Linking Fertility-Associated Gene Polymorphisms to Aberrant Sperm Phenotypes
将生育相关基因多态性与异常精子表型联系起来
基本信息
- 批准号:9977699
- 负责人:
- 金额:$ 20.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-12 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgricultureAllelesAmino AcidsAnimalsAntigensArtificial InseminationBiologicalBiological AssayBiological MarkersBiological ModelsBreedingCandidate Disease GeneCattleCellsConceptionsDNADNA Sequence AlterationDataDatabasesElectronsEmbryo LossEmbryonic DevelopmentEvaluationFertilityFlow CytometryFrequenciesFrozen SemenGenesGeneticGenetic PolymorphismGenomicsGenotypeGoalsHealthHeritabilityHumanImageIn VitroIndividualIndustryInfertilityKnockout MiceLifeLightLinkLivestockMale InfertilityMeasurableMeasuresMedicineMethodsMicroscopicMicroscopyMutateMutationOutcomePatternPhenotypePopulationPregnancyPregnancy lossProteinsProteomicsRecordsReproductive BiologyResearchSamplingSeminal fluidServicesSpermatogenesisStructureTestingVariantWorkbasecellular imagingdesignearly pregnancy lossembryonic proteinexperimental studyfallsfertility improvementgene productgenetic selectiongenetic variantgenome sequencinghuman maleidiopathic infertilityimprovedin silicoin vivoinnovationinsertion/deletion mutationloss of functionloss of function mutationmalemale fertilitymenmicroscopic imagingnonsynonymous mutationnovel diagnosticsphenotypic biomarkerprotein structure functionreproductivesoundsperm cellsperm functionsperm morphologysperm proteinsperm qualitysubfertilitytooltraitwhole genome
项目摘要
Sutovsky, Peter - PD
SUMMARY
The present project is directly relevant to the goals of RFA PAR-13-204, Dual Purpose with Dual Benefit: Research in
Biomedicine and Agriculture Using Agriculturally Important Domestic Species. It will be the first project to systematically
link the genetic traits affecting male fertility to sperm phenotypes easily measurable in a human/animal semen sample.
Whole genome sequencing has identified a large number of gene polymorphisms with the potential to affect male
fertility in humans and livestock. However, there is very little understanding of how these polymorphisms may affect the
phenotypes of spermatozoa, their fertilizing ability and their influence on pre-embryo development and early embryo
loss. We hypothesize that unique mutations/polymorphisms in genes expressed during spermatogenesis and pre-
embryo development (further “fertility associated genes”) are responsible for male subfertility and for early embryo loss
during pregnancy. Our goal is to link these genetic traits to sperm phenotypes measurable in a semen sample and
reflected by the males’ fertility in vivo and in vitro. We chose artificial insemination (AI) bulls as model system because
their genotypes are publically accessible, they have extensive fertility records from AI services, and their fertility in vivo
correlates with their in vitro fertility. We have identified 3,601 candidate fertility-related genes with loss-of-function
LOF) polymorphisms in the whole genome sequences of 219 bulls representing 18 breeds and performed phenotype
analysis on several candidate gene products that revealed significant differences between fertile but under-performing
bulls with less than satisfactory AI fertility and top bulls with highest AI fertility. Both genes also show non-synonymous
polymorphisms in humans.
AIM 1 of this project will employ genotyping and in silico search to identify genetic differences between fertile and
subfertile bulls, including polymorphisms associated with high/low conception rates in AI, as well as those prevalent in
yearling bulls that failed Breeding Soundness Evaluation (BSE). We hypothesize that fertile bulls fall on the opposite ends
of fertility range due to identifiable polymorphisms in relatively few genes controlling spermatogenesis, sperm
phenotype and sperm function. AIM 2 will use a combination of proteomic and cell biological approaches, including but
not limited to innovative image based flow cytometry (IBFC), to link genetic fertility traits to the sperm phenotypes
easily measurable in a semen sample. Based on the identification of sperm antigens expressed only or predominantly by
carriers of the fertility-affecting mutations, we will develop multiplex, flow cytometry-based high throughput semen
quality assays for routine use in field AI. We hypothesize that a non-synonymous change in a gene controlling
spermatogenesis or sperm function will alter the sperm phenotype via change in the quantity, localization and/or
function of a sperm or embryo protein encoded by this gene, thus influencing fertility of the carrier male.
Altogether, we expect to identify and validate sperm phenotype biomarkers encoded by fertility associated polymorphic
genes, and to improve sire management by genetic selection and objective, automated semen evaluation. This project
will also yield new methods and potentially new treatments for human male and idiopathic infertility. The field of
reproductive biology will be advanced through better understanding of the link between male genotype and sperm
phenotype.
Sutovsky,Peter - PD
总结
本项目与RFA PAR-13-204的目标直接相关,双重目的和双重效益:
生物医学和农业利用重要的国内物种。这将是第一个系统地
将影响男性生育力的遗传性状与人类/动物精液样本中易于测量的精子表型联系起来。
全基因组测序已经确定了大量的基因多态性与潜在的影响男性
人类和牲畜的生育能力。然而,很少有人了解这些多态性如何影响基因表达。
精子的表型、可受精性及其对前胚胎发育和早期胚胎的影响
损失我们假设,在精子发生过程中表达的基因中的独特突变/多态性和精子发生前的基因中的独特突变/多态性可能与精子发生有关。
胚胎发育(进一步称为“生育力相关基因”)是导致男性生育力低下和早期胚胎丢失的原因
孕期我们的目标是将这些遗传特征与精液样本中可测量的精子表型联系起来,
雄性在体内和体外的生育能力反映了这一点。我们选择人工授精(AI)公牛作为模型系统,因为
他们的基因型是可遗传的,他们有来自AI服务的广泛的生育记录,他们的体内生育能力
与它们的体外受精能力有关。我们已经确定了3,601个功能丧失的候选生育相关基因
LOF)多态性,并对代表18个品种和表现型的219头公牛的全基因组序列进行了分析
对几个候选基因产物的分析显示,可育但表现不佳的基因产物之间存在显着差异,
AI繁殖力不太满意的公牛和AI繁殖力最高的顶级公牛。这两个基因也显示出非同义的
人类的多态性
本项目的目的1将采用基因分型和计算机检索,以确定可育和
生育力低下的公牛,包括与AI高/低受孕率相关的多态性,以及在人类中普遍存在的多态性
未通过育种健全性评估(BSE)的一岁公牛。我们假设有生育能力的公牛会落在相反的两端
由于在控制精子发生的相对较少的基因中可识别的多态性,
表型和精子功能。AIM 2将使用蛋白质组学和细胞生物学方法的组合,
不限于创新的基于图像的流式细胞术(IBFC),将遗传生育性状与精子表型联系起来
很容易在精液样本中检测到基于对精子抗原的鉴定,
携带影响生育力的突变,我们将开发多重,流式细胞术为基础的高通量精液
用于现场AI常规使用的质量检测。我们假设,一个基因的非同义变化控制
精子发生或精子功能将通过改变精子的数量、定位和/或
由该基因编码的精子或胚胎蛋白质的功能,从而影响携带者男性的生育力。
总之,我们期望鉴定和验证精子表型生物标志物编码的生育相关的多态性,
基因,并通过遗传选择和客观,自动精液评估来改善父系管理。这个项目
也将为人类男性和特发性不育症提供新的方法和潜在的新疗法。领域
通过更好地理解男性基因型和精子之间的联系,
表型
项目成果
期刊论文数量(14)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Potential Use of Tannin Extracts as Additives in Semen Destined for Cryopreservation: A Review.
- DOI:10.3390/ani12091130
- 发表时间:2022-04-28
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Zinc ion flux during mammalian sperm capacitation.
- DOI:10.1038/s41467-018-04523-y
- 发表时间:2018-05-25
- 期刊:
- 影响因子:16.6
- 作者:Kerns K;Zigo M;Drobnis EZ;Sutovsky M;Sutovsky P
- 通讯作者:Sutovsky P
An Exploration of Current and Perspective Semen Analysis and Sperm Selection for Livestock Artificial Insemination.
- DOI:10.3390/ani11123563
- 发表时间:2021-12-15
- 期刊:
- 影响因子:0
- 作者:Zuidema D;Kerns K;Sutovsky P
- 通讯作者:Sutovsky P
The development of new biomarkers of spermatozoa quality in cattle.
- DOI:10.3389/fvets.2023.1258295
- 发表时间:2023
- 期刊:
- 影响因子:3.2
- 作者:Fallon L;Diaz-Miranda E;Hamilton L;Sutovsky P;Zigo M;Spencer TE;Ortega MS
- 通讯作者:Ortega MS
Identification of genomic variants causing sperm abnormalities and reduced male fertility.
鉴定基因组变异,导致精子异常和雄性生育能力降低。
- DOI:10.1016/j.anireprosci.2018.02.007
- 发表时间:2018-07
- 期刊:
- 影响因子:2.2
- 作者:Taylor JF;Schnabel RD;Sutovsky P
- 通讯作者:Sutovsky P
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PETER Sutovsky SUTOVSKY其他文献
PETER Sutovsky SUTOVSKY的其他文献
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{{ truncateString('PETER Sutovsky SUTOVSKY', 18)}}的其他基金
Linking Fertility-Associated Gene Polymorphisms to Aberrant Sperm Phenotypes
将生育相关基因多态性与异常精子表型联系起来
- 批准号:
9351559 - 财政年份:2016
- 资助金额:
$ 20.58万 - 项目类别:
Ubiquitin-Based Semen Qualtiy Assay in Toxicology
基于泛素的毒理学精液质量测定
- 批准号:
6314778 - 财政年份:2000
- 资助金额:
$ 20.58万 - 项目类别:
Ubiquitin-Based Semen Qualtiy Assay in Toxicology
基于泛素的毒理学精液质量测定
- 批准号:
6446071 - 财政年份:2000
- 资助金额:
$ 20.58万 - 项目类别:
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