleles into homozygous alleles without exogenous templates. Furthermore, we identify additional IHR-promoting factors and describe features of IHR events. Together, our findings show conclusive evidence for IHR in mouse embryos and describe an efficient method for enhanced gene conversion.
Assuntos
Reparo do DNA/genética , Conversão Gênica , Rad51 Recombinase/metabolismo , Alelos , Animais , Sequência de Bases , Proteína 9 Associada à CRISPR/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cromossomos de Mamíferos/genética , Quebras de DNA de Cadeia Dupla , Embrião de Mamíferos , Feminino , Loci Gênicos , Recombinação Homóloga/genética , Homozigoto , Humanos , Mutação INDEL/genética , Camundongos Endogâmicos C57BL , Mosaicismo , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Ribonucleoproteínas/metabolismo , Zigoto/metabolismoRESUMO
We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4+ T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4+ T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.
Assuntos
Antígenos CD28/deficiência , Padrões de Herança/genética , Papillomaviridae/fisiologia , Pele/virologia , Linfócitos T/imunologia , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Antígenos CD28/genética , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/imunologia , Criança , Endopeptidases/metabolismo , Feminino , Genes Recessivos , Células HEK293 , Homozigoto , Humanos , Imunidade Humoral , Memória Imunológica , Células Jurkat , Queratinócitos/patologia , Masculino , Camundongos Endogâmicos C57BL , Oncogenes , Papiloma/patologia , Papiloma/virologia , Linhagem , Sinais Direcionadores de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.
Assuntos
Inflamação/enzimologia , Proteínas Serina-Treonina Quinases/deficiência , Fator de Necrose Tumoral alfa/farmacologia , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose , Autoimunidade/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Morte Celular/efeitos dos fármacos , Citocinas/metabolismo , Enzima Desubiquitinante CYLD/metabolismo , Feminino , Células HEK293 , Homozigoto , Humanos , Quinase I-kappa B/metabolismo , Imunofenotipagem , Inflamação/patologia , Interferon Tipo I/metabolismo , Interferon gama/metabolismo , Mutação com Perda de Função/genética , Masculino , Linhagem , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Receptor 3 Toll-Like/metabolismo , Transcriptoma/genética , Vesiculovirus/efeitos dos fármacos , Vesiculovirus/fisiologiaRESUMO
Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αß T and non-classic CD4+ αß TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αß T, and CD4+ αß TH1∗ cells unable to compensate for this deficit.
Assuntos
Imunidade Adaptativa , Imunidade Inata , Interferon gama/imunologia , Mycobacterium/imunologia , Proteínas com Domínio T/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Linhagem da Célula , Pré-Escolar , Cromatina/metabolismo , Ilhas de CpG/genética , Metilação de DNA/genética , Células Dendríticas/metabolismo , Epigênese Genética , Feminino , Homozigoto , Humanos , Mutação INDEL/genética , Lactente , Interferon gama/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Mutação com Perda de Função/genética , Masculino , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/microbiologia , Linhagem , Proteínas com Domínio T/química , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/genética , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma/genéticaRESUMO
The evolution of reproductive barriers is the first step in the formation of new species and can help us understand the diversification of life on Earth. These reproductive barriers often take the form of hybrid incompatibilities, in which alleles derived from two different species no longer interact properly in hybrids1-3. Theory predicts that hybrid incompatibilities may be more likely to arise at rapidly evolving genes4-6 and that incompatibilities involving multiple genes should be common7,8, but there has been sparse empirical data to evaluate these predictions. Here we describe a mitonuclear incompatibility involving three genes whose protein products are in physical contact within respiratory complex I of naturally hybridizing swordtail fish species. Individuals homozygous for mismatched protein combinations do not complete embryonic development or die as juveniles, whereas those heterozygous for the incompatibility have reduced complex I function and unbalanced representation of parental alleles in the mitochondrial proteome. We find that the effects of different genetic interactions on survival are non-additive, highlighting subtle complexity in the genetic architecture of hybrid incompatibilities. Finally, we document the evolutionary history of the genes involved, showing signals of accelerated evolution and evidence that an incompatibility has been transferred between species via hybridization.
Assuntos
Núcleo Celular , Complexo I de Transporte de Elétrons , Peixes , Genes Letais , Especiação Genética , Hibridização Genética , Proteínas Mitocondriais , Animais , Alelos , Complexo I de Transporte de Elétrons/genética , Peixes/classificação , Peixes/embriologia , Peixes/genética , Peixes/crescimento & desenvolvimento , Homozigoto , Genes Letais/genética , Especificidade da Espécie , Desenvolvimento Embrionário/genética , Proteínas Mitocondriais/genética , Núcleo Celular/genética , Heterozigoto , Evolução MolecularRESUMO
Increasing planting density is a key strategy for enhancing maize yields1-3. An ideotype for dense planting requires a 'smart canopy' with leaf angles at different canopy layers differentially optimized to maximize light interception and photosynthesis4-6, among other features. Here we identified leaf angle architecture of smart canopy 1 (lac1), a natural mutant with upright upper leaves, less erect middle leaves and relatively flat lower leaves. lac1 has improved photosynthetic capacity and attenuated responses to shade under dense planting. lac1 encodes a brassinosteroid C-22 hydroxylase that predominantly regulates upper leaf angle. Phytochrome A photoreceptors accumulate in shade and interact with the transcription factor RAVL1 to promote its degradation via the 26S proteasome, thereby inhibiting activation of lac1 by RAVL1 and decreasing brassinosteroid levels. This ultimately decreases upper leaf angle in dense fields. Large-scale field trials demonstrate that lac1 boosts maize yields under high planting densities. To quickly introduce lac1 into breeding germplasm, we transformed a haploid inducer and recovered homozygous lac1 edits from 20 diverse inbred lines. The tested doubled haploids uniformly acquired smart-canopy-like plant architecture. We provide an important target and an accelerated strategy for developing high-density-tolerant cultivars, with lac1 serving as a genetic chassis for further engineering of a smart canopy in maize.
Assuntos
Brassinosteroides , Fotossíntese , Folhas de Planta , Zea mays , Zea mays/crescimento & desenvolvimento , Zea mays/genética , Folhas de Planta/metabolismo , Folhas de Planta/crescimento & desenvolvimento , Brassinosteroides/metabolismo , Fitocromo A/metabolismo , Fitocromo A/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Haploidia , Homozigoto , Mutação , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , LuzRESUMO
Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.
Assuntos
Infecções por Vírus Epstein-Barr , Interleucina-27 , Receptores de Interleucina , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Adulto Jovem , Alelos , Linfócitos B/patologia , Linfócitos B/virologia , Linfócitos T CD8-Positivos/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/terapia , Finlândia , Frequência do Gene , Herpesvirus Humano 4 , Homozigoto , Mononucleose Infecciosa/complicações , Mononucleose Infecciosa/genética , Mononucleose Infecciosa/terapia , Interleucina-27/imunologia , Interleucina-27/metabolismo , Mutação com Perda de Função , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Resultado do TratamentoRESUMO
Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE.
Assuntos
Encéfalo , Encefalite por Herpes Simples , Herpesvirus Humano 1 , Proteínas de Membrana , Internalização do Vírus , Animais , Feminino , Humanos , Masculino , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/virologia , Encefalite por Herpes Simples/virologia , Encefalite por Herpes Simples/metabolismo , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 1/fisiologia , Homozigoto , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Nectinas/genética , Nectinas/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neurônios/virologia , Células-Tronco Pluripotentes/citologia , Replicação Viral , Pré-Escolar , Adulto Jovem , LinhagemRESUMO
The Mexico City Prospective Study is a prospective cohort of more than 150,000 adults recruited two decades ago from the urban districts of Coyoacán and Iztapalapa in Mexico City1. Here we generated genotype and exome-sequencing data for all individuals and whole-genome sequencing data for 9,950 selected individuals. We describe high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Indigenous American, European and African ancestry, with extensive admixture from Indigenous populations in central, southern and southeastern Mexico. Indigenous Mexican segments of the genome had lower levels of coding variation but an excess of homozygous loss-of-function variants compared with segments of African and European origin. We estimated ancestry-specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Indigenous Mexican ancestry at exome variants, all available through a public browser. Using whole-genome sequencing, we developed an imputation reference panel that outperforms existing panels at common variants in individuals with high proportions of central, southern and southeastern Indigenous Mexican ancestry. Our work illustrates the value of genetic studies in diverse populations and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States, where the Hispanic/Latino population is predominantly of Mexican descent.
Assuntos
Sequenciamento do Exoma , Genoma Humano , Genótipo , Hispânico ou Latino , Adulto , Humanos , África/etnologia , América/etnologia , Europa (Continente)/etnologia , Frequência do Gene/genética , Genética Populacional , Genoma Humano/genética , Técnicas de Genotipagem , Hispânico ou Latino/genética , Homozigoto , Mutação com Perda de Função/genética , México , Estudos ProspectivosRESUMO
The Indigenous peoples of Australia have a rich linguistic and cultural history. How this relates to genetic diversity remains largely unknown because of their limited engagement with genomic studies. Here we analyse the genomes of 159 individuals from four remote Indigenous communities, including people who speak a language (Tiwi) not from the most widespread family (Pama-Nyungan). This large collection of Indigenous Australian genomes was made possible by careful community engagement and consultation. We observe exceptionally strong population structure across Australia, driven by divergence times between communities of 26,000-35,000 years ago and long-term low but stable effective population sizes. This demographic history, including early divergence from Papua New Guinean (47,000 years ago) and Eurasian groups1, has generated the highest proportion of previously undescribed genetic variation seen outside Africa and the most extended homozygosity compared with global samples. A substantial proportion of this variation is not observed in global reference panels or clinical datasets, and variation with predicted functional consequence is more likely to be homozygous than in other populations, with consequent implications for medical genomics2. Our results show that Indigenous Australians are not a single homogeneous genetic group and their genetic relationship with the peoples of New Guinea is not uniform. These patterns imply that the full breadth of Indigenous Australian genetic diversity remains uncharacterized, potentially limiting genomic medicine and equitable healthcare for Indigenous Australians.
Assuntos
Povos Aborígenes Australianos e Ilhéus do Estreito de Torres , Genoma Humano , Variação Estrutural do Genoma , Humanos , Austrália/etnologia , Povos Aborígenes Australianos e Ilhéus do Estreito de Torres/genética , Povos Aborígenes Australianos e Ilhéus do Estreito de Torres/história , Conjuntos de Dados como Assunto , Genética Médica , Genoma Humano/genética , Variação Estrutural do Genoma/genética , Genômica , História Antiga , Homozigoto , Idioma , Nova Guiné/etnologia , Densidade Demográfica , Dinâmica PopulacionalRESUMO
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.
Assuntos
Encéfalo , Reserva Cognitiva , Escolaridade , Estudo de Associação Genômica Ampla , Esclerose Múltipla , Fatores de Proteção , Humanos , Adulto Jovem , Envelhecimento , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Tronco Encefálico/imunologia , Tronco Encefálico/patologia , Tronco Encefálico/fisiopatologia , Estudos de Casos e Controles , Progressão da Doença , Homozigoto , Limitação da Mobilidade , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/psicologia , Fatores de TempoRESUMO
Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics2-6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.
Assuntos
Bancos de Espécimes Biológicos , Genética Médica , Genoma Humano , Genômica , Hispânico ou Latino , Humanos , Glicemia/genética , Glicemia/metabolismo , Estatura/genética , Índice de Massa Corporal , Interação Gene-Ambiente , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/classificação , Hispânico ou Latino/genética , Homozigoto , México , Fenótipo , Triglicerídeos/sangue , Triglicerídeos/genética , Reino Unido , Genoma Humano/genéticaRESUMO
Genomic analyses of Neanderthals have previously provided insights into their population history and relationship to modern humans1-8, but the social organization of Neanderthal communities remains poorly understood. Here we present genetic data for 13 Neanderthals from two Middle Palaeolithic sites in the Altai Mountains of southern Siberia: 11 from Chagyrskaya Cave9,10 and 2 from Okladnikov Cave11-making this one of the largest genetic studies of a Neanderthal population to date. We used hybridization capture to obtain genome-wide nuclear data, as well as mitochondrial and Y-chromosome sequences. Some Chagyrskaya individuals were closely related, including a father-daughter pair and a pair of second-degree relatives, indicating that at least some of the individuals lived at the same time. Up to one-third of these individuals' genomes had long segments of homozygosity, suggesting that the Chagyrskaya Neanderthals were part of a small community. In addition, the Y-chromosome diversity is an order of magnitude lower than the mitochondrial diversity, a pattern that we found is best explained by female migration between communities. Thus, the genetic data presented here provide a detailed documentation of the social organization of an isolated Neanderthal community at the easternmost extent of their known range.
Assuntos
Homem de Neandertal , Animais , Feminino , Humanos , Cavernas , Genoma/genética , Hibridização Genética , Homem de Neandertal/genética , Sibéria , DNA Mitocondrial/genética , Cromossomo Y/genética , Masculino , Família , HomozigotoRESUMO
Dominance is usually considered a constant value that describes the relative difference in fitness or phenotype between heterozygotes and the average of homozygotes at a focal polymorphic locus. However, the observed dominance can vary with the genetic background of the focal locus. Here, alleles at other loci modify the observed phenotype through position effects or dominance modifiers that are sometimes associated with pathogen resistance, lineage, sex, or mating type. Theoretical models have illustrated how variable dominance appears in the context of multi-locus interaction (epistasis). Here, we review empirical evidence for variable dominance and how the observed patterns may be captured by proposed epistatic models. We highlight how integrating epistasis and dominance is crucial for comprehensively understanding adaptation and speciation.
Assuntos
Epistasia Genética , Modelos Genéticos , Heterozigoto , Fenótipo , Homozigoto , AlelosRESUMO
The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.
Assuntos
Desenvolvimento Infantil/fisiologia , Estado Nutricional/fisiologia , Puberdade/fisiologia , Receptor Tipo 3 de Melanocortina/metabolismo , Maturidade Sexual/fisiologia , Adolescente , Idoso de 80 Anos ou mais , Animais , Criança , Ciclo Estral/genética , Ciclo Estral/fisiologia , Feminino , Homozigoto , Humanos , Hipotálamo/citologia , Hipotálamo/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Melanocortinas/metabolismo , Menarca/genética , Menarca/fisiologia , Camundongos , Fenótipo , Puberdade/genética , Receptor Tipo 3 de Melanocortina/deficiência , Receptor Tipo 3 de Melanocortina/genética , Maturidade Sexual/genética , Fatores de Tempo , Aumento de PesoRESUMO
Tardigrades are small aquatic invertebrates known for their remarkable tolerance to diverse extreme stresses. To elucidate the in vivo mechanisms underlying this extraordinary resilience, methods for genetically manipulating tardigrades have long been desired. Despite our prior success in somatic cell gene editing by microinjecting Cas9 ribonucleoproteins (RNPs) into the body cavity of tardigrades, the generation of gene-edited individuals remained elusive. In this study, employing an extremotolerant parthenogenetic tardigrade species, Ramazzottius varieornatus, we established conditions that led to the generation of gene-edited tardigrade individuals. Drawing inspiration from the direct parental CRISPR (DIPA-CRISPR) technique employed in several insects, we simply injected a concentrated Cas9 RNP solution into the body cavity of parental females shortly before their initial oviposition. This approach yielded gene-edited G0 progeny. Notably, only a single allele was predominantly detected at the target locus for each G0 individual, indicative of homozygous mutations. By co-injecting single-stranded oligodeoxynucleotides (ssODNs) with Cas9 RNPs, we achieved the generation of homozygously knocked-in G0 progeny, and these edited alleles were inherited by G1/G2 progeny. This is the first example of heritable gene editing in the entire phylum of Tardigrada. This establishment of a straightforward method for generating homozygous knockout/knock-in individuals not only facilitates in vivo analyses of the molecular mechanisms underpinning extreme tolerance, but also opens up avenues for exploring various topics, including Evo-Devo, in tardigrades.
Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Homozigoto , Partenogênese , Tardígrados , Animais , Tardígrados/genética , Edição de Genes/métodos , Partenogênese/genética , Feminino , Técnicas de Introdução de Genes/métodos , Técnicas de Inativação de Genes , AlelosRESUMO
Ferroptosis is an iron-dependent type of regulated cell death resulting from extensive lipid peroxidation and plays a critical role in various physiological and pathological processes. However, the regulatory mechanisms for ferroptosis sensitivity remain incompletely understood. Here, we report that homozygous deletion of Usp8 (ubiquitin-specific protease 8) in intestinal epithelial cells (IECs) leads to architectural changes in the colonic epithelium and shortens mouse lifespan accompanied by increased IEC death and signs of lipid peroxidation. However, mice with heterozygous deletion of Usp8 in IECs display normal phenotype and become resistant to azoxymethane/dextran sodium sulfate-induced colorectal tumorigenesis. Mechanistically, USP8 interacts with and deubiquitinates glutathione peroxidase 4 (GPX4), leading to GPX4 stabilization. Thus, USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis in vitro. Notably, USP8 inhibition in combination with ferroptosis inducers retards tumor growth and enhances CD8+ T cell infiltration, which potentiates tumor response to anti-PD-1 immunotherapy in vivo. These findings uncover that USP8 counteracts ferroptosis by stabilizing GPX4 and highlight targeting USP8 as a potential therapeutic strategy to boost ferroptosis for enhancing cancer immunotherapy.