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1.
Genome Biol Evol ; 11(9): 2678-2690, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400206

RESUMO

Gene fusion occurs when two or more individual genes with independent open reading frames becoming juxtaposed under the same open reading frame creating a new fused gene. A small number of gene fusions described in detail have been associated with novel functions, for example, the hominid-specific PIPSL gene, TNFSF12, and the TWE-PRIL gene family. We use Sequence Similarity Networks and species level comparisons of great ape genomes to identify 45 new genes that have emerged by transcriptional readthrough, that is, transcription-derived gene fusion. For 35 of these putative gene fusions, we have been able to assess available RNAseq data to determine whether there are reads that map to each breakpoint. A total of 29 of the putative gene fusions had annotated transcripts (9/29 of which are human-specific). We carried out RT-qPCR in a range of human tissues (placenta, lung, liver, brain, and testes) and found that 23 of the putative gene fusion events were expressed in at least one tissue. Examining the available ribosome foot-printing data, we find evidence for translation of three of the fused genes in human. Finally, we find enrichment for transcription-derived gene fusions in regions of known segmental duplication in human. Together, our results implicate chromosomal structural variation brought about by segmental duplication with the emergence of novel transcripts and translated protein products.

2.
Front Immunol ; 9: 636, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867916

RESUMO

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15-24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls.


Assuntos
Antígeno CTLA-4/genética , Imunodeficiência de Variável Comum/genética , Genótipo , Mutação/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Adolescente , Células Cultivadas , Criança , Pré-Escolar , Estudos de Coortes , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Leucócitos Mononucleares/fisiologia , Ativação Linfocitária , Modelos Biológicos , Sequenciamento Completo do Exoma
3.
4.
Mol Ecol Resour ; 18(2): 319-333, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29058768

RESUMO

Target-capture approach has improved over the past years, proving to be very efficient tool for selectively sequencing genetic regions of interest. These methods have also allowed the use of noninvasive samples such as faeces (characterized by their low quantity and quality of endogenous DNA) to be used in conservation genomic, evolution and population genetic studies. Here we aim to test different protocols and strategies for exome capture using the Roche SeqCap EZ Developer kit (57.5 Mb). First, we captured a complex pool of DNA libraries. Second, we assessed the influence of using more than one faecal sample, extract and/or library from the same individual, to evaluate its effect on the molecular complexity of the experiment. We validated our experiments with 18 chimpanzee faecal samples collected from two field sites as a part of the Pan African Programme: The Cultured Chimpanzee. Those two field sites are in Kibale National Park, Uganda (N = 9) and Loango National Park, Gabon (N = 9). We demonstrate that at least 16 libraries can be pooled, target enriched through hybridization, and sequenced allowing for the genotyping of 951,949 exome markers for population genetic analyses. Further, we observe that molecule richness, and thus, data acquisition, increase when using multiple libraries from the same extract or multiple extracts from the same sample. Finally, repeated captures significantly decrease the proportion of off-target reads from 34.15% after one capture round to 7.83% after two capture rounds, supporting our conclusion that two rounds of target enrichment are advisable when using complex faecal samples.


Assuntos
DNA/genética , DNA/isolamento & purificação , Fezes/química , Genética Populacional/métodos , Metagenômica/métodos , Animais , Gabão , Pan troglodytes , Amostragem , Uganda
5.
BMC Genomics ; 18(1): 977, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29258433

RESUMO

BACKGROUND: Whole genome re-sequencing data from dogs and wolves are now commonly used to study how natural and artificial selection have shaped the patterns of genetic diversity. Single nucleotide polymorphisms, microsatellites and variants in mitochondrial DNA have been interrogated for links to specific phenotypes or signals of domestication. However, copy number variation (CNV), despite its increasingly recognized importance as a contributor to phenotypic diversity, has not been extensively explored in canids. RESULTS: Here, we develop a new accurate probabilistic framework to create fine-scale genomic maps of segmental duplications (SDs), compare patterns of CNV across groups and investigate their role in the evolution of the domestic dog by using information from 34 canine genomes. Our analyses show that duplicated regions are enriched in genes and hence likely possess functional importance. We identify 86 loci with large CNV differences between dogs and wolves, enriched in genes responsible for sensory perception, immune response, metabolic processes, etc. In striking contrast to the observed loss of nucleotide diversity in domestic dogs following the population bottlenecks that occurred during domestication and breed creation, we find a similar proportion of CNV loci in dogs and wolves, suggesting that other dynamics are acting to particularly select for CNVs with potentially functional impacts. CONCLUSIONS: This work is the first comparison of genome wide CNV patterns in domestic and wild canids using whole-genome sequencing data and our findings contribute to study the impact of novel kinds of genetic changes on the evolution of the domestic dog.


Assuntos
Variações do Número de Cópias de DNA , Cães/genética , Lobos/genética , Animais , Cruzamento , Genômica , Duplicações Segmentares Genômicas , Análise de Sequência de DNA
6.
Sci Rep ; 7(1): 15224, 2017 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-29123202

RESUMO

The genus Pan is the closest related to humans (Homo sapiens) and it includes two species: Pan troglodytes (chimpanzees) and Pan paniscus (bonobos). Different characteristics, some of biomedical aspect, separate them from us. For instance, some common human medical conditions are rare in chimpanzees (menopause, Alzheimer disease) although it is unclear to which extent longevity plays an active role in these differences. However, both humans and chimpanzees present similar pathologies, thus, understanding traits in chimpanzees can help unravel the molecular basis of human conditions. Here, we sequenced the genome of Nico, a central chimpanzee diagnosed with a particular biomedical condition, the Chiari malformation. We performed a variant calling analysis comparing his genome to 25 whole genomes from healthy individuals (bonobos and chimpanzees), and after predicting the effects of the genetic variants, we looked for genes within the OMIM database. We found a novel, private, predicted as damaging mutation in Nico in LRP5, a gene related to bone density alteration pathologies, and we suggest a link between this mutation and his Chiari malformation as previously shown in humans. Our results reinforce the idea that a comparison between humans and chimpanzees can be established in this genetic frame of common diseases.


Assuntos
Doenças dos Símios Antropoides/genética , Doenças dos Símios Antropoides/patologia , Malformação de Arnold-Chiari/genética , Malformação de Arnold-Chiari/patologia , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Mutação , Animais , Masculino , Pan troglodytes , Sequenciamento Completo do Genoma
7.
Science ; 354(6311): 477-481, 2016 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-27789843

RESUMO

Our closest living relatives, chimpanzees and bonobos, have a complex demographic history. We analyzed the high-coverage whole genomes of 75 wild-born chimpanzees and bonobos from 10 countries in Africa. We found that chimpanzee population substructure makes genetic information a good predictor of geographic origin at country and regional scales. Multiple lines of evidence suggest that gene flow occurred from bonobos into the ancestors of central and eastern chimpanzees between 200,000 and 550,000 years ago, probably with subsequent spread into Nigeria-Cameroon chimpanzees. Together with another, possibly more recent contact (after 200,000 years ago), bonobos contributed less than 1% to the central chimpanzee genomes. Admixture thus appears to have been widespread during hominid evolution.


Assuntos
Evolução Molecular , Variação Genética , Pan paniscus/genética , Pan troglodytes/genética , Animais , Camarões , Fluxo Gênico , Genoma , Genômica , Haplótipos , Nigéria , População
8.
Genome Biol Evol ; 8(6): 2020-30, 2016 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-27345955

RESUMO

The genus Pan is the closest genus to our own and it includes two species, Pan paniscus (bonobos) and Pan troglodytes (chimpanzees). The later is constituted by four subspecies, all highly endangered. The study of the Pan genera has been incessantly complicated by the intricate relationship among subspecies and the statistical limitations imposed by the reduced number of samples or genomic markers analyzed. Here, we present a new method to reconstruct complete mitochondrial genomes (mitogenomes) from whole genome shotgun (WGS) datasets, mtArchitect, showing that its reconstructions are highly accurate and consistent with long-range PCR mitogenomes. We used this approach to build the mitochondrial genomes of 20 newly sequenced samples which, together with available genomes, allowed us to analyze the hitherto most complete Pan mitochondrial genome dataset including 156 chimpanzee and 44 bonobo individuals, with a proportional contribution from all chimpanzee subspecies. We estimated the separation time between chimpanzees and bonobos around 1.15 million years ago (Mya) [0.81-1.49]. Further, we found that under the most probable genealogical model the two clades of chimpanzees, Western + Nigeria-Cameroon and Central + Eastern, separated at 0.59 Mya [0.41-0.78] with further internal separations at 0.32 Mya [0.22-0.43] and 0.16 Mya [0.17-0.34], respectively. Finally, for a subset of our samples, we compared nuclear versus mitochondrial genomes and we found that chimpanzee subspecies have different patterns of nuclear and mitochondrial diversity, which could be a result of either processes affecting the mitochondrial genome, such as hitchhiking or background selection, or a result of population dynamics.


Assuntos
Evolução Molecular , Genoma Mitocondrial/genética , Pan paniscus/genética , Pan troglodytes/genética , Animais , Variação Genética , Genética Populacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Filogenia
9.
Genome Biol Evol ; 8(3): 871-7, 2016 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-26912403

RESUMO

Loss of function (LoF) genetic variants are predicted to disrupt gene function, and are therefore expected to substantially reduce individual's viability. Knowing the genetic burden of LoF variants in endangered species is of interest for a better understanding of the effects of declining population sizes on species viability. In this study, we have estimated the number of LoF polymorphic variants in six great ape populations, based on whole-genome sequencing data in 79 individuals. Our results show that although the number of functional variants per individual is conditioned by the effective population size, the number of variants with a drastic phenotypic effect is very similar across species. We hypothesize that for those variants with high selection coefficients, differences in effective population size are not important enough to affect the efficiency of natural selection to remove them. We also describe that mostly CpG LoF mutations are shared across species, and an accumulation of LoF variants at olfactory receptor genes in agreement with its pseudogenization in humans and other primate species.


Assuntos
Evolução Molecular , Variação Genética/genética , Hominidae/genética , Seleção Genética/genética , Animais , Carga Genética , Genoma Humano , Humanos , Mutação , Polimorfismo de Nucleotídeo Único
10.
Science ; 348(6231): 242-245, 2015 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-25859046

RESUMO

Mountain gorillas are an endangered great ape subspecies and a prominent focus for conservation, yet we know little about their genomic diversity and evolutionary past. We sequenced whole genomes from multiple wild individuals and compared the genomes of all four Gorilla subspecies. We found that the two eastern subspecies have experienced a prolonged population decline over the past 100,000 years, resulting in very low genetic diversity and an increased overall burden of deleterious variation. A further recent decline in the mountain gorilla population has led to extensive inbreeding, such that individuals are typically homozygous at 34% of their sequence, leading to the purging of severely deleterious recessive mutations from the population. We discuss the causes of their decline and the consequences for their future survival.


Assuntos
Variação Genética , Genoma , Gorilla gorilla/genética , Endogamia , Adaptação Fisiológica , Animais , Evolução Biológica , Variações do Número de Cópias de DNA , República Democrática do Congo , Espécies em Perigo de Extinção , Feminino , Gorilla gorilla/classificação , Gorilla gorilla/fisiologia , Homozigoto , Desequilíbrio de Ligação , Masculino , Mutação , Dinâmica Populacional , Ruanda , Seleção Genética , Análise de Sequência de DNA , Especificidade da Espécie , Fatores de Tempo
11.
PLoS Genet ; 11(12): e1005721, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26720152

RESUMO

The birth of new genes is an important motor of evolutionary innovation. Whereas many new genes arise by gene duplication, others originate at genomic regions that did not contain any genes or gene copies. Some of these newly expressed genes may acquire coding or non-coding functions and be preserved by natural selection. However, it is yet unclear which is the prevalence and underlying mechanisms of de novo gene emergence. In order to obtain a comprehensive view of this process, we have performed in-depth sequencing of the transcriptomes of four mammalian species--human, chimpanzee, macaque, and mouse--and subsequently compared the assembled transcripts and the corresponding syntenic genomic regions. This has resulted in the identification of over five thousand new multiexonic transcriptional events in human and/or chimpanzee that are not observed in the rest of species. Using comparative genomics, we show that the expression of these transcripts is associated with the gain of regulatory motifs upstream of the transcription start site (TSS) and of U1 snRNP sites downstream of the TSS. In general, these transcripts show little evidence of purifying selection, suggesting that many of them are not functional. However, we find signatures of selection in a subset of de novo genes which have evidence of protein translation. Taken together, the data support a model in which frequently-occurring new transcriptional events in the genome provide the raw material for the evolution of new proteins.


Assuntos
Evolução Molecular , Genes , Genoma Humano , Pan troglodytes/genética , Ribonucleoproteína Nuclear Pequena U1/genética , Animais , Sequência de Bases , Feminino , Expressão Gênica , Humanos , Macaca/genética , Masculino , Camundongos , Regiões Promotoras Genéticas , Sequências Reguladoras de Ácido Nucleico , Testículo/fisiologia , Sítio de Iniciação de Transcrição
12.
Nature ; 513(7517): 195-201, 2014 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-25209798

RESUMO

Gibbons are small arboreal apes that display an accelerated rate of evolutionary chromosomal rearrangement and occupy a key node in the primate phylogeny between Old World monkeys and great apes. Here we present the assembly and analysis of a northern white-cheeked gibbon (Nomascus leucogenys) genome. We describe the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We further show that the gibbon genera (Nomascus, Hylobates, Hoolock and Symphalangus) experienced a near-instantaneous radiation ∼5 million years ago, coincident with major geographical changes in southeast Asia that caused cycles of habitat compression and expansion. Finally, we identify signatures of positive selection in genes important for forelimb development (TBX5) and connective tissues (COL1A1) that may have been involved in the adaptation of gibbons to their arboreal habitat.


Assuntos
Genoma/genética , Hylobates/classificação , Hylobates/genética , Cariótipo , Filogenia , Animais , Evolução Molecular , Hominidae/classificação , Hominidae/genética , Humanos , Dados de Sequência Molecular , Retroelementos/genética , Seleção Genética , Terminação da Transcrição Genética
13.
BMC Genomics ; 15: 465, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24923435

RESUMO

BACKGROUND: Although a variety of genetic changes have been implicated in causing phenotypic differences among dogs, the role of copy number variants (CNVs) and their impact on phenotypic variation is still poorly understood. Further, very limited knowledge exists on structural variation in the gray wolf, the ancestor of the dog, or other closely related wild canids. Documenting CNVs variation in wild canids is essential to identify ancestral states and variation that may have appeared after domestication. RESULTS: In this work, we genotyped 1,611 dog CNVs in 23 wolf-like canids (4 purebred dogs, one dingo, 15 gray wolves, one red wolf, one coyote and one golden jackal) to identify CNVs that may have arisen after domestication. We have found an increase in GC-rich regions close to the breakpoints and around 1 kb away from them suggesting that some common motifs might be associated with the formation of CNVs. Among the CNV regions that showed the largest differentiation between dogs and wild canids we found 12 genes, nine of which are related to two known functions associated with dog domestication; growth (PDE4D, CRTC3 and NEB) and neurological function (PDE4D, EML5, ZNF500, SLC6A11, ELAVL2, RGS7 and CTSB). CONCLUSIONS: Our results provide insight into the evolution of structural variation in canines, where recombination is not regulated by PRDM9 due to the inactivation of this gene. We also identified genes within the most differentiated CNV regions between dogs and wolves, which could reflect selection during the domestication process.


Assuntos
Canidae/classificação , Canidae/genética , Animais de Estimação/genética , Animais , Pontos de Quebra do Cromossomo , Cromossomos de Mamíferos , Variações do Número de Cópias de DNA , Cães , Evolução Molecular , Variação Genética , Animais de Estimação/classificação , Filogenia , Seleção Genética
14.
Nature ; 499(7459): 471-5, 2013 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-23823723

RESUMO

Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.


Assuntos
Variação Genética , Hominidae/genética , África , Animais , Animais Selvagens/genética , Animais de Zoológico/genética , Ásia Sudeste , Evolução Molecular , Fluxo Gênico/genética , Genética Populacional , Genoma/genética , Gorilla gorilla/classificação , Gorilla gorilla/genética , Hominidae/classificação , Humanos , Endogamia , Pan paniscus/classificação , Pan paniscus/genética , Pan troglodytes/classificação , Pan troglodytes/genética , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Densidade Demográfica
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