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1.
Genet Sel Evol ; 52(1): 35, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32611306

RESUMO

Base editing has the potential to improve important economic traits in agriculture and can precisely convert single nucleotides in DNA or RNA sequences into minimal double-strand DNA breaks (DSB). Adenine base editors (ABE) have recently emerged as a base editing tool for the conversion of targeted A:T to G:C, but have not yet been used in sheep. ABEmax is one of the latest versions of ABE, which consists of a catalytically-impaired nuclease and a laboratory-evolved DNA-adenosine deaminase. The Booroola fecundity (FecBB) mutation (g.A746G, p.Q249R) in the bone morphogenetic protein receptor 1B (BMPR1B) gene influences fecundity in many sheep breeds. In this study, by using ABEmax we successfully obtained lambs with defined point mutations that result in an amino acid substitution (p.Gln249Arg). The efficiency of the defined point mutations was 75% in newborn lambs, since six lambs were heterozygous at the FecBB mutation site (g.A746G, p.Q249R), and two lambs were wild-type. We did not detect off-target mutations in the eight edited lambs. Here, we report the validation of the first gene-edited sheep generated by ABE and highlight its potential to improve economically important traits in livestock.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Fertilidade/genética , Edição de Genes/métodos , Adenina/metabolismo , Adenosina Desaminase/metabolismo , Adenosina Desaminase/fisiologia , Animais , Cruzamento , Feminino , Engenharia Genética/métodos , Genótipo , Heterozigoto , Tamanho da Ninhada de Vivíparos/genética , Masculino , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único , Gravidez , Ovinos/genética
2.
Proc Natl Acad Sci U S A ; 117(32): 19425-19434, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719113

RESUMO

Spiral artery remodeling is an important physiological process in the pregnant uterus which increases blood flow to the fetus. Impaired spiral artery remodeling contributes to preeclampsia, a major disease in pregnancy. Corin, a transmembrane serine protease, is up-regulated in the pregnant uterus to promote spiral artery remodeling. To date, the mechanism underlying uterine corin up-regulation remains unknown. Here we show that Krüppel-like factor (KLF) 17 is a key transcription factor for uterine corin expression in pregnancy. In cultured human uterine endometrial cells, KLF17 binds to the CORIN promoter and enhances the promoter activity. Disruption of the KLF17 gene in the endometrial cells abolishes CORIN expression. In mice, Klf17 is up-regulated in the pregnant uterus. Klf17 deficiency prevents uterine Corin expression in pregnancy. Moreover, Klf17-deficient mice have poorly remodeled uterine spiral arteries and develop gestational hypertension and proteinuria. Together, our results reveal an important function of KLF17 in regulating Corin expression and uterine physiology in pregnancy.


Assuntos
Artérias/fisiologia , Serina Endopeptidases/genética , Fatores de Transcrição/metabolismo , Útero/fisiologia , Animais , Células Cultivadas , Feminino , Fertilidade/genética , Regulação da Expressão Gênica , Humanos , Hipertensão Induzida pela Gravidez/genética , Masculino , Camundongos , Camundongos Knockout , Gravidez , Regiões Promotoras Genéticas , Proteinúria/genética , Serina Endopeptidases/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Útero/irrigação sanguínea , Útero/metabolismo , Remodelação Vascular
3.
Proc Natl Acad Sci U S A ; 117(29): 17094-17103, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32611817

RESUMO

Declining ejaculate performance with male age is taxonomically widespread and has broad fitness consequences. Ejaculate success requires fully functional germline (sperm) and soma (seminal fluid) components. However, some aging theories predict that resources should be preferentially diverted to the germline at the expense of the soma, suggesting differential impacts of aging on sperm and seminal fluid and trade-offs between them or, more broadly, between reproduction and lifespan. While harmful effects of male age on sperm are well known, we do not know how much seminal fluid deteriorates in comparison. Moreover, given the predicted trade-offs, it remains unclear whether systemic lifespan-extending interventions could ameliorate the declining performance of the ejaculate as a whole. Here, we address these problems using Drosophila melanogaster. We demonstrate that seminal fluid deterioration contributes to male reproductive decline via mating-dependent mechanisms that include posttranslational modifications to seminal proteins and altered seminal proteome composition and transfer. Additionally, we find that sperm production declines chronologically with age, invariant to mating activity such that older multiply mated males become infertile principally via reduced sperm transfer and viability. Our data, therefore, support the idea that both germline and soma components of the ejaculate contribute to male reproductive aging but reveal a mismatch in their aging patterns. Our data do not generally support the idea that the germline is prioritized over soma, at least, within the ejaculate. Moreover, we find that lifespan-extending systemic down-regulation of insulin signaling results in improved late-life ejaculate performance, indicating simultaneous amelioration of both somatic and reproductive aging.


Assuntos
Envelhecimento , Drosophila melanogaster , Proteínas de Plasma Seminal , Espermatozoides , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Feminino , Fertilidade/genética , Fertilidade/fisiologia , Infertilidade Masculina/genética , Infertilidade Masculina/fisiopatologia , Masculino , Proteoma/análise , Proteoma/genética , Proteoma/fisiologia , Proteínas de Plasma Seminal/análise , Proteínas de Plasma Seminal/fisiologia , Comportamento Sexual Animal/fisiologia , Espermatozoides/química , Espermatozoides/fisiologia
4.
Proc Natl Acad Sci U S A ; 117(27): 15748-15754, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571943

RESUMO

Trade-offs between growth, reproduction, and lifespan constrain animal life histories, leading to evolutionary diversification of life history cycles in different environments. In female mammals, gestation and lactation are expected to impose the major costs of reproduction, driving reproductive trade-offs, although mating also requires interactions with males that could themselves influence life history. Here we show that a male's presence by itself leads to lifelong alterations in life history in female mice. Housing C57BL/6J female mice with sterilized males early in life led to an increase in body weight, an effect that persisted across life even when females were later allowed to produce pups. We found that those females previously housed with sterile males also showed enhanced late-life offspring production when allowed to reproduce, indicating that earlier mating can influence subsequent fecundity. This effect was the opposite to that seen in females previously housed with intact males, which showed the expected trade-off between early-life and late-life reproduction. However, housing with a sterile male early in life came at a cost to lifespan, which was observed in the absence of females ever undergoing fertilization. Endocrinologically, mating also permanently reduced the concentration of circulating prolactin, a pituitary hormone influencing maternal care. Changes in hormone axes that influence reproduction could therefore help alter life history allocation in response to opposite-sex stimuli. Our results demonstrate that mating itself can increase growth and subsequent fecundity in mammals, and that responses to sexual stimuli could account for some lifespan trade-offs normally attributed to pregnancy and lactation.


Assuntos
Evolução Biológica , Fertilidade/fisiologia , Longevidade/fisiologia , Reprodução/fisiologia , Animais , Fenômenos Biológicos , Peso Corporal/genética , Peso Corporal/fisiologia , Comunicação Celular , Feminino , Fertilidade/genética , Infertilidade Masculina/genética , Lactação , Longevidade/genética , Masculino , Camundongos , Reprodução/genética , Comportamento Sexual Animal/fisiologia
5.
PLoS Genet ; 16(5): e1008361, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32463812

RESUMO

Osteocalcin (OCN), the most abundant noncollagenous protein in the bone matrix, is reported to be a bone-derived endocrine hormone with wide-ranging effects on many aspects of physiology, including glucose metabolism and male fertility. Many of these observations were made using an OCN-deficient mouse allele (Osc-) in which the 2 OCN-encoding genes in mice, Bglap and Bglap2, were deleted in ES cells by homologous recombination. Here we describe mice with a new Bglap and Bglap2 double-knockout (dko) allele (Bglap/2p.Pro25fs17Ter) that was generated by CRISPR/Cas9-mediated gene editing. Mice homozygous for this new allele do not express full-length Bglap or Bglap2 mRNA and have no immunodetectable OCN in their serum. FTIR imaging of cortical bone in these homozygous knockout animals finds alterations in the collagen maturity and carbonate to phosphate ratio in the cortical bone, compared with wild-type littermates. However, µCT and 3-point bending tests do not find differences from wild-type littermates with respect to bone mass and strength. In contrast to the previously reported OCN-deficient mice with the Osc-allele, serum glucose levels and male fertility in the OCN-deficient mice with the Bglap/2pPro25fs17Ter allele did not have significant differences from wild-type littermates. We cannot explain the absence of endocrine effects in mice with this new knockout allele. Possible explanations include the effects of each mutated allele on the transcription of neighboring genes, or differences in genetic background and environment. So that our findings can be confirmed and extended by other interested investigators, we are donating this new Bglap and Bglap2 double-knockout strain to the Jackson Laboratories for academic distribution.


Assuntos
Sistema Endócrino/fisiologia , Osteocalcina/genética , Animais , Densidade Óssea/genética , Osso e Ossos/metabolismo , Sistema Endócrino/metabolismo , Feminino , Fertilidade/genética , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteocalcina/deficiência
6.
PLoS One ; 15(4): e0230422, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271764

RESUMO

The inability of beef cattle to maintain full term pregnancies has become an economic concern for the beef industry. Herd management and nutritional improvements have alleviated environmental impacts on embryonic and fetal loss, yet additional gains can be made through genomic selection. The objectives of this study were to identify loci and gene-sets in crossbred beef heifers associated with the number of services required to become pregnant (TBRD) and heifer conception rate at first service (HCR1). Heifers (n = 709) from a commercial beef operation underwent one round of artificial insemination, before exposure to bulls for natural service for 50 days. Pregnancy and time of conception was determined by ultrasound 35 days after the breeding season. Heifers were genotyped using the GeneSeek (Lincoln, NE) Bovine GGP50K BeadChip prior to genome-wide association analyses (GWAA) conducted using an EIGENSTRAT-like model to identify loci associated (P < 1 × 10-5) with TBRD and HCR1. One locus was associated (P = 8.97 × 10-6) with TBRD on BTA19 and included the positional candidate gene ASIC2, which is differentially expressed in the endometrium of fertility classified heifers, and the positional candidate gene, SPACA3. Gene-set enrichment analyses using SNP (GSEA-SNP) data, was performed and identified one gene-set, oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen as enriched (NES = 3.15) with TBRD and contained nine leading edge genes that contributed to the enrichment of the gene set. The enriched gene-set is involved in catalyzing oxidation-reduction reactions, which have been associated with oxidative stressors impacting pregnancy success. No loci were associated nor gene-sets enriched with HCR1. Identification of loci, positional candidate genes, gene-sets and leading edge genes enriched for fertility facilitate genomic selection that allows producers to select for reproductively superior cattle, reduce costs associated with infertility, and increase percent calf crop.


Assuntos
Bovinos/genética , Loci Gênicos , Hibridização Genética/genética , Taxa de Gravidez , Prenhez , Reprodução/genética , Animais , Cruzamento , Quimera/genética , Cruzamentos Genéticos , Feminino , Fertilidade/genética , Fertilização/genética , Estudos de Associação Genética/veterinária , Técnicas de Genotipagem , Masculino , Polimorfismo de Nucleotídeo Único , Gravidez , Prenhez/genética
7.
Proc Natl Acad Sci U S A ; 117(14): 7837-7844, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32229564

RESUMO

The blood-testis barrier (BTB) is thought to be indispensable for spermatogenesis because it creates a special environment for meiosis and protects haploid cells from the immune system. The BTB divides the seminiferous tubules into the adluminal and basal compartments. Spermatogonial stem cells (SSCs) have a unique ability to transmigrate from the adluminal compartment to the basal compartment through the BTB upon transplantation into the seminiferous tubule. Here, we analyzed the role of Cldn11, a major component of the BTB, in spermatogenesis using spermatogonial transplantation. Cldn11-deficient mice are infertile due to the cessation of spermatogenesis at the spermatocyte stage. Cldn11-deficient SSCs failed to colonize wild-type testes efficiently, and Cldn11-deficient SSCs that underwent double depletion of Cldn3 and Cldn5 showed minimal colonization, suggesting that claudins on SSCs are necessary for transmigration. However, Cldn11-deficient Sertoli cells increased SSC homing efficiency by >3-fold, suggesting that CLDN11 in Sertoli cells inhibits transmigration of SSCs through the BTB. In contrast to endogenous SSCs in intact Cldn11-deficient testes, those from WT or Cldn11-deficient testes regenerated sperm in Cldn11-deficient testes. The success of this autologous transplantation appears to depend on removal of endogenous germ cells for recipient preparation, which reprogrammed claudin expression patterns in Sertoli cells. Consistent with this idea, in vivo depletion of Cldn3/5 regenerated endogenous spermatogenesis in Cldn11-deficient mice. Thus, coordinated claudin expression in both SSCs and Sertoli cells expression is necessary for SSC homing and regeneration of spermatogenesis, and autologous stem cell transplantation can rescue congenital defects of a self-renewing tissue.


Assuntos
Fertilidade/genética , Infertilidade/terapia , Espermatogônias/transplante , Transplante de Células-Tronco , Animais , Modelos Animais de Doenças , Fertilidade/fisiologia , Humanos , Infertilidade/genética , Infertilidade/patologia , Masculino , Camundongos , Espermatogênese/genética , Espermatogônias/crescimento & desenvolvimento , Espermatozoides/crescimento & desenvolvimento , Espermatozoides/transplante , Células-Tronco/citologia , Transplante Autólogo/métodos
8.
J Dairy Sci ; 103(6): 5227-5233, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32278560

RESUMO

Functional traits, such as fertility and lactation persistency, are becoming relevant breeding goals for dairy cattle. Fertility is a key element for herd profitability and animal welfare; in particular, calving interval (CIN) is an indicator of female fertility that can be easily recorded. Lactation persistency (LPE; i.e., the ability of a cow to maintain a high milk yield after the lactation peak) is economically important and is related to several other traits, such as feed efficiency, health, and reproduction. The selection of these functional traits is constrained by their low heritability. In this study, variance components for CIN and LPE in the Italian Simmental cattle breed were estimated using genomic and pedigree information under the single-step genomic framework. A data set of 594,257 CIN records (from 275,399 cows) and 285,213 LPE records (from 1563,389 cows) was considered. Phenotypes were limited up to the third parity. The pedigree contained about 2 million animals, and 7,246 genotypes were available. Lactation persistency was estimated using principal component analysis on test day records, with higher values of the second extracted principal component (PC2) values associated with lower LPE, and lower PC2 values associated with higher LPE. Heritability of CIN and LPE were estimated using single-trait repeatability models. A multiple-trait analysis using CIN and production traits (milk, fat, and protein yields) was performed to estimate genetic correlations among these traits. Heritability for CIN in the single-trait model was low (0.06 ± 0.002). Unfavorable genetic correlations were found between CIN and production traits. A measure of LPE was derived using principal component analysis on test day records. The heritability and repeatability of LPE were 0.11 ± 0.004 and 0.20 ± 0.02, respectively. Genetic correlation between CIN and LPE was weak but had a favorable direction. Despite the low heritability estimates, results of the present work suggest the possibility of including these traits in the Italian Simmental breeding program. The use of a single-step approach may provide better results for young genotyped animals without their own phenotypes.


Assuntos
Bovinos/fisiologia , Fertilidade/genética , Lactação/genética , Leite/metabolismo , Reprodução , Animais , Cruzamento , Bovinos/genética , Feminino , Genômica , Paridade , Fenótipo , Gravidez
9.
J Dairy Sci ; 103(5): 4510-4516, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32171516

RESUMO

More than 99% of all known Holstein artificial insemination (AI) bulls in the United States can be traced through their male lineage to just 2 bulls born in the 1950s, and all Holstein bulls can be traced back to 2 bulls born in the late 1800s. As the Y chromosome is passed exclusively from sire to son, this suggests that variation is limited for much of the Y chromosome. Two additional male lineages that are separate from modern lineages before 1890 were present at the start of the AI era and had semen available from the USDA National Animal Germplasm Program (Fort Collins, CO). Semen from representatives of those lineages were used for in vitro embryo production by mating to elite modern genetic females, resulting in the birth of 7 bulls and 8 heifers. Genomic evaluation of the bulls suggested that lineages from the beginning of the AI era could be reconstituted to breed average for total economic merit in 1 generation when mated to elite females due to high genetic merit for fertility, near-average genetic merit for fat and protein yield, and below-average genetic merit for udder and physical conformation. Semen from the bulls is commercially available to facilitate Y chromosome research and efforts to restore lost genetic diversity.


Assuntos
Composição Corporal/genética , Bovinos/genética , Indústria de Laticínios , Fertilidade/genética , Variação Genética , Inseminação Artificial/veterinária , Sêmen/fisiologia , Animais , Masculino , Análise do Sêmen/veterinária
10.
Parasitol Res ; 119(4): 1317-1325, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32152713

RESUMO

Programmed cell death protein 10 (PCDP10) is widely distributed in animal tissues and exerts extensive biological effects. This study aimed to investigate the effect of Schistosoma japonicum PCDP10 (SjPCDP10) on the fecundity of schistosomes. We performed real-time PCR to assess Sjpcdp10 expression levels at different developmental stages of S. japonicum. Immunoprotection against S. japonicum was assessed in vivo in mice, and Sjpcdp10 expression was inhibited via RNA interference (RNAi) to determine its role in fecundity. Real-time PCR analysis revealed that Sjpcdp10 mRNA was expressed during different developmental stages in S. japonicum, reaching maximum and minimum levels in female worms and lung-stage schistosomula, respectively. Recombinant SjPCDP10 had a molecular weight of approximately 28 kDa, displaying good immunogenicity but poor immunoprotection. SjPCDP10 was primarily localized in the egg, eggshell, epiphragm of adult worms, and especially the vitelline glands of female worms. RNAi-mediated knockdown of Sjpcdp10 by greater than 90%, and the protein expression decreased by 73%, reduced the number of eggs per female worm significantly more than RNAi-mediated knockdown of Egfp (negative control) (P < 0.05). The present results indicate that Sjpcdp10 knockdown affects the fecundity of schistosomes and may play a vital role in oogenesis.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Fertilidade/genética , Proteínas de Helminto/genética , Schistosoma japonicum/imunologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Feminino , Proteínas de Fluorescência Verde/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Interferência de RNA , RNA Mensageiro , RNA Interferente Pequeno/genética , Coelhos , Reação em Cadeia da Polimerase em Tempo Real , Schistosoma japonicum/genética , Schistosoma japonicum/parasitologia
11.
Am Nat ; 195(4): 743-751, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32216661

RESUMO

Selfish genetic elements that gain a transmission advantage through the destruction of sperm have grave implications for drive male fertility. In the X-linked meiotic drive system (SR) of a stalk-eyed fly, we found that SR males have greatly enlarged testes and maintain high fertility despite the destruction of half of their sperm, even when challenged with fertilizing large numbers of females. Conversely, we observed reduced allocation of resources to the accessory glands that probably explains the lower mating frequency of SR males. Body size and eye span were also reduced, which are likely to impair viability and precopulatory success. We discuss the potential evolutionary causes of these differences between drive and standard males.


Assuntos
Dípteros/genética , Dípteros/fisiologia , Fertilidade/genética , Meiose , Animais , Tamanho Corporal , Copulação/fisiologia , Feminino , Masculino , Razão de Masculinidade , Espermatozoides , Testículo/anatomia & histologia , Cromossomo X/genética
12.
J Anim Sci ; 98(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32047922

RESUMO

The existence of buffering mechanisms is an emerging property of biological networks, and this results in the buildup of robustness through evolution. So far, there are no explicit methods to find loci implied in buffering mechanisms. However, buffering can be seen as interaction with genetic background. Here we develop this idea into a tractable model for quantitative genetics, in which the buffering effect of one locus with many other loci is condensed into a single statistical effect, multiplicative on the total additive genetic effect. This allows easier interpretation of the results and simplifies the problem of detecting epistasis from quadratic to linear in the number of loci. Using this formulation, we construct a linear model for genome-wide association studies that estimates and declares the significance of multiplicative epistatic effects at single loci. The model has the form of a variance components, norm reaction model and likelihood ratio tests are used for significance. This model is a generalization and explanation of previous ones. We test our model using bovine data: Brahman and Tropical Composite animals, phenotyped for body weight at yearling and genotyped at high density. After association analysis, we find a number of loci with buffering action in one, the other, or both breeds; these loci do not have a significant statistical additive effect. Most of these loci have been reported in previous studies, either with an additive effect or as footprints of selection. We identify buffering epistatic SNPs present in or near genes reported in the context of signatures of selection in multi-breed cattle population studies. Prominent among these genes are those associated with fertility (INHBA, TSHR, ESRRG, PRLR, and PPARG), growth (MSTN, GHR), coat characteristics (KIT, MITF, PRLR), and heat resistance (HSPA6 and HSPA1A). In these populations, we found loci that have a nonsignificant statistical additive effect but a significant epistatic effect. We argue that the discovery and study of loci associated with buffering effects allow attacking the difficult problems, among others, of the release of maintenance variance in artificial and natural selection, of quick adaptation to the environment, and of opposite signs of marker effects in different backgrounds. We conclude that our method and our results generate promising new perspectives for research in evolutionary and quantitative genetics based on the study of loci that buffer effect of other loci.


Assuntos
Bovinos/genética , Epistasia Genética , Fertilidade/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/veterinária , Animais , Peso Corporal , Cruzamento , Feminino , Genótipo , Masculino , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Seleção Genética
13.
Nucleic Acids Res ; 48(7): 3906-3921, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32025726

RESUMO

RNA interference targets aberrant transcripts with cognate small interfering RNAs, which derive from double-stranded RNA precursors. Several functional screens have identified Drosophila blanks/lump (CG10630) as a facilitator of RNAi, yet its molecular function has remained unknown. The protein carries two dsRNA binding domains (dsRBD) and blanks mutant males have a spermatogenesis defect. We demonstrate that blanks selectively boosts RNAi triggered by dsRNA of nuclear origin. Blanks binds dsRNA via its second dsRBD in vitro, shuttles between nucleus and cytoplasm and the abundance of siRNAs arising at many sites of convergent transcription is reduced in blanks mutants. Since features of nascent RNAs - such as introns and transcription beyond the polyA site - contribute to the small RNA pool, we propose that Blanks binds dsRNA formed by cognate nascent RNAs in the nucleus and fosters its export to the cytoplasm for dicing. We refer to the resulting small RNAs as blanks exported siRNAs (bepsiRNAs). While bepsiRNAs were fully dependent on RNA binding to the second dsRBD of blanks in transgenic flies, male fertility was not. This is consistent with a previous report that linked fertility to the first dsRBD of Blanks. The role of blanks in spermatogenesis appears thus unrelated to its role in dsRNA export.


Assuntos
Proteínas de Drosophila/metabolismo , Precursores de RNA/metabolismo , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Proteínas Argonauta/metabolismo , Linhagem Celular , Núcleo Celular/metabolismo , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/química , Fertilidade/genética , Sequências Repetitivas Dispersas , Masculino , Mutação , Domínios Proteicos , RNA Helicases/metabolismo , Interferência de RNA , Transporte de RNA , RNA Antissenso , RNA de Cadeia Dupla/metabolismo , Proteínas de Ligação a RNA/química , Ribonuclease III/metabolismo , Transcrição Genética
14.
Nat Cell Biol ; 22(2): 235-245, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32015436

RESUMO

PIWI-interacting RNAs (piRNAs) promote fertility in many animals. However, whether this is due to their conserved role in repressing repetitive elements (REs) remains unclear. Here, we show that the progressive loss of fertility in Caenorhabditis elegans lacking piRNAs is not caused by derepression of REs or other piRNA targets but, rather, is mediated by epigenetic silencing of all of the replicative histone genes. In the absence of piRNAs, downstream components of the piRNA pathway relocalize from germ granules and piRNA targets to histone mRNAs to synthesize antisense small RNAs (sRNAs) and induce transgenerational silencing. Removal of the downstream components of the piRNA pathway restores histone mRNA expression and fertility in piRNA mutants, and the inheritance of histone sRNAs in wild-type worms adversely affects their fertility for multiple generations. We conclude that sRNA-mediated silencing of histone genes impairs the fertility of piRNA mutants and may serve to maintain piRNAs across evolution.


Assuntos
Proteínas Argonauta/genética , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Inativação Gênica , Histonas/genética , RNA Interferente Pequeno/genética , Animais , Animais Geneticamente Modificados , Proteínas Argonauta/deficiência , Proteínas Argonauta/metabolismo , Evolução Biológica , Sistemas CRISPR-Cas , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Fertilidade/genética , Edição de Genes , Histonas/metabolismo , Padrões de Herança , Mutação , RNA Antissenso/genética , RNA Antissenso/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Sequências Repetitivas de Ácido Nucleico
15.
J Dairy Sci ; 103(4): 3304-3311, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32063375

RESUMO

Service sire has been recognized as an important factor affecting dairy herd fertility. Our group has reported promising results on gene mapping and genomic prediction of dairy bull fertility using autosomal SNP markers. Little is known, however, about the genetic contribution of sex chromosomes, which are enriched in genes related to sexual development and reproduction. As such, the main goal of this study was to investigate the effect of SNP markers on X and Y chromosomes (BTAX and BTAY, respectively) on sire conception rate (SCR) in US Holstein bulls. The analysis included a total of 5,014 bulls with SCR records and genotypes for roughly 291k SNP located on the autosomes, 1.5k SNP located on the pseudoautosomal region (PAR), 13.7k BTAX-specific SNP, and 24 BTAY-specific SNP. We first performed genomic scans of the sex chromosomes, and then we evaluated the genomic prediction of SCR including BTAX SNP markers in the predictive models. Two markers located on PAR and 3 markers located on the X-specific region showed significant associations with sire fertility. Interestingly, these regions harbor genes, such as FAM9B, TBL1X, and PIH1D3, that are directly implicated in testosterone concentration, spermatogenesis, and sperm motility. On the other hand, BTAY showed very low genetic variability, and none of the segregating markers were associated with SCR. Notably, model predictive ability was largely improved by including BTAX markers. Indeed, the combination of autosomal with BTAX SNP delivered predictive correlations around 0.343, representing an increase in accuracy of about 7.5% compared with the standard whole autosomal genome approach. Overall, this study provides evidence of the importance of both PAR and X-specific regions in male fertility in dairy cattle. These findings may help to improve conception rates in dairy herds through accurate genome-guided decisions on bull fertility.


Assuntos
Bovinos/genética , Fertilidade/genética , Marcadores Genéticos , Cromossomos Sexuais , Animais , Bovinos/fisiologia , Mapeamento Cromossômico , Feminino , Fertilização/genética , Genoma , Genótipo , Masculino , Polimorfismo de Nucleotídeo Único , Regiões Pseudoautossômicas , Motilidade Espermática/genética , Espermatogênese/genética
16.
PLoS One ; 15(2): e0228576, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049962

RESUMO

Anopheles arabiensis is an opportunistic malaria vector that rests and feeds outdoors, circumventing current vector control methods. Furthermore, this vector will readily feed on animal as well as human hosts. Targeting the vector, while feeding on animals, can provide an additional intervention for the current vector control activities. Agricultural animals are regularly vaccinated with recombinant proteins for the control of multiple endo- and ecto-parasitic infestations. The use of a Subolesin-vaccine showed a mark reduction in tick reproductive fitness. The orthologous gene of Subolesin, called Akirin in insects, might provide a valuable species-specific intervention against outdoor biting An. arabiensis. However, the biological function of this nuclear protein has not yet been investigated in this mosquito. The effects on An. arabiensis lifetable parameters were evaluated after Akirin was knocked down using commercial small-interfering RNA (siRNA) and in vitro transcribed double-stranded RNA (dsRNA). The siRNA mediated interference of Akirin significantly reduced fecundity by 17%, fertility by 23% and longevity by 32% when compared to the controls in the female mosquitoes tested. Similarly, dsRNA treatment had a 25% decrease in fecundity, 29% decrease in fertility, and 48% decrease in longevity, when compared to the control treatments. Mosquitoes treated with Akirin dsRNA had a mean survival time of 15-days post-inoculation, which would impact on their ability to transmit malaria parasites. These results strongly suggest that Akirin has a pleiotropic function in An. arabiensis longevity and reproductive fitness.


Assuntos
Anopheles/genética , Fertilidade/genética , Proteínas de Insetos/genética , Longevidade/genética , Animais , Anopheles/fisiologia , Feminino , Masculino , Interferência de RNA
17.
Genetics ; 214(1): 3-48, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31907300

RESUMO

Life-history traits or "fitness components"-such as age and size at maturity, fecundity and fertility, age-specific rates of survival, and life span-are the major phenotypic determinants of Darwinian fitness. Analyzing the evolution and genetics of these phenotypic targets of selection is central to our understanding of adaptation. Due to its simple and rapid life cycle, cosmopolitan distribution, ease of maintenance in the laboratory, well-understood evolutionary genetics, and its versatile genetic toolbox, the "vinegar fly" Drosophila melanogaster is one of the most powerful, experimentally tractable model systems for studying "life-history evolution." Here, I review what has been learned about the evolution and genetics of life-history variation in D. melanogaster by drawing on numerous sources spanning population and quantitative genetics, genomics, experimental evolution, evolutionary ecology, and physiology. This body of work has contributed greatly to our knowledge of several fundamental problems in evolutionary biology, including the amount and maintenance of genetic variation, the evolution of body size, clines and climate adaptation, the evolution of senescence, phenotypic plasticity, the nature of life-history trade-offs, and so forth. While major progress has been made, important facets of these and other questions remain open, and the D. melanogaster system will undoubtedly continue to deliver key insights into central issues of life-history evolution and the genetics of adaptation.


Assuntos
Drosophila melanogaster/genética , Aptidão Genética , Animais , Evolução Biológica , Drosophila melanogaster/fisiologia , Ecologia , Fertilidade/genética , Estágios do Ciclo de Vida/genética , Longevidade , Seleção Genética
18.
Artigo em Inglês | MEDLINE | ID: mdl-31981876

RESUMO

The formation of allopolyploid crops basically depends on the successful interspecific hybridization and polyploidization, which generally involves in a combination of distinct but related genomes from independent species. But cytological analysis of these initially synthesized allohaploids immediately after genome merging is poorly explored in regards to anther and pollen development to date. In this study, Brassica trigenomic allohaploids (ABC) were produced to investigate the immediate effects of the genome combinations on pollen fertility during anther development via crosses between natural allotetraploid B. carinata (BBCC) and diploid B. rapa (AA). The results showed that in the synthetic Brassica allotriploids (ABC), the anther development was completely disrupted, and the pollen grains were mostly inviable with varied genetic complements. In addition, the meiosis course was aberrantly altered and eccentric chromosomal configurations including multivalent, bridges and lags occurred frequently during metaphase I to anaphase II. Genomic in situ hybridization (GISH) further revealed that B genome of homoeology was frequently apt to interact with A and C genomes, and cytoskeletal organizations was improperly distributed during meiosis in these synthetic Brassica allotriploids. Furthermore, we also confirmed that the expression of typical meiosis-related genes was obviously repressed during anther development in these Brassica allotriploids. Taken together, our results provide a detailed cytology for insights into pollen development in the synthetic allotriploid hybrids, which are conventionally considered as a useful genetic resource for polyploid Brassica breeding.


Assuntos
Brassica , Meiose , Pólen , Brassica/química , Brassica/genética , Cromossomos de Plantas/genética , Diploide , Fertilidade/genética , Genoma de Planta , Humanos , Hibridização Genética , Pólen/genética , Poliploidia
19.
Int J Mol Sci ; 21(2)2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31947687

RESUMO

: Inflammation has a well-known suppressive effect on fertility. The function of gonadotropin-releasing hormone (GnRH) neurons, the central regulator of fertility is substantially altered during inflammation in females. In our review we discuss the latest results on how the function of GnRH neurons is modified by inflammation in females. We first address the various effects of inflammation on GnRH neurons and their functional consequences. Second, we survey the possible mechanisms underlying the inflammation-induced actions on GnRH neurons. The role of several factors will be discerned in transmitting inflammatory signals to the GnRH neurons: cytokines, kisspeptin, RFamide-related peptides, estradiol and the anti-inflammatory cholinergic pathway. Since aging and obesity are both characterized by reproductive decline our review also focuses on the mechanisms and pathophysiological consequences of the impact of inflammation on GnRH neurons in aging and obesity.


Assuntos
Citocinas/metabolismo , Hormônio Liberador de Gonadotropina/biossíntese , Inflamação/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Envelhecimento/genética , Envelhecimento/imunologia , Envelhecimento/metabolismo , Animais , Astrócitos/metabolismo , Biomarcadores , Barreira Hematoencefálica/metabolismo , Estradiol/metabolismo , Retroalimentação Fisiológica , Feminino , Fertilidade/genética , Hormônio Liberador de Gonadotropina/genética , Humanos , Inflamação/etiologia , Kisspeptinas/genética , Kisspeptinas/metabolismo , Lipopolissacarídeos/imunologia , Microglia/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Reprodução/genética , Reprodução/imunologia
20.
Int J Gynecol Cancer ; 30(1): 83-88, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31780568

RESUMO

INTRODUCTION: The clinical impact on fertility in carriers of BRCA1 and BRCA2 mutations remains unclear. The aim of this study was to assess ovarian reserve as measured by anti-mullerian hormone levels in BRCA1 or BRCA2 mutation carriers, as well as to investigate the impact of anti-mullerian hormone levels on reproductive outcomes. METHODS: The study involved a cohort of women who tested positive for BRCA1 and BRCA2 screening or were tested for a BRCA1 or BRCA2 family mutation. Blood samples were collected for anti-mullerian hormone analysis and the reproductive outcomes were analyzed after a mean follow-up of 9 years. Participants were classified into BRCA mutation-positive versus BRCA mutation-negative. Controls were healthy relatives who tested negative for the family mutation. All patients were contacted by telephone to collect data on reproductive outcomes. Linear regression was used to predict anti-mullerian hormone levels by BRCA status adjusted for a polynomial form of age. RESULTS: Results of anti-mullerian hormone analysis and reproductive outcomes were available for 135 women (BRCA mutation-negative, n=66; BRCA1 mutation-positive, n=32; BRCA2 mutation-positive, n=37). Anti-mullerian hormone curves according to BRCA status and adjusted by age showed that BRCA2 mutation-positive patients have lower levels of anti-mullerian hormone as compared with BRCA-negative and BRCA1 mutation-positive. Among the women who tried to conceive, infertility was observed in 18.7% of BRCA mutation-negative women, in 22.2% of BRCA1 mutation-positive women, and in 30.8% of BRCA2 mutation-positive women (p=0.499). In the multivariable analysis, there were no factors independently associated with infertility. DISCUSSION: BRCA2 mutation-positive carriers showed more diminished anti-mullerian hormone levels than BRCA1 mutation-positive and BRCA mutation-negative women. However, these differences do not appear to have a negative impact on reproductive outcome. This is important to consider at the time of reproductive counseling in women with BRCA1 or BRCA2 mutations.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Mutação em Linhagem Germinativa , Reserva Ovariana/genética , Reprodução/genética , Adulto , Hormônio Antimülleriano/sangue , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Fertilidade/genética , Genes BRCA2 , Humanos
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