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

描述（由申请人提供）：聚糖多样性和抗聚糖抗体作为基因流动的屏障哺乳动物细胞覆盖着一层致密的糖链（聚糖）。多糖多样性模式存在于细胞类型之间、个体之间和物种之间。这种模式的进化机制尚不清楚，但考虑到非自体聚糖是先天免疫和适应性免疫的靶标，已经提出了聚糖多样性的保护功能。哺乳动物的聚糖通常终止于称为唾液酸（Sias）的糖。两种最常见的Sias是N-乙酰神经氨酸（Neu5Ac）和N-糖基神经氨酸（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，人类与所有其他旧大陆猴（OWM）和猿类一起失去了制造另一种常见聚糖——1-Gal表位的能力。因此，每个人类细胞的分子细胞表面“景观”不同于大多数其他哺乳动物，因为它们缺乏数百万个1-Gal分子和数千万个Neu5Gc分子。人类也会对这两种“异种聚糖”产生抗体，但我们如何获得免疫仍然未知。本项目将测试这两种异种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，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）——缺乏地方性感染和古老的共同进化。包膜病毒或精子和胎儿组织上的聚糖可以成为免疫系统的目标。我们提出，聚糖结合病原体的自然选择可能是初始聚糖多样化的基础，但生殖不相容形式的性选择可能导致物种之间聚糖库的固定。在这个过程中，这些聚糖的差异为包膜病毒的跨物种传播提供了部分保护。我们将利用基因敲除小鼠和小鼠细胞系来测试聚糖错配和抗聚糖抗体对病毒和生殖基因流动的影响。我们还将测试来自人血清的抗聚糖抗体对新旧世界猴细胞系中产生的病毒的中和作用，这两种病毒的异种聚糖谱自然不同。该项目有望对尚不清楚的聚糖进化机制、生殖兼容性和跨物种病毒感染的决定因素提供重要见解。

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.