Genomic Mechanisms of Chromosomal Rearrangements in Drosophila Pseudoobscura

果蝇染色体重排的基因组机制

• 批准号: 8159229
• 负责人: STEPHEN W SCHAEFFER
• 金额: $ 28.96万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8159229
• 关键词: Adult; Alleles; Biological Models; Biology; Birth; Chromosomal Rearrangement; Chromosome inversion; Chromosomes; Climate; Code; DNA Transposable Elements; Data; Disease; Drosophila genus; Environment; Equilibrium; Evolution; Exons; Fertility; Frequencies; Future; Gene Expression; Gene Expression Profile; Gene Mutation; Gene Order; Gene Structure; Genes; Genetic; Genetic Crossing Over; Genetic Drift; Genetic Polymorphism; Genetic Recombination; Genome; Genomics; Germ Cells; Goals; Hereditary Disease; Human; Individual; Laboratories; Larva; Lead; Lesion; Life; Linkage Disequilibrium; Linkage Disequilibrium Mapping; Location; Maintenance; Maps; Messenger RNA; Modeling; Molecular; Molecular Abnormality; Molecular Genetics; Mutation; Nature; Nucleotides; Paracentric Inversion; Pattern; Population; Population Genetics; Pregnancy; Proteins; Repetitive Sequence; Reproduction; Research Design; Seasons; Sequence Analysis; Series; Southwestern United States; Staging; Symptoms; System; Technology; Testing; Transcript; Variant; base; comparative genomics; design; egg; fitness; genetic analysis; improved; next generation; research study; sperm cell; tool

DESCRIPTION (provided by applicant): Chromosomal inversions are often detected in humans when individuals present symptoms of genetic diseases. Individuals with two different inversions can have lower fertility because genetic exchange between inverted chromosomes can lead to the formation of sperm or eggs with less or more genetic information. Inversions, however, can also be present in populations at high frequencies with no apparent negative effects on viability or reproduction. This proposal will test hypotheses about how inversions arise, spread, and are maintained in populations. Drosophila pseudoobscura is a model system for the study of inversions because its third chromosome is polymorphic for over 30 different gene arrangements in populations. These arrangements were generated through a series of overlapping paracentric inversions. The inversion frequencies vary among populations forming clines or gradients whose major frequency shifts occur with major climatic zones in the southwestern United States. The gene arrangement frequencies cycle with the seasons and show altitudinal clines. Population cage experiments in the laboratory have shown that different gene arrangements are maintained at stable equilibrium frequencies. This study will use next generation technologies to re-sequence 50 strains of D. pseudoobscura that carry one of six major chromosomal arrangements. Next generation sequencing analysis of mRNA will be used to quantify expression differences among the six different inversion backgrounds for two different Drosophila life stages, larvae and adults. The re-sequencing data will identify inversion breakpoint sequences and improve the D. pseudoobscura genome assembly. The transcriptome data will be used to improve the annotation of gene models in D. pseudoobscura. Molecular population genetic analyses of nucleotide polymorphism and gene expression data will test four classes of hypotheses about how a new inversion spreads through a population: (1) indirect effects due to reduced recombination leading to chromosomes free of deleterious mutations or enhancing the linkage of adaptive genes; (2) genetic drift that fixes underdominant arrangements; (3) direct effects of the chromosomal lesion such as alteration of gene structure or expression; or (4) genetic hitchhiking with an adaptive allele. These analyses will test two hypotheses about how inversions are maintained in populations: (1) by overdominance; or (2) as a protected polymorphism. Genes that show differential expression or protein variation may be manipulated in future experiments designed to understand the molecular genetic basis that underpins inversion evolution. PUBLIC HEALTH RELEVANCE: Chromosomal rearrangements in humans usually have negative fitness effects because eggs or sperm can have more or less genetic information when crossing over occurs in heterozygous individuals. Inversions are detected in humans when genetic abnormalities are uncovered during gestation or after birth, but these genetic mutations can sometimes exist without deleterious effects. This study will use next generation sequencing technologies to understand the genetic forces that explain how inversion mutations arise, spread, and are maintained in nature populations of Drosophila pseudoobscura.

描述（由申请人提供）： 当个体出现遗传疾病症状时，通常在人类中检测到染色体反转。具有两个不同反转的个体可以具有较低的生育能力，因为倒置染色体之间的遗传交换可以导致形成具有较少或更多遗传信息的精子或卵。但是，在高频的种群中也可以存在反演，对生存能力或繁殖没有明显的负面影响。该提案将检验有关倒置如何在人群中出现，传播和维持的假设。 果蝇假期是一个用于倒置研究的模型系统，因为其第三个染色体是人群中30多种不同基因排列的多态性。这些布置是通过一系列重叠的偏心反转产生的。反转频率在形成克林斯或主要频率转移的梯度的种群中有所不同。基因排列频率随季节循环并显示高度层。实验室中的种群笼实验表明，不同的基因排列保持在稳定的平衡频率下。 这项研究将使用下一代技术来重新序列50个菌株的伪造菌菌株，该菌株具有六种主要的染色体排列之一。 MRNA的下一代测序分析将用于量化两个不同的果蝇生命阶段，幼虫和成人的六种不同反演背景之间的表达差异。重新测序数据将识别反转断点序列并改善D. pseudoobscura基因组组件。转录组数据将用于改善D. pseudoobscura中基因模型的注释。核苷酸多态性和基因表达数据的分子种群遗传分析将测试四类关于新反转如何通过人群传播的假设：（1）由于重组的减少而导致的间接作用，导致染色体导致无效突变或增强自适应基因连接的染色体; （2）固定不足的排列的遗传漂移； （3）染色体病变的直接作用，例如基因结构或表达的改变；或（4）具有自适应等位基因的遗传搭便车。这些分析将检验两个假设，该假设关于人口中的倒置如何维持：（1）过度责任；或（2）作为受保护的多态性。在未来的实验中可以操纵显示出差异表达或蛋白质变异的基因，旨在了解基于反转演化的分子遗传基础。 公共卫生相关性： 人类中的染色体重排通常具有负适应性效应，因为卵或精子在杂合个体中交叉时可能具有或多或少具有遗传信息。当在妊娠期间或出生后发现遗传异常时，在人类中检测到反转，但是这些遗传突变有时可能存在而没有有害影响。这项研究将使用下一代测序技术来了解解释反转突变如何在果蝇中的自然种群中出现，传播和维持的遗传力。