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2.
Anim Genet ; 51(1): 106-110, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31729055

RESUMO

The sequencing of the pig genome revealed the existence of homozygous individuals for a nonsense mutation in the argininosuccinate synthase 1 (ASS1) gene (rs81212146, c.944T>A, L315X). Paradoxically, an AA homozygous genotype for this polymorphism is expected to abolish the function of the ASS1 enzyme that participates in the urea cycle, leading to citrullinemia, hyperammonemia, coma and death. Sequencing of five Duroc boars that sired a population of 350 Duroc barrows revealed the segregation of the c.944T>A polymorphism, so we aimed to investigate its phenotypic consequences. Genotyping of this mutation in the 350 Duroc barrows revealed the existence of seven individuals homozygous (AA) for the nonsense mutation. These AA pigs had a normal weight despite the fact that mild citrullinemia often involves impaired growth. Sequencing of the region surrounding the mutation in TT, TA and AA individuals revealed that the A substitution in the second position of the codon (c.944T>A) is in complete linkage disequilibrium with a C replacement (c.943T>C) in the first position of the codon. This second mutation would compensate for the potentially damaging effect of the c.944T>A replacement. In fact, this is the most probable reason why pigs with homozygous AA genotypes at the 944 site of the ASS1 coding region are alive. Our results illustrate the complexities of predicting the consequences of nonsense mutations on gene function and phenotypes, not only because of annotation issues but also owing to the existence of genetic mechanisms that sometimes limit the penetrance of highly harmful mutations.


Assuntos
Argininossuccinato Sintase/genética , Genes Letais , Sus scrofa/genética , Animais , Citrulinemia/genética , Citrulinemia/veterinária , Códon sem Sentido , Genótipo , Homozigoto , Desequilíbrio de Ligação , Masculino
3.
Anim Genet ; 51(1): 122-126, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31691328

RESUMO

A GWAS was performed for inborn X-linked facial dysmorphia with severe growth retardation in Labrador Retrievers. This lethal condition was mapped on the X chromosome at 17-21 Mb and supported by eight SNPs in complete LD. Dams of affected male puppies were heterozygous for the significantly associated SNPs and male affected puppies carried the associated alleles hemizygously. In the near vicinity to the associated region, RPS6KA3 was identified as a candidate gene causing facial dysmorphia in humans and mice known as Coffin-Lowry syndrome. Haplotype analysis showed significant association with the phenotypes of all 18 animals under study. This haplotype was validated through normal male progeny from a dam with the not-associated haplotype on both X chromosomes but male affected full-sibs with the associated haplotype.


Assuntos
Craniossinostoses/veterinária , Doenças do Cão/genética , Cães/genética , Genes Letais , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Animais , Craniossinostoses/genética , Feminino , Estudos de Associação Genética/veterinária , Haplótipos , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Cromossomo X/genética
4.
J Dairy Sci ; 103(1): 613-618, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31733870

RESUMO

Vorderwald cattle are a dual-purpose cattle breed with high migrant contributions from Montbéliarde bulls in the recent past. Through the wide use of Montbéliarde bulls, undesirable alleles were also disseminated into the Vorderwald population. Haplotypes on bovine chromosome 19 (MH1) and 29 (MH2), supposed to harbor lethal mutations, were identified in Montbéliarde cattle. A study in French Montbéliarde cattle identified the PFAS:g.28511199C>T (rs455876205) variant as the most likely MH1 embryonic lethal mutation. The objective of the present study was to determine whether the PFAS:g.28511199C>T variant was introduced into Vorderwald cattle through Montbéliarde bulls and disseminated in this population. The present study expands on previous work on the deleterious SLC37A2 variant (ss2019324563) of the MH2 locus. Herein, we traced the ss2019324563 variant back to the Montbéliarde bull, which was the most likely source for this deleterious mutation in Vorderwald cattle. We genotyped 354 Vorderwald cattle for the PFAS variant, resulting in 41 heterozygous individuals and a T allele frequency of 0.058. An aborted fetus homozygous mutant for SLC37A2 from our previous study on the MH2 locus in Vorderwald cattle was wild type for the PFAS variant. Both lethal mutations were segregating independently of each other, and we found no indications of joint occurrence in a larger number of animals. Neither SLC37A2 nor PFAS double heterozygous mutants were lethal. The earliest animal with a heterozygous PFAS genotype was 1 of 5 migrant Montbéliarde bulls, and this bull was the most likely origin of the deleterious PFAS allele in Vorderwald cattle. All Vorderwald cattle under study born before introgression of this Montbéliarde bull were homozygous wild type. In addition, all 41 heterozygous Vorderwald cattle had genetic contributions from this Montbéliarde bull, whereas in 74 Vorderwald cattle without genes from Montbéliarde bulls, the PFAS T allele was not observed. In a sample of actual German Fleckvieh the PFAS T allele could be found at a very low frequency. Our study demonstrated the introgression of lethal variants through Montbéliarde bulls into a traditional cattle breed highly adapted to harsh local conditions. These findings underline the need to screen bulls for lethal mutations before their wide use in breeding, particularly in breeds with a focus on preservation of their genetic uniqueness.


Assuntos
Cruzamento , Bovinos/genética , Genes Letais , Mutação , Alelos , Animais , Cruzamentos Genéticos , Feminino , Genótipo , Haplótipos , Homozigoto , Masculino
5.
Pestic Biochem Physiol ; 161: 47-53, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31685195

RESUMO

The western flower thrips, Frankliniella occidentalis, is a major pest that damages a wide variety of crops and vegetables. Following extensive use of insecticides, it has developed high levels of resistance to almost all groups of insecticides due to its high reproduction rate and short generation time. Therefore, an alternative pest control strategy, such as RNA interference (RNAi)-based control, is essential. To establish an ingestion RNAi-based control, a total of 57 genes involved in various biological processes were selected, and their double-stranded RNAs (dsRNA) were delivered to an insecticide-susceptible strain of F. occidentalis via the leaf disc-feeding method using a bioassay chamber optimized by 3D printing. The mortality of dsRNA-ingested thrips was examined every 24 h until 120 h post-treatment. Of the 57 genes screened, dsRNAs of the Toll-like receptor 6, apolipophorin, coatomer protein subunit epsilon and sorting and assembly machinery component were most lethal when ingested by thrips. The dsRNA-fed thrips showed substantially reduced transcription levels of target genes, demonstrating that the observed mortality was likely due to RNAi. When these genes were tested for ingestion RNAi against an insecticide-resistant strain of F. occidentalis, bioassay results were similar. In conclusion, this study provides the first evidence that ingestion RNAi can be lethal to F. occidentalis, a mesophyll sucking pest, and further suggests that transgenic plants expressing hairpin RNA of these essential genes can be employed to control insecticide-resistant thrips.


Assuntos
Genes Letais , Inseticidas/farmacologia , Interferência de RNA , RNA de Cadeia Dupla/farmacologia , Tisanópteros/genética , Animais , Bioensaio , Produtos Agrícolas/parasitologia , Folhas de Planta , Plantas Geneticamente Modificadas , Tisanópteros/efeitos dos fármacos
6.
J Dairy Sci ; 102(12): 11116-11123, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31548059

RESUMO

Widespread use of a limited number of elite sires in dairy cattle breeding increases the risk of some deleterious allelic variants spreading in the population. Genomic data are being used to detect relatively common (frequency >1%) haplotypes that never occur in the homozygous state in live animals. Such haplotypes likely include recessive lethal or semilethal alleles. The aim of this study was to detect such haplotypes in the Nordic Holstein population and to identify causal genetic factors underlying these haplotypes. Illumina BovineSNP50 BeadChip (Illumina Inc., San Diego, CA) genotypes for 26,312 Nordic Holstein animals were phased to construct haplotypes. Haplotypes that are common in the population but never observed as homozygous were identified. Two such haplotypes overlapped with previously identified recessive lethal mutations in Holsteins-namely, structural maintenance of chromosomes 2 (HH3) and brachyspina. In addition, we identified 9 novel putative recessive lethal-carrying haplotypes, with 26 to 36 homozygous individuals expected among the genotyped animals but only 0 to 3 homozygotes observed. For 2 out of 9 homozygous-deficient haplotypes, insemination records of at-risk mating (carrier bull with daughter of carrier sire) showed reduced insemination success compared with not-at-risk mating (noncarrier bull with daughter of noncarrier sire), supporting early embryonic mortality. To detect the causative variant underlying each homozygous-deficient haplotype, data from the 1000 Bull Genome Project were used. However, no variants or deletions identified in the chromosome regions covered by the haplotypes showed concordance with haplotype carrier status. The carrier status of detected haplotypes could be used to select bulls to reduce the frequency of the latent lethal mutations in the population. If desired, at-risk matings could be avoided.


Assuntos
Bovinos/genética , Perda do Embrião/genética , Genes Letais , Haplótipos , Mutação , Alelos , Animais , Cruzamento , Feminino , Genes Recessivos , Genótipo , Homozigoto , Masculino
7.
PLoS Pathog ; 15(9): e1007936, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31504075

RESUMO

Wolbachia are the most widespread maternally-transmitted bacteria in the animal kingdom. Their global spread in arthropods and varied impacts on animal physiology, evolution, and vector control are in part due to parasitic drive systems that enhance the fitness of infected females, the transmitting sex of Wolbachia. Male killing is one common drive mechanism wherein the sons of infected females are selectively killed. Despite decades of research, the gene(s) underlying Wolbachia-induced male killing remain unknown. Here using comparative genomic, transgenic, and cytological approaches in fruit flies, we identify a candidate gene in the eukaryotic association module of Wolbachia prophage WO, termed WO-mediated killing (wmk), which transgenically causes male-specific lethality during early embryogenesis and cytological defects typical of the pathology of male killing. The discovery of wmk establishes new hypotheses for the potential role of phage genes in sex-specific lethality, including the control of arthropod pests and vectors.


Assuntos
Prófagos/genética , Prófagos/patogenicidade , Wolbachia/patogenicidade , Wolbachia/virologia , Animais , Animais Geneticamente Modificados , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Drosophila/embriologia , Drosophila/microbiologia , Drosophila/virologia , Drosophila melanogaster/embriologia , Drosophila melanogaster/microbiologia , Drosophila melanogaster/virologia , Feminino , Genes Letais , Genes Virais , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/fisiologia , Masculino , Prófagos/fisiologia , Razão de Masculinidade , Simbiose/genética , Simbiose/fisiologia , Proteínas Virais/genética , Proteínas Virais/fisiologia
8.
Anim Genet ; 50(6): 695-704, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31486122

RESUMO

The domestic dog serves as an excellent model to investigate the genetic basis of disease. More than 400 heritable traits analogous to human diseases have been described in dogs. To further canine medical genetics research, we established the Dog Biomedical Variant Database Consortium (DBVDC) and present a comprehensive list of functionally annotated genome variants that were identified with whole genome sequencing of 582 dogs from 126 breeds and eight wolves. The genomes used in the study have a minimum coverage of 10× and an average coverage of ~24×. In total, we identified 23 133 692 single-nucleotide variants (SNVs) and 10 048 038 short indels, including 93% undescribed variants. On average, each individual dog genome carried ∼4.1 million single-nucleotide and ~1.4 million short-indel variants with respect to the reference genome assembly. About 2% of the variants were located in coding regions of annotated genes and loci. Variant effect classification showed 247 141 SNVs and 99 562 short indels having moderate or high impact on 11 267 protein-coding genes. On average, each genome contained heterozygous loss-of-function variants in 30 potentially embryonic lethal genes and 97 genes associated with developmental disorders. More than 50 inherited disorders and traits have been unravelled using the DBVDC variant catalogue, enabling genetic testing for breeding and diagnostics. This resource of annotated variants and their corresponding genotype frequencies constitutes a highly useful tool for the identification of potential variants causative for rare inherited disorders in dogs.


Assuntos
Cães/genética , Sequenciamento Completo do Genoma , Lobos/genética , Animais , Modelos Animais de Doenças , Genes Letais , Filogenia
9.
Genetics ; 213(2): 685-703, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31420322

RESUMO

Structural maintenance of chromosomes flexible hinge domain-containing 1 (SMCHD1) is an architectural factor critical for X-chromosome inactivation (XCI) and the repression of select autosomal gene clusters. In mice, homozygous nonsense mutations in Smchd1 cause female-specific embryonic lethality due to an XCI defect. However, although human mutations in SMCHD1 are associated with congenital arhinia and facioscapulohumeral muscular dystrophy type 2 (FSHD2), the diseases do not show a sex-specific bias, despite the essential nature of XCI in humans. To investigate whether there is a dosage imbalance for the sex chromosomes, we here analyze transcriptomic data from arhinia and FSHD2 patient blood and muscle cells. We find that X-linked dosage compensation is maintained in these patients. In mice, SMCHD1 controls not only protocadherin (Pcdh) gene clusters, but also Hox genes critical for craniofacial development. Ablating Smchd1 results in aberrant expression of these genes, coinciding with altered chromatin states and three-dimensional (3D) topological organization. In a subset of FSHD2 and arhinia patients, we also found dysregulation of clustered PCDH, but not HOX genes. Overall, our study demonstrates preservation of XCI in arhinia and FSHD2, and implicates SMCHD1 in the regulation of the 3D organization of select autosomal gene clusters.


Assuntos
Atresia das Cóanas/genética , Proteínas Cromossômicas não Histona/genética , Microftalmia/genética , Distrofia Muscular Facioescapuloumeral/genética , Nariz/anormalidades , Inativação do Cromossomo X/genética , Animais , Caderinas/genética , Atresia das Cóanas/patologia , Códon sem Sentido/genética , Feminino , Genes Letais/genética , Humanos , Camundongos , Microftalmia/patologia , Distrofia Muscular Facioescapuloumeral/patologia , Nariz/patologia , Transcriptoma/genética
10.
Nat Commun ; 10(1): 3465, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371714

RESUMO

Brain morphogenesis is an important process contributing to higher-order cognition, however our knowledge about its biological basis is largely incomplete. Here we analyze 118 neuroanatomical parameters in 1,566 mutant mouse lines and identify 198 genes whose disruptions yield NeuroAnatomical Phenotypes (NAPs), mostly affecting structures implicated in brain connectivity. Groups of functionally similar NAP genes participate in pathways involving the cytoskeleton, the cell cycle and the synapse, display distinct fetal and postnatal brain expression dynamics and importantly, their disruption can yield convergent phenotypic patterns. 17% of human unique orthologues of mouse NAP genes are known loci for cognitive dysfunction. The remaining 83% constitute a vast pool of genes newly implicated in brain architecture, providing the largest study of mouse NAP genes and pathways. This offers a complementary resource to human genetic studies and predict that many more genes could be involved in mammalian brain morphogenesis.


Assuntos
Encéfalo , Estudos de Associação Genética , Morfogênese/genética , Neuroanatomia , Neurogênese/genética , Animais , Encéfalo/metabolismo , Ciclo Celular , Cognição , Citoesqueleto , Redes Reguladoras de Genes , Genes Letais/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Mutação , Fenótipo , Sinapses
12.
Eur J Haematol ; 103(4): 319-328, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31254415

RESUMO

OBJECTIVES: Familial cases of hematological malignancies are associated with germline mutations. In particular, heterozygous mutations of SRP72 correlate with the development of myelodysplasia and bone marrow aplasia in two families. The signal recognition particle 72 kDa protein (SRP72) is part of the SRP complex, responsible for targeting of proteins to the endoplasmic reticulum. The main objective of this study is to investigate the role of SRP72 in the hematopoietic system, thus explaining why a reduced dose could increase susceptibility to hematological malignancies. METHODS: We developed an Srp72 null mouse model and characterized its hematopoietic system using flow cytometry, bone marrow transplantations, and gene expression analysis. RESULTS: Heterozygous loss of Srp72 in mice is not associated with major changes in hematopoiesis, although causes mild reductions in blood and BM cellularity and minor changes within the stem/progenitor compartment. We did not observe any hematological disorder. Interestingly, gene expression analysis demonstrated that genes encoding secreted factors, including cytokines and receptors, were transcriptionally down-regulated in Srp72+/- animals. CONCLUSIONS: The Srp72+/- mouse model only partially recapitulates the phenotype observed in families with inherited SRP72 lesions. Nonetheless, these results can provide mechanistic insights into why SRP72 mutations are associated with aplasia and myelodysplasia in humans.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Hematopoese/genética , Perda de Heterozigosidade , Mutação , Fenótipo , Partícula de Reconhecimento de Sinal/genética , Animais , Biomarcadores , Contagem de Células Sanguíneas , Medula Óssea/patologia , Modelos Animais de Doenças , Edição de Genes , Expressão Gênica , Genes Letais , Genótipo , Camundongos , Camundongos Knockout
13.
Artigo em Inglês | MEDLINE | ID: mdl-31075502

RESUMO

Cherax quadricarinatus, as one of the world's most valuable freshwater shrimp species, has received extensive attention in recent years. As males grow larger and faster than females, development of the sex control breeding techniques is of great interest, but knowledge on sex determination and differentiation in C. quadricarinatus remains poorly unknown. Sxl (Sex-lethal) is an important gene in the sexual differentiation regulatory hierarchy. It reflects the ratio of sex chromosomes to autosomes into molecule changes and directs sex-specific splicing forms of precursor mRNA. In the present study, the full-length cDNA sequences of four Sxl splice variants were identified from C. quadricarinatus, designated as CqSxl1, CqSxl2, CqSxl3 and CqSxl4, respectively. Sequence analysis determined different splicing sites near the translation termination region of four Sxl transcript isoforms. Two highly conserved classical RRM domains were found according to predicted secondary structures of Sxl proteins. mRNA expression of CqSxl in different tissues, developmental stage of embryos and testes were investigated by real-time quantitative PCR. Among four isoforms, CqSxl3 showed tissue specificity with higher expression levels in testis than in ovary. CqSxl1 and CqSxl4 were found widely expressed in various tissues and CqSxl2 was almost undetectable. In early developmental stages, the expression levels of CqSxl1/3/4 gradually increased along with embyonic development. In addition, CqSxl genes presented the higher transcript levels in the early stage of testis development. Furthermore, CqSxl3 silencing induced a significant decrease of the transcript of Cq-IAG, an androgenic hormone-encoding gene responsible for masculine development. These data indicate that CqSxl3 might be involved in male sex determination in C. quadricarinatus. Our study will contribute to understanding the mechanism of sex determination in C. quadricarinatus, and also can provide theoretical guidance for establishing a sex control technology.


Assuntos
Proteínas de Artrópodes , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Genes Letais , Processamento de RNA/fisiologia , RNA Mensageiro , Diferenciação Sexual/fisiologia , Animais , Proteínas de Artrópodes/biossíntese , Proteínas de Artrópodes/genética , /genética , Feminino , Perfilação da Expressão Gênica , Masculino , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
14.
G3 (Bethesda) ; 9(5): 1581-1595, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30948422

RESUMO

A large portion of the Drosophila melanogaster genome is contained within heterochromatic regions of chromosomes, predominantly at centromeres and telomeres. The remaining euchromatic portions of the genome have been extensively characterized with respect to gene organization, function and regulation. However, it has been difficult to derive similar data for sequences within centromeric (centric) heterochromatin because these regions have not been as amenable to analysis by standard genetic and molecular tools. Here we present an updated genetic and molecular analysis of chromosome 3L centric heterochromatin (3L Het). We have generated and characterized a number of new, overlapping deficiencies (Dfs) which remove regions of 3L Het. These Dfs were critically important reagents in our subsequent genetic analysis for the isolation and characterization of lethal point mutations in the region. The assignment of these mutations to genetically-defined essential loci was followed by matching them to gene models derived from genome sequence data: this was done by using molecular mapping plus sequence analysis of mutant alleles, thereby aligning genetic and physical maps of the region. We also identified putative essential gene sequences in 3L Het by using RNA interference to target candidate gene sequences. We report that at least 25, or just under 2/3 of loci in 3L Het, are essential for viability and/or fertility. This work contributes to the functional annotation of centric heterochromatin in Drosophila, and the genetic and molecular tools generated should help to provide important insights into the organization and functions of gene sequences in 3L Het.


Assuntos
Centrômero/genética , Cromossomos de Insetos , Drosophila melanogaster/genética , Genes Essenciais , Genômica , Heterocromatina/genética , Animais , Mapeamento Cromossômico , Técnicas de Silenciamento de Genes , Genes Letais , Teste de Complementação Genética , Testes Genéticos , Genômica/métodos , Genótipo , Modelos Genéticos , Mutagênese/efeitos da radiação , Mutação , Interferência de RNA , Raios X
15.
Mol Cell ; 74(6): 1138-1147.e6, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-30982744

RESUMO

Adenine N6 methylation in DNA (6mA) is widespread among bacteria and phage and is detected in mammalian genomes, where its function is largely unexplored. Here we show that 6mA deposition and removal are catalyzed by the Mettl4 methyltransferase and Alkbh4 dioxygenase, respectively, and that 6mA accumulation in genic elements corresponds with transcriptional silencing. Inactivation of murine Mettl4 depletes 6mA and causes sublethality and craniofacial dysmorphism in incross progeny. We identify distinct 6mA sensor domains of prokaryotic origin within the MPND deubiquitinase and ASXL1, a component of the Polycomb repressive deubiquitinase (PR-DUB) complex, both of which act to remove monoubiquitin from histone H2A (H2A-K119Ub), a repressive mark. Deposition of 6mA by Mettl4 triggers the proteolytic destruction of both sensor proteins, preserving genome-wide H2A-K119Ub levels. Expression of the bacterial 6mA methyltransferase Dam, in contrast, fails to destroy either sensor. These findings uncover a native, adversarial 6mA network architecture that preserves Polycomb silencing.


Assuntos
Adenina/análogos & derivados , Homólogo AlkB 4 da Lisina Desmetilase/genética , Anormalidades Craniofaciais/genética , DNA/genética , Metiltransferases/genética , Proteínas Repressoras/genética , Adenina/metabolismo , Homólogo AlkB 4 da Lisina Desmetilase/metabolismo , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , DNA/metabolismo , Metilação de DNA , Enzimas Desubiquitinantes/genética , Enzimas Desubiquitinantes/metabolismo , Feminino , Inativação Gênica , Genes Letais , Histonas/genética , Histonas/metabolismo , Endogamia , Masculino , Metiltransferases/deficiência , Camundongos , Camundongos Knockout , Proteólise , Proteínas Repressoras/metabolismo , Transdução de Sinais , DNA Metiltransferases Sítio Específica (Adenina-Específica)/genética , DNA Metiltransferases Sítio Específica (Adenina-Específica)/metabolismo , Transcrição Genética , Ubiquitina/genética , Ubiquitina/metabolismo
16.
Med Sci (Paris) ; 35(3): 245-251, 2019 Mar.
Artigo em Francês | MEDLINE | ID: mdl-30931909

RESUMO

Alfred H. Sturtevant was the first to raise the question: why does the mutation rate not become reduced to zero? Indeed, most new mutations with a phenotypic effect are deleterious. Therefore, individuals who produce less mutants produce more viable and fertile offspring. Consequently, natural selection should increase the frequency of antimutator genotypes and progressively reduce the mutation rate to zero. However, no species has ever been found with a mutation rate equal to zero. Recent analyses suggest that setting the mutation rate above zero depends mainly on the effective size of the genome and the effective population size. The mutation rate is a trade-off between natural selection that operates to improve replication fidelity and the random genetic drift that sets the ultimate lower limit. This trade off illustrates the limitation of the power of natural selection in a world where natural populations have a finite size.


Assuntos
Evolução Molecular , Taxa de Mutação , Animais , Drosophila/genética , Genes Letais/fisiologia , Deriva Genética , Humanos , Relação entre Gerações , Modelos Genéticos , Mutação/fisiologia , Seleção Genética/genética
17.
Int J Mol Sci ; 20(8)2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013667

RESUMO

UbiA prenyltransferase domain-containing protein 1 (UBIAD1) is a vitamin K2 biosynthetic enzyme. We previously showed the lethality of this enzyme in UBIAD1 knockout mice during the embryonic stage. However, the biological effects of UBIAD1 deficiency after birth remain unclear. In the present study, we used a tamoxifen-inducible systemic UBIAD1 knockout mouse model to determine the role of UBIAD1 in adult mice. UBIAD1 knockout resulted in the death of the mice within about 60 days of administration of tamoxifen. The pancreas presented with the most prominent abnormality in the tamoxifen-induced UBIAD1 knockout mice. The pancreas was reduced remarkably in size; furthermore, the pancreatic acinar cells disappeared and were replaced by vacuoles. Further analysis revealed that the vacuoles were adipocytes. UBIAD1 deficiency in the pancreatic acinar cells caused an increase in oxidative stress and autophagy, leading to apoptotic cell death in the tamoxifen-induced UBIAD 1 knockout mice. These results indicate that UBIAD1 is essential for maintaining the survival of pancreatic acinar cells in the pancreas.


Assuntos
Células Acinares/metabolismo , Dimetilaliltranstransferase/genética , Pâncreas/citologia , Pâncreas/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Atrofia , Autofagia/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/genética , Dimetilaliltranstransferase/metabolismo , Feminino , Genes Letais , Genótipo , Imuno-Histoquímica , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Knockout , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Neutrófilos/patologia , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/patologia , Fenótipo , Tamoxifeno/farmacologia
18.
PLoS Genet ; 15(3): e1008055, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30875370

RESUMO

Lethal recessive alleles cause pre- or postnatal death in homozygous affected individuals, reducing fertility. Especially in small size domestic and wild populations, those alleles might be exposed by inbreeding, caused by matings between related parents that inherited the same recessive lethal allele from a common ancestor. In this study we report five relatively common (up to 13.4% carrier frequency) recessive lethal haplotypes in two commercial pig populations. The lethal haplotypes have a large effect on carrier-by-carrier matings, decreasing litter sizes by 15.1 to 21.6%. The causal mutations are of different type including two splice-site variants (affecting POLR1B and TADA2A genes), one frameshift (URB1), and one missense (PNKP) variant, resulting in a complete loss-of-function of these essential genes. The recessive lethal alleles affect up to 2.9% of the litters within a single population and are responsible for the death of 0.52% of the total population of embryos. Moreover, we provide compelling evidence that the identified embryonic lethal alleles contribute to the observed heterosis effect for fertility (i.e. larger litters in crossbred offspring). Together, this work marks specific recessive lethal variation describing its functional consequences at the molecular, phenotypic, and population level, providing a unique model to better understand fertility and heterosis in livestock.


Assuntos
Genes Letais , Mutação com Perda de Função , Sus scrofa/embriologia , Sus scrofa/genética , Sequência de Aminoácidos , Animais , Feminino , Fertilidade/genética , Genes Recessivos , Deriva Genética , Genética Populacional , Haplótipos , Vigor Híbrido/genética , Hibridização Genética/genética , Tamanho da Ninhada de Vivíparos/genética , Masculino , Gravidez , RNA Polimerase I/genética , Análise de Sequência de RNA , Sequenciamento Completo do Genoma
19.
Molecules ; 24(6)2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917606

RESUMO

The genetic modification of the mouse genome using the cre-lox system has been an invaluable tool in deciphering gene and protein function in a temporal and/or spatial manner. However, it has its pitfalls, as researchers have shown that the unregulated expression of cre recombinase can cause DNA damage, the consequences of which can be very detrimental to mouse health. Previously published literature on the most utilized cardiac-specific cre, αMHC-cre, mouse model exhibited a nonlethal hypertrophic cardiomyopathy (HCM) with aging. However, using the same αMHC-cre mice, we observed a cardiac pathology, resulting in complete lethality by 11 months of age. Echocardiography and histology revealed that the αMHC-cre mice were displaying symptoms of dilated cardiomyopathy (DCM) by seven months of age, which ultimately led to their demise in the absence of any HCM at any age. Molecular analysis showed that this phenotype was associated with the DNA damage response through the downregulation of activated p38 and increased expression of JNK, p53, and Bax, known inducers of myocyte death resulting in fibrosis. Our data urges strong caution when interpreting the phenotypic impact of gene responses using αMHC-cre mice, since a lethal DCM was induced by the cre driver in an age-dependent manner in this commonly utilized model system.


Assuntos
Envelhecimento/genética , Cardiomiopatia Dilatada/diagnóstico por imagem , Integrases/metabolismo , Cadeias Pesadas de Miosina/genética , Envelhecimento/metabolismo , Animais , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , Dano ao DNA , Modelos Animais de Doenças , Ecocardiografia , Regulação da Expressão Gênica , Genes Letais , Integrases/genética , Camundongos , Cadeias Pesadas de Miosina/metabolismo , Fenótipo
20.
Am J Hum Genet ; 104(3): 439-453, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30773278

RESUMO

SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors and which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of wild-type TONSL. In addition, in vitro cell-based assays and in silico analyses of TONSL structure support the pathogenicity of those TONSL variants. Intriguingly, a knock-in (KI) Tonsl mouse model leads to embryonic lethality, implying the physiological importance of TONSL. Overall, these findings indicate that genetic variants resulting in reduced function of TONSL cause SPONASTRIME dysplasia and highlight the importance of TONSL in embryonic development and postnatal growth.


Assuntos
Fibroblastos/patologia , Genes Letais , Mutação , NF-kappa B/genética , Osteocondrodisplasias/patologia , Adolescente , Adulto , Animais , Células Cultivadas , Criança , Pré-Escolar , Dano ao DNA , Derme/metabolismo , Derme/patologia , Feminino , Fibroblastos/metabolismo , Humanos , Lactente , Recém-Nascido , Camundongos , Camundongos Endogâmicos C57BL , Osteocondrodisplasias/genética , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
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