Epistasis: its role in complex tratis, gene expression and speciation

描述（由申请人提供）：我们的目标是使用理论模型，基因表达阵列，分子遗传标记（SNP和微卫星）和分子进化理论，以更好地了解基因相互作用（上位性）如何产生复杂的表型。作为我们的实验系统，我们将使用最近收集的人口的红粉甲虫，赤拟谷盗，表现出的形式与受损的行为，形态畸形，降低生育力和生存能力的种群间杂种的初期形态的特点。我们的具体目标包括：（1）确认来自不同种群的一对基因的功能一致性，这些基因在共同的遗传背景下聚集在一起时会导致杂种适合度的总体降低;（2）通过这些基因在物种内和物种间的表达模式和序列多样性来表征这些基因的分子进化;（3）鉴定、确认和表征损害群体间杂种的运动行为的一组不同的相互作用基因;（4）利用Nimblegen（c）微阵列表征群体间杂种与其亲本之间的基因表达差异;（5）将双位点群体遗传理论扩展和检验到一个新的物种形成模型，该模型基于一对基因之间的相互作用，一个基因与母体表达，一个基因与合子表达。我们广泛的初步研究，交叉对来自北美和南美，非洲和亚洲的人口，揭示了优势，上位性，母体遗传效应，和基因型与环境的相互作用，导致形态和行为异常，降低生存能力和生育能力的种群间杂种。对于最极端的情况下，混合健身减少，我们已经表明，通过反复回交的基因组菌株，GA-2，和微卫星标记定位，一个特定的基因对相互作用，以减少混合健身。我们还发现，种群间行为异常发生在不同种群之间的交配和回交中;它们不是导致杂种适应度极度降低的基因之一（如上所述）;它们涉及连锁基因组合的破坏。通过继续与基因组菌株进行回交，我们可以分离出在共同遗传背景下导致行为异常的基因组合，确认它们的功能特性，并描述它们在物种内和物种间的进化。公共卫生相关性：基因相互作用（上位性）在物种形成中发挥着重要作用。杂种中有害的基因组合会产生负面的表型，如畸形、生育能力降低和生存能力降低，这与复杂的人类遗传疾病相似，如糖尿病、自闭症、肥胖症和精神分裂症。虽然已经确定了参与物种间生殖隔离的单个基因，但基因组合及其特定的因果相互作用尚不清楚。

DESCRIPTION (provided by applicant): Our goal is to use theoretical models, gene expression arrays, molecular genetic markers (SNPs and microsatellites) and molecular evolutionary theory to better understand how gene interactions (epistasis) produce complex phenotypes. As our experimental system, we will use recently collected populations of the red flour beetle, Tribolium castaneum, which exhibit characteristics of incipient speciation in the form of inter-population hybrids with impaired behavior, morphological deformities, and reduced fertility and viability. Our specific aims include (1) confirming the functional identity of a pair of genes from different populations that cause a total reduction of hybrid fitness when brought together in a common genetic background; (2) characterizing the molecular evolution of these genes through their patterns of expression and sequence diversity within and among species; (3) identifying, confirming and characterizing a different set of interacting genes which impair the motor behavior of inter-population hybrids; (4) characterizing the differences in gene expression between inter-population hybrids and their parents using Nimblegen(c) microarrays; and, (5) extending and testing two-locus population genetic theory to a new model of speciation based on interactions between a pair of genes, one with maternal and one with zygotic expression. Our extensive preliminary studies, crossing pairs of populations from North and South America, Africa and Asia, have revealed that dominance, epistasis, maternal genetic effects, and genotype-by-environment interaction cause morphological and behavioral abnormalities and reduced viability and fertility in inter-population hybrids. For the most extreme case of hybrid fitness reduction, we have shown, through repeated back-crossing to the genome strain, GA-2, and microsatellite marker mapping, that a specific pair of genes interacts to reduce hybrid fitness. We have also shown that inter-population behavioral abnormalities occur in matings and backcrosses between a different pair of populations; that they are not caused one of the genes responsible for the extreme reduction of hybrid fitness (above); and that they involve the breakdown of linked gene combinations. By continuing our back-crosses to the genomic strain, we can isolate the gene combinations causing the behavioral abnormalities in a common genetic background, confirm their functional identity, and characterize their evolution within and among species. PUBLIC HEALTH RELEVANCE: Gene interactions (epistasis) play a central role in speciation in particular. Deleterious gene combinations in hybrids produce negative phenotypes like deformities, reduced fertility, and reduced viability, which are similar to those of complex human genetic diseases, like diabetes, autism, obesity, and schizophrenia. Although single genes involved in reproductive isolation between species have been identified, the gene combinations and their specific causal interactions are not known.