RESUMO
The expansion of people speaking Bantu languages is the most dramatic demographic event in Late Holocene Africa and fundamentally reshaped the linguistic, cultural and biological landscape of the continent1-7. With a comprehensive genomic dataset, including newly generated data of modern-day and ancient DNA from previously unsampled regions in Africa, we contribute insights into this expansion that started 6,000-4,000 years ago in western Africa. We genotyped 1,763 participants, including 1,526 Bantu speakers from 147 populations across 14 African countries, and generated whole-genome sequences from 12 Late Iron Age individuals8. We show that genetic diversity amongst Bantu-speaking populations declines with distance from western Africa, with current-day Zambia and the Democratic Republic of Congo as possible crossroads of interaction. Using spatially explicit methods9 and correlating genetic, linguistic and geographical data, we provide cross-disciplinary support for a serial-founder migration model. We further show that Bantu speakers received significant gene flow from local groups in regions they expanded into. Our genetic dataset provides an exhaustive modern-day African comparative dataset for ancient DNA studies10 and will be important to a wide range of disciplines from science and humanities, as well as to the medical sector studying human genetic variation and health in African and African-descendant populations.
Assuntos
DNA Antigo , Emigração e Imigração , Genética Populacional , Idioma , Humanos , África Ocidental , Conjuntos de Dados como Assunto , República Democrática do Congo , DNA Antigo/análise , Emigração e Imigração/história , Efeito Fundador , Fluxo Gênico/genética , Variação Genética/genética , História Antiga , Idioma/história , Linguística/história , Zâmbia , Mapeamento GeográficoRESUMO
Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)5. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms5, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.
Assuntos
Alelos , DNA Polimerase gama , Vírus da Encefalite Transmitidos por Carrapatos , Herpesvirus Humano 1 , Tolerância Imunológica , SARS-CoV-2 , Animais , Feminino , Humanos , Masculino , Camundongos , Idade de Início , COVID-19/imunologia , COVID-19/virologia , COVID-19/genética , DNA Polimerase gama/genética , DNA Polimerase gama/imunologia , DNA Polimerase gama/metabolismo , DNA Mitocondrial/imunologia , DNA Mitocondrial/metabolismo , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/genética , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/virologia , Efeito Fundador , Técnicas de Introdução de Genes , Herpes Simples/genética , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Interferon Tipo I/imunologia , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/imunologia , Mutação , RNA Mitocondrial/imunologia , RNA Mitocondrial/metabolismo , SARS-CoV-2/imunologiaRESUMO
Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics1. Population bottleneck events, such as those that occurred in the history of the Finnish population, enrich some homozygous variants to higher frequencies, which facilitates the identification of variants that cause diseases with recessive inheritance2,3. Here we examine the homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using data from the nationwide electronic health records of 176,899 Finnish individuals. We find associations for homozygous genotypes across a broad spectrum of phenotypes, including known associations with retinal dystrophy and novel associations with adult-onset cataract and female infertility. Of the recessive disease associations that we identify, 13 out of 20 would have been missed by the additive model that is typically used in genome-wide association studies. We use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a conventional definition of dominant or recessive. In particular, we find variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects. Similarly, we find presumed benign variants with disease effects. Our results show how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.
Assuntos
Alelos , Bancos de Espécimes Biológicos , Doença , Animais , Feminino , Estudo de Associação Genômica Ampla , Fenótipo , Doença/genética , Finlândia , Distrofias Retinianas , Catarata , Infertilidade Feminina , Genes Recessivos , Heterozigoto , Efeito Fundador , Dosagem de Genes , Registros Eletrônicos de SaúdeRESUMO
During the evolution of SARS-CoV-2 in humans, a D614G substitution in the spike glycoprotein (S) has emerged; virus containing this substitution has become the predominant circulating variant in the COVID-19 pandemic1. However, whether the increasing prevalence of this variant reflects a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains unknown. Here we use isogenic SARS-CoV-2 variants to demonstrate that the variant that contains S(D614G) has enhanced binding to the human cell-surface receptor angiotensin-converting enzyme 2 (ACE2), increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a human ACE2 knock-in mouse model, and markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Our data show that the D614G substitution in S results in subtle increases in binding and replication in vitro, and provides a real competitive advantage in vivo-particularly during the transmission bottleneck. Our data therefore provide an explanation for the global predominance of the variant that contains S(D614G) among the SARS-CoV-2 viruses that are currently circulating.
Assuntos
COVID-19/transmissão , COVID-19/virologia , Mutação , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/genética , Replicação Viral/genética , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Brônquios/citologia , Brônquios/virologia , COVID-19/epidemiologia , Linhagem Celular , Células Cultivadas , Cricetinae , Modelos Animais de Doenças , Células Epiteliais/virologia , Feminino , Furões/virologia , Efeito Fundador , Técnicas de Introdução de Genes , Aptidão Genética , Humanos , Masculino , Mesocricetus , Camundongos , Mucosa Nasal/citologia , Mucosa Nasal/virologia , Ligação Proteica , RNA Viral/análise , Receptores de Coronavírus/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidadeRESUMO
The domestication of animals led to a major shift in human subsistence patterns, from a hunter-gatherer to a sedentary agricultural lifestyle, which ultimately resulted in the development of complex societies. Over the past 15,000 years, the phenotype and genotype of multiple animal species, such as dogs, pigs, sheep, goats, cattle and horses, have been substantially altered during their adaptation to the human niche. Recent methodological innovations, such as improved ancient DNA extraction methods and next-generation sequencing, have enabled the sequencing of whole ancient genomes. These genomes have helped reconstruct the process by which animals entered into domestic relationships with humans and were subjected to novel selection pressures. Here, we discuss and update key concepts in animal domestication in light of recent contributions from ancient genomics.
Assuntos
Animais Selvagens , Domesticação , Genômica , Criação de Animais Domésticos , Animais , DNA Antigo , DNA Mitocondrial , Efeito Fundador , Genômica/história , Genômica/métodos , História Antiga , Modelos Teóricos , Seleção Genética , Análise Espaço-TemporalRESUMO
Studying range expansions is central for understanding genetic variation through space and time as well as for identifying refugia and biological invasions. Range expansions are characterized by serial founder events causing clines of decreasing genetic diversity away from the center of origin and asymmetries in the two-dimensional allele frequency spectra. These asymmetries, summarized by the directionality index (ψ), are sensitive to range expansions and persist for longer than clines in genetic diversity. In continuous and finite meta-populations, genetic drift tends to be stronger at the edges of the species distribution in equilibrium populations and populations undergoing range expansions alike. Such boundary effects are expected to affect geographic patterns in genetic diversity and ψ. Here we demonstrate that boundary effects cause high false positive rates in equilibrium meta-populations when testing for range expansions. In the simulations, the absolute value of ψ (|ψ|) in equilibrium data sets was proportional to the fixation index (FST). By fitting signatures of range expansions as a function of É |ψ|/FST and geographic clines in ψ, strong evidence for range expansions could be detected in data from a recent rapid invasion of the cane toad, Rhinella marina, in Australia, but not in 28 previously published empirical data sets from Australian scincid lizards that were significant for the standard range expansion tests. Thus, while clinal variation in ψ is still the most sensitive statistic to range expansions, to detect true signatures of range expansions in natural populations, its magnitude needs to be considered in relation to the overall levels of genetic structuring in the data.
Assuntos
Genética Populacional , Animais , Genética Populacional/métodos , Modelos Genéticos , Variação Genética , Espécies Introduzidas , Austrália , Deriva Genética , Frequência do Gene , Efeito FundadorRESUMO
Progress in earlier detection and clinical management has increased life expectancy and quality of life in people with Down syndrome (DS). However, no drug has been approved to help individuals with DS live independently and fully. Although rat models could support more robust physiological, behavioral, and toxicology analysis than mouse models during preclinical validation, no DS rat model is available as a result of technical challenges. We developed a transchromosomic rat model of DS, TcHSA21rat, which contains a freely segregating, EGFP-inserted, human chromosome 21 (HSA21) with >93% of its protein-coding genes. RNA-seq of neonatal forebrains demonstrates that TcHSA21rat expresses HSA21 genes and has an imbalance in global gene expression. Using EGFP as a marker for trisomic cells, flow cytometry analyses of peripheral blood cells from 361 adult TcHSA21rat animals show that 81% of animals retain HSA21 in >80% of cells, the criterion for a "Down syndrome karyotype" in people. TcHSA21rat exhibits learning and memory deficits and shows increased anxiety and hyperactivity. TcHSA21rat recapitulates well-characterized DS brain morphology, including smaller brain volume and reduced cerebellar size. In addition, the rat model shows reduced cerebellar foliation, which is not observed in DS mouse models. Moreover, TcHSA21rat exhibits anomalies in craniofacial morphology, heart development, husbandry, and stature. TcHSA21rat is a robust DS animal model that can facilitate DS basic research and provide a unique tool for preclinical validation to accelerate DS drug development.
Assuntos
Ansiedade/genética , Cromossomos Humanos Par 21 , Síndrome de Down/genética , Efeito Fundador , Hipercinese/genética , Animais , Ansiedade/metabolismo , Ansiedade/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Modelos Animais de Doenças , Síndrome de Down/metabolismo , Síndrome de Down/patologia , Feminino , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Hipercinese/metabolismo , Hipercinese/patologia , Cariótipo , Aprendizagem , Masculino , Mutagênese Insercional , Tamanho do Órgão , Postura , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Ratos , Ratos TransgênicosRESUMO
Founder events play a critical role in shaping genetic diversity, fitness and disease risk in a population. Yet our understanding of the prevalence and distribution of founder events in humans and other species remains incomplete, as most existing methods require large sample sizes or phased genomes. Thus, we developed ASCEND that measures the correlation in allele sharing between pairs of individuals across the genome to infer the age and strength of founder events. We show that ASCEND can reliably estimate the parameters of founder events under a range of demographic scenarios. We then apply ASCEND to two species with contrasting evolutionary histories: ~460 worldwide human populations and ~40 modern dog breeds. In humans, we find that over half of the analyzed populations have evidence for recent founder events, associated with geographic isolation, modes of sustenance, or cultural practices such as endogamy. Notably, island populations have lower population sizes than continental groups and most hunter-gatherer, nomadic and indigenous groups have evidence of recent founder events. Many present-day groups--including Native Americans, Oceanians and South Asians--have experienced more extreme founder events than Ashkenazi Jews who have high rates of recessive diseases due their known history of founder events. Using ancient genomes, we show that the strength of founder events differs markedly across geographic regions and time--with three major founder events related to the peopling of Americas and a trend in decreasing strength of founder events in Europe following the Neolithic transition and steppe migrations. In dogs, we estimate extreme founder events in most breeds that occurred in the last 25 generations, concordant with the establishment of many dog breeds during the Victorian times. Our analysis highlights a widespread history of founder events in humans and dogs and elucidates some of the demographic and cultural practices related to these events.
Assuntos
Povo Asiático , Genética Populacional , Alelos , Animais , Cães , Etnicidade , Efeito Fundador , Humanos , Densidade DemográficaRESUMO
Microtia is a congenital malformation that encompasses mild hypoplasia to complete loss of the external ear, or pinna. Although the contribution of genetic variation and environmental factors to microtia remains elusive, Amerindigenous populations have the highest reported incidence. Here, using both transmission disequilibrium tests and association studies in microtia trios (parents and affected child) and microtia cohorts enrolled in Latin America, we map an â¼10-kb microtia locus (odds ratio = 4.7; P = 6.78e-18) to the intergenic region between Roundabout 1 (ROBO1) and Roundabout 2 (ROBO2) (chr3: 78546526 to 78555137). While alleles at the microtia locus significantly increase the risk of microtia, their penetrance is low (<1%). We demonstrate that the microtia locus contains a polymorphic complex repeat element that is expanded in affected individuals. The locus is located near a chromatin loop region that regulates ROBO1 and ROBO2 expression in induced pluripotent stem cellderived neural crest cells. Furthermore, we use single nuclear RNA sequencing to demonstrate ROBO1 and ROBO2 expression in both fibroblasts and chondrocytes of the mature human pinna. Because the microtia allele is enriched in Amerindigenous populations and is shared by some East Asian subjects with craniofacial malformations, we propose that both populations share a mutation that arose in a common ancestor prior to the ancient migration of Eurasian populations into the Americas and that the high incidence of microtia among Amerindigenous populations reflects the population bottleneck that occurred during the migration out of Eurasia.
Assuntos
Indígena Americano ou Nativo do Alasca , Microtia Congênita , Microtia Congênita/genética , Orelha Externa , Efeito Fundador , Humanos , Mutação , Proteínas do Tecido Nervoso/genética , Receptores Imunológicos/genética , Indígena Americano ou Nativo do Alasca/genética , Proteínas RoundaboutRESUMO
Facioscapulohumeral muscular dystrophy (FSHD) is an inherited myopathy clinically characterized by weakness in the facial, shoulder girdle and upper a muscles. FSHD is caused by chromatin relaxation of the D4Z4 macrosatellite repeat, mostly by a repeat contraction, facilitating ectopic expression of DUX4 in skeletal muscle. Genetic diagnosis for FSHD is generally based on the sizing and haplotyping of the D4Z4 repeat on chromosome 4 by Southern blotting (SB), molecular combing or single-molecule optical mapping, which is usually straight forward but can be complicated by atypical rearrangements of the D4Z4 repeat. One of these rearrangements is a D4Z4 proximally extended deletion (DPED) allele, where not only the D4Z4 repeat is partially deleted, but also sequences immediately proximal to the repeat are lost, which can impede accurate diagnosis in all genetic methods. Previously, we identified several DPED alleles in FSHD and estimated the size of the proximal deletions by a complex pulsed-field gel electrophoresis and SB strategy. Here, using the next-generation sequencing, we have defined the breakpoint junctions of these DPED alleles at the base pair resolution in 12 FSHD families and 4 control individuals facilitating a PCR-based diagnosis of these DPED alleles. Our resultsshow that half of the DPED alleles are derivates of an ancient founder allele. For some DPED alleles, we found that genetic elements are deleted such as DUX4c, FRG2, DBE-T and myogenic enhancers necessitating re-evaluation of their role in FSHD pathogenesis.
Assuntos
Distrofia Muscular Facioescapuloumeral , Alelos , Cromatina , Cromossomos Humanos Par 4/genética , Efeito Fundador , Humanos , Distrofia Muscular Facioescapuloumeral/genética , Distrofia Muscular Facioescapuloumeral/metabolismoRESUMO
Meniere disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial MD (FMD) has been reported, being 9-10% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in FMD has been described, OTOG being the most common mutated gene, with a compound heterozygous recessive inheritance. We hypothesize that an OTOG-related founder effect may explain the higher prevalence of FMD in the European population. Therefore, the present study aimed to compare the allele frequency (AF) and distribution of OTOG rare variants across different populations. For this purpose, the coding regions with high constraint (low density of rare variants) were retrieved in the OTOG coding sequence in Non-Finnish European (NFE).. Missense variants (AF < 0.01) were selected from a 100 FMD patient cohort, and their population AF was annotated using gnomAD v2.1. A linkage analysis was performed, and odds ratios were calculated to compare AF between NFE and other populations. Thirteen rare missense variants were observed in 13 FMD patients, with 2 variants (rs61978648 and rs61736002) shared by 5 individuals and another variant (rs117315845) shared by two individuals. The results confirm the observed enrichment of OTOG rare missense variants in FMD. Furthermore, eight variants were enriched in the NFE population, and six of them were in constrained regions. Structural modeling predicts five missense variants that could alter the otogelin stability. We conclude that several variants reported in FMD are in constraint regions, and they may have a founder effect and explain the burden of FMD in the European population.
Assuntos
Frequência do Gene , Doença de Meniere , Mutação de Sentido Incorreto , População Branca , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Europa (Continente)/epidemiologia , Efeito Fundador , Ligação Genética , Predisposição Genética para Doença , Doença de Meniere/genética , Doença de Meniere/epidemiologia , Prevalência , População Branca/genética , População EuropeiaRESUMO
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/genéticaRESUMO
Autosomal recessive CARD9 deficiency can underly deep and superficial fungal diseases. We identified two Japanese patients, suffering from superficial and invasive Candida albicans diseases, carrying biallelic variants of CARD9. Both patients, in addition to another Japanese and two Korean patients who were previously reported, carried the c.820dup CARD9 variant, either in the homozygous (two patients) or heterozygous (three patients) state. The other CARD9 alleles were c.104G > A, c.1534C > T and c.1558del. The c.820dup CARD9 variant has thus been reported, in the homozygous or heterozygous state, in patients originating from China, Japan, or South Korea. The Japanese, Korean, and Chinese patients share a 10 Kb haplotype encompassing the c.820dup CARD9 variant. This variant thus originates from a common ancestor, estimated to have lived less than 4,000 years ago. While phaeohyphomycosis caused by Phialophora spp. was common in the Chinese patients, none of the five patients in our study displayed Phialophora spp.-induced disease. This difference between Chinese and our patients probably results from environmental factors. (161/250).
Assuntos
Proteínas Adaptadoras de Sinalização CARD , Efeito Fundador , Humanos , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/deficiência , Masculino , Feminino , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/diagnóstico , Haplótipos , Mutação/genética , Ásia Oriental , Alelos , Candida albicans/genética , Adulto , Linhagem , Povo Asiático/genéticaRESUMO
Dyssegmental dysplasia (DD) is a severe skeletal dysplasia comprised of two subtypes: lethal Silverman-Handmaker type (DDSH) and nonlethal Rolland-Desbuquois type (DDRD). DDSH is caused by biallelic pathogenic variants in HSPG2 encoding perlecan, whereas the genetic cause of DDRD remains undetermined. Schwartz-Jampel syndrome (SJS) is also caused by biallelic pathogenic variants in HSPG2 and is an allelic disorder of DDSH. In SJS and DDSH, 44 and 8 pathogenic variants have been reported in HSPG2, respectively. Here, we report that five patients with DDRD carried four pathogenic variants in HSPG2: c.9970 G > A (p.G3324R), c.559 C > T (p.R187X), c7006 + 1 G > A, and c.11562 + 2 T > G. Two patients were homozygous for p.G3324R, and three patients were heterozygous for p.G3324R. Haplotype analysis revealed a founder haplotype spanning 85,973 bp shared in the five patients. SJS, DDRD, and DDSH are allelic disorders with pathogenic variants in HSPG2.
Assuntos
Haplótipos , Proteoglicanas de Heparan Sulfato , Osteocondrodisplasias , Feminino , Humanos , Masculino , Alelos , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/patologia , Efeito Fundador , Proteoglicanas de Heparan Sulfato/genética , Mutação , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Doenças FetaisRESUMO
Many species are shifting their ranges in response to climate-driven environmental changes, particularly in high-latitude regions. However, the patterns of dispersal and colonization during range shifting events are not always clear. Understanding how populations are connected through space and time can reveal how species navigate a changing environment. Here, we present a fine-scale population genomics study of gentoo penguins (Pygoscelis papua), a presumed site-faithful colonial nesting species that has increased in population size and expanded its range south along the Western Antarctic Peninsula. Using whole genome sequencing, we analysed 129 gentoo penguin individuals across 12 colonies located at or near the southern range edge. Through a detailed examination of fine-scale population structure, admixture, and population divergence, we inferred that gentoo penguins historically dispersed rapidly in a stepping-stone pattern from the South Shetland Islands leading to the colonization of Anvers Island, and then the adjacent mainland Western Antarctica Peninsula. Recent southward expansion along the Western Antarctic Peninsula also followed a stepping-stone dispersal pattern coupled with limited post-divergence gene flow from colonies on Anvers Island. Genetic diversity appeared to be maintained across colonies during the historical dispersal process, and range-edge populations are still growing. This suggests large numbers of migrants may provide a buffer against founder effects at the beginning of colonization events to maintain genetic diversity similar to that of the source populations before migration ceases post-divergence. These results coupled with a continued increase in effective population size since approximately 500-800 years ago distinguish gentoo penguins as a robust species that is highly adaptable and resilient to changing climate.
Assuntos
Efeito Fundador , Spheniscidae , Humanos , Animais , Densidade Demográfica , Spheniscidae/genética , Regiões Antárticas , Sequenciamento Completo do GenomaRESUMO
Understanding how phenotypic divergence arises among natural populations remains one of the major goals in evolutionary biology. As part of competitive exclusion experiment conducted in 1971, 10 individuals of Italian wall lizard (Podarcis siculus (Rafinesque-Schmaltz, 1810)) were transplanted from Pod Kopiste Island to the nearby island of Pod Mrcaru (Adriatic Sea). Merely 35 years after the introduction, the newly established population on Pod Mrcaru Island had shifted their diet from predominantly insectivorous towards omnivorous and changed significantly in a range of morphological, behavioural, physiological and ecological characteristics. Here, we combine genomic and quantitative genetic approaches to determine the relative roles of genetic adaptation and phenotypic plasticity in driving this rapid phenotypic shift. Our results show genome-wide genetic differentiation between ancestral and transplanted population, with weak genetic erosion on Pod Mrcaru Island. Adaptive processes following the founder event are indicated by highly differentiated genomic loci associating with ecologically relevant phenotypic traits, and/or having a putatively adaptive role across multiple lizard populations. Diverged traits related to head size and shape or bite force showed moderate heritability in a crossing experiment, but between-population differences in these traits did not persist in a common garden environment. Our results confirm the existence of sufficient additive genetic variance for traits to evolve under selection while also demonstrating that phenotypic plasticity and/or genotype by environment interactions are the main drivers of population differentiation at this early evolutionary stage.
Assuntos
Efeito Fundador , Genética Populacional , Lagartos , Fenótipo , Animais , Lagartos/genética , Ilhas , Variação Genética , Itália , Adaptação Fisiológica/genética , MasculinoRESUMO
Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia, and Cardiac defects (PDAC) syndrome is a genetically heterogeneous multiple congenital malformation syndrome. Although pathogenic variants in RARB and STRA6 are established causes of PDAC, many PDAC cases remain unsolved at the molecular level. Recently, we proposed biallelic WNT7B variants as a novel etiology based on several families with typical features of PDAC syndrome albeit with variable expressivity. Here, we report three patients from two families that share a novel founder variant in WNT7B (c.739C > T; Arg247Trp). The phenotypic expression of this variant ranges from typical PDAC features to isolated genitourinary anomalies. Similar to previously reported PDAC-associated WNT7B variants, this variant was found to significantly impair WNT7B signaling activity further corroborating its proposed pathogenicity. This report adds further evidence to WNT7B-related PDAC and expands its variable expressivity.
Assuntos
Fenótipo , Proteínas Wnt , Humanos , Proteínas Wnt/genética , Masculino , Feminino , Anoftalmia/genética , Anoftalmia/patologia , Microftalmia/genética , Microftalmia/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Efeito Fundador , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Linhagem , Mutação , Predisposição Genética para Doença , Síndrome , Pulmão/patologia , Pulmão/anormalidadesRESUMO
The FMR1 5' regulation gene region harbors a CGG trinucleotide repeat expansion (CGG-TRE) that causes Fragile X syndrome (FXS) when it expands to more than 200 repetitions. Ricaurte is a small village in southwestern Colombia, with an FXS prevalence of 1 in 38 men and 1 in 100 women (~100 times higher than the worldwide reported prevalence), defining Ricaurte as the largest FXS cluster in the world. In the present study, using next-generation sequencing of whole exome capture, we genotype 55 individuals from Ricaurte (49 with either full mutation or with premutation), four individuals from neighboring villages (with either the full mutation or with the premutation), and one unaffected woman, native of Ricaurte, who did not belong to any of the affected families. With advanced clustering and haplotype reconstruction, we modeled a common haplotype of 33 SNPs spanning 83,567,899 bp and harboring the FMR1 gene. This reconstructed haplotype was found in all the men from Ricaurte who carried the expansion, demonstrating that the genetic conglomerate of FXS in this population is due to a founder effect. The definition of this founder effect and its population outlining will allow a better prediction, follow-up, precise and personalized characterization of epidemiological parameters, better knowledge of the disease's natural history, and confident improvement of the clinical attention, life quality, and health interventions for this community.
Assuntos
Síndrome do Cromossomo X Frágil , Masculino , Humanos , Feminino , Síndrome do Cromossomo X Frágil/epidemiologia , Síndrome do Cromossomo X Frágil/genética , Efeito Fundador , Epidemiologia Molecular , Proteína do X Frágil da Deficiência Intelectual/genética , Expansão das Repetições de Trinucleotídeos , MutaçãoRESUMO
Distal arthrogryposis type 5D (DA5D) is clinically characterized by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and scoliosis. We report nine affected individuals from eight unrelated Indian families with DA5D. Although the overall musculoskeletal phenotype is not very distinct from other distal arthrogryposis, the presence of fixed knee extension contractures with or without scoliosis could be an important early pointer to DA5D. We also report a possible founder variant in ECEL1 along with four novel variants and further expand the genotypic spectrum of DA5D.
Assuntos
Artrogripose , Efeito Fundador , Fenótipo , Humanos , Artrogripose/genética , Artrogripose/patologia , Masculino , Feminino , Índia , Criança , Pré-Escolar , Linhagem , Adolescente , Mutação/genética , Lactente , Estudos de Associação Genética , Estudos de Coortes , Genótipo , Adulto , MetaloendopeptidasesRESUMO
PREMISE: The domestication of wild plant species can begin with gathering and transport of propagules by Indigenous peoples. The effect on genomic composition, especially in clonal, self-incompatible perennials would be instantaneous and drastic with respect to new, anthropogenic populations subsequently established. Reductions in genetic diversity and mating capability would be symptomatic and the presence of unique alleles and genetic sequences would reveal the origins and ancestry of populations associated with archaeological sites. The current distribution of the Four Corners potato, Solanum jamesii Torr. in the Southwestern USA, may thus reflect the early stages of a domestication process that began with tuber transport. METHODS: Herein genetic sequencing (GBS) data are used to further examine the hypothesis of domestication in this culturally significant species by sampling 25 archaeological and non-archaeological populations. RESULTS: Archaeological populations from Utah, Colorado and northern Arizona have lower levels of polymorphic loci, unique alleles, and heterozygosity than non-archaeological populations from the Mogollon region of central Arizona and New Mexico. Principle components analysis, Fst values, and structure analysis revealed that genetic relationships among archaeological populations did not correspond to geographic proximity. Populations in Escalante, Utah were related to those on the Mogollon Rim (400 km south) and had multiple origins and significant disjunctions with those populations in Bears Ears, Chaco Canyon, and Mesa Verde sites. CONCLUSIONS: Movement of tubers from the Mogollon region may have occurred many times and in multiple directions during the past, resulting in the complex genetic patterns seen in populations from across the Four Corners region.