Glycan Diversity and Anti-Glycan Antibodies as Barriers to Gene Flow

描述(由申请人提供)：作为基因流动障碍的葡聚糖多样性和抗葡聚糖抗体哺乳动物细胞被一层致密的糖链(葡聚糖)覆盖。不同的细胞类型、不同的个体和不同的物种之间存在着不同的糖链多样性模式。这种模式背后的进化机制尚不清楚，但鉴于非自体多糖是先天免疫和获得性免疫的靶标，已提出了糖链多样性的保护功能。哺乳动物的糖链通常终止于一种叫做唾液酸(SIA)的糖类中。两种最常见的SIA是N-乙酰神经氨酸(Neu5Ac)和N-羟基神经氨酸(Neu5Gc)。由于基因失活，人类已经失去了从其前体Neu5Ac产生Neu5Gc的能力。由于另一种突变，人类以及所有其他东半球猴子(OWM)和类人猿已经失去了制造另一种常见的糖链--1-半乳糖表位的能力。因此，每个人类细胞的分子细胞表面“景观”与大多数其他哺乳动物的不同之处在于缺乏数百万个1-Gal分子和数千万个Neu5Gc分子。人类也会对这两种“异聚糖”产生抗体，但我们是如何获得免疫的还不清楚。该项目将测试这两种异聚糖对不同形式的基因流动、病毒感染和繁殖的影响。人类在非洲灵长类动物中是独一无二的，因为人类缺乏地方性感染，并且直到最近才与两种不同的包膜逆转录病毒-免疫缺陷病毒(SIV/HIV)和泡沫病毒(SFV)-共同进化。被包裹的病毒或精子和胎儿组织上的葡聚糖可以成为免疫系统的靶标。我们认为，糖链结合病原体的自然选择可能是最初糖链多样化的基础，但生殖不亲和性选择可能导致不同物种之间的糖链酶谱固定。在这个过程中，这些多糖的差异提供了部分保护，使其免受包膜病毒跨物种传播的影响。我们将利用基因敲除小鼠和小鼠细胞系来测试糖链错配和抗糖链抗体对病毒和生殖基因流的影响。我们还将测试来自人血清的抗多糖抗体对新旧世界猴子细胞系产生的病毒的中和作用，这两种细胞系的异聚糖图谱自然不同。该项目有望对尚不清楚的多糖进化机制、繁殖亲和性和跨物种病毒感染的决定因素提供重要的见解。 公共卫生相关性：作为基因流动障碍的葡聚糖多样性和抗葡聚糖抗体人类细胞与大多数其他哺乳动物的不同之处在于，大多数人类产生循环抗体的每个细胞表面都没有数百万个分子。导致这一变化的潜在基因变化是已知的，但对有利于我们物种这种变化的进化机制却一无所知。我们建议测试这种差异对繁殖和跨物种病毒感染的影响，例如在新出现的疾病中。

DESCRIPTION (provided by applicant): Glycan Diversity and Anti-Glycan Antibodies as Barriers to Gene Flow Mammalian cells are covered with a dense layer of sugar chains (glycans). Patterns of glycan diversity exist between cell types, between individuals, and between species. The evolutionary mechanisms underlying such patterns remain unknown but protective functions of glycan diversity have been proposed, given that non-self glycans are targets of innate and adaptive immunity. Mammalian glycans commonly terminate in sugars called sialic acids (Sias). The two most common Sias are N-Acetylneuraminic acid (Neu5Ac) and N- Glycolylneuraminic acid (Neu5Gc). Humans have lost the ability to produce Neu5Gc from its precursor Neu5Ac due to a gene inactivation. Humans together with all other old world monkeys (OWM) and apes have lost the ability to make another common glycan, the 1-Gal epitope, due to another mutation. The molecular cell surface "landscape" of each human cell thus differs from those of most other mammals by lacking millions of 1-Gal molecules and tens of millions of Neu5Gc molecules. Humans also make antibodies to both of these "xenoglycans" but how we get immunized remains unknown. This project will test the effect of these two xenoglycans on different forms of gene flow, viral infection and reproduction. Humans are unique among African primates for lacking endemic infection and ancient coevolution with two different enveloped retroviruses, immune deficiency viruses (SIV/HIV) and foamy viruses (SFV) until very recently. Glycans on enveloped viruses or sperm and fetal tissues can be targeted by the immune system. We propose that natural selection by glycan-binding pathogens may underlie initial glycan diversification, but that sexual selection in the form reproductive incompatibility may lead to fixation of glycan repertoires between species. In the process, these glycan differences provide partial protection from cross-species transmission of enveloped viruses. We will utilize gene knockout mice and mouse cell lines to test the effect of glycan mismatch and anti-glycan antibodies on both, viral and reproductive gene flow. We will also test the effect of anti-glycan antibodies from human sera for their neutralizing effects on viruses produced in Old and New World monkey cell lines which naturally differ in their xenoglycan profiles. This project promises important insights into the mechanism of poorly understood glycan evolution, reproductive compatibility and determinants of cross-species viral infections. PUBLIC HEALTH RELEVANCE: Glycan Diversity and Anti-Glycan Antibodies as Barriers to Gene Flow Human cells differ from those of most other mammals by the absence of millions of molecules from each cell surface against which most humans make circulating antibodies. The underlying genetic change responsible for this is known, but nothing is known of the evolutionary mechanisms, which favored this change in our species. We propose to test the consequences of this difference for reproduction and cross-species viral infections, such as in emerging diseases.