抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

The character of a cell is defined by its constituent proteins, which are the result of specific patterns of gene expression. Crucial determinants of gene expression patterns are DNA-binding transcription factors that choose genes for transcriptional activation or repression by recognizing the sequence of DNA bases in their promoter regions. Interaction of these factors with their cognate sequences triggers a chain of events, often involving changes in the structure of chromatin, that leads to the assembly of an active transcription complex (e.g., Cosma et al. 1999). But the types of transcription factors present in a cell are not alone sufficient to define its spectrum of gene activity, as the transcriptional potential of a genome can become restricted in a stable manner during development. The constraints imposed by developmental history probably account for the very low efficiency of cloning animals from the nuclei of differentiated cells (Rideout et al. 2001; Wakayama and Yanagimachi 2001). A “transcription factors only” model would predict that the gene expression pattern of a differentiated nucleus would be completely reversible upon exposure to a new spectrum of factors. Although many aspects of expression can be reprogrammed in this way (Gurdon 1999), some marks of differentiation are evidently so stable that immersion in an alien cytoplasm cannot erase the memory. The genomic sequence of a differentiated cell is thought to be identical in most cases to that of the zygote from which it is descended (mammalian B and T cells being an obvious exception). This means that the marks of developmental history are unlikely to be caused by widespread somatic mutation. Processes less irrevocable than mutation fall under the umbrella term “epigenetic” mechanisms. A current definition of epigenetics is: “The study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence” (Russo et al. 1996). There are two epigenetic systems that affect animal development and fulfill the criterion of heritability: DNA methylation and the Polycomb-trithorax group (Pc-G/trx) protein complexes. (Histone modification has some attributes of an epigenetic process, but the issue of heritability has yet to be resolved.) This review concerns DNA methylation, focusing on the generation, inheritance, and biological significance of genomic methylation patterns in the development of mammals. Data will be discussed favoring the notion that DNA methylation may only affect genes that are already silenced by other mechanisms in the embryo. Embryonic transcription, on the other hand, may cause the exclusion of the DNA methylation machinery. The heritability of methylation states and the secondary nature of the decision to invite or exclude methylation support the idea that DNA methylation is adapted for a specific cellular memory function in development. Indeed, the possibility will be discussed that DNA methylation and Pc-G/trx may represent alternative systems of epigenetic memory that have been interchanged over evolutionary time. Animal DNA methylation has been the subject of several recent reviews (Bird and Wolffe 1999; Bestor 2000; Hsieh 2000; Costello and Plass 2001; Jones and Takai 2001). For recent reviews of plant and fungal DNA methylation, see Finnegan et al. (2000), Martienssen and Colot (2001), and Matzke et al. (2001).

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DNA methylation patterns and epigenetic memory

After infection and a prolonged incubation period, the scrapie agent causes a degenerative disease of the central nervous system in sheep and goats. Six lines of evidence including sensitivity to proteases demonstrate that this agent contains a protein that is required for infectivity. Although the scrapie agent is irreversibly inactivated by alkali, five procedures with more specificity for modifying nucleic acids failed to cause inactivation. The agent shows heterogeneity with respect to size, apparently a result of its hydrophobicity; the smallest form may have a molecular weight of 50,000 or less. Because the novel properties of the scrapie agent distinguish it from viruses, plasmids, and viroids, a new term "prion" is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids. Knowledge of the scrapie agent structure may have significance for understanding the causes of several degenerative diseases.

http://science.sciencemag.org/content/sci/216/4542/136.full.pdf

Novel proteinaceous infectious particles cause scrapie

Nobel Lecture: Prions

Genetics and analysis of quantitative traits

Genomic imprinting in mammalian development: a parental tug-of-war

Pregnancy has commonly been viewed as a cooperative interaction between a mother and her fetus. The effects of natural selection on genes expressed in fetuses, however, may be opposed by the effects of natural selection on genes expressed in mothers. In this sense, a genetic conflict can be said to exist between maternal and fetal genes. Fetal genes will be selected to increase the transfer of nutrients to their fetus, and maternal genes will be selected to limit transfers in excess of some maternal optimum. Thus a process of evolutionary escalation is predicted in which fetal actions are opposed by maternal countermeasures. The phenomenon of genomic imprinting means that a similar conflict exists within fetal cells between genes that are expressed when maternally derived, and genes that are expressed when paternally derived. During implantation, fetally derived cells (trophoblast) invade the maternal endometrium and remodel the endometrial spiral arteries into low-resistance vessels that are unable to constrict. This invasion has three consequences. First, the fetus gains direct access to its mother's arterial blood. Therefore, a mother cannot reduce the nutrient content of blood reaching the placenta without reducing the nutrient supply to her own tissues. Second, the volume of blood reaching the placenta becomes largely independent of control by the local maternal vasculature. Third, the placenta is able to release hormones and other substances directly into the maternal circulation. Placental hormones, including human chorionic gonadotropin (hCG) and human placental lactogen (hPL), are predicted to manipulate maternal physiology for fetal benefit. For example, hPL is proposed to act on maternal prolactin receptors to increase maternal resistance to insulin. If unopposed, the effect of hPL would be to maintain higher blood glucose levels for longer periods after meals. This action, however, is countered by increased maternal production of insulin. Gestational diabetes develops if the mother is unable to mount an adequate response to fetal manipulation. Similarly, fetal genes are predicted to enhance the flow of maternal blood through the placenta by increasing maternal blood pressure. Preeclampsia can be interpreted as an attempt by a poorly nourished fetus to increase its supply of nutrients by increasing the resistance of its mother's peripheral circulation.

/pdf/genetic-conflicts-in-human-pregnancy-4ip4vrvtau.pdf

Genetic conflicts in human pregnancy.

Scrapie is a slowly developing disease of the nervous system. Experiments on the effects of ultra-violet irradiation of suspensions of infected mouse brain extracts confirm that the agent responsible for it does not depend on a nucleic acid for its ability to replicate. No evidence is obtained, however, to indicate whether the agent is associated with a protein.

Does the Agent of Scrapie Replicate without Nucleic Acid

Genomic imprinting results in preferential expression of the paternal or maternal allele of certain genes. We have performed a genome-wide characterization of imprinting in the mouse embryonic and adult brain. This approach uncovered parent-of-origin allelic effects of more than 1300 loci. We identified parental bias in the expression of individual genes and of specific transcript isoforms, with differences between brain regions. Many imprinted genes are expressed in neural systems associated with feeding and motivated behaviors, and parental biases preferentially target genetic pathways governing metabolism and cell adhesion. We observed a preferential maternal contribution to gene expression in the developing brain and a major paternal contribution in the adult brain. Thus, parental expression bias emerges as a major mode of epigenetic regulation in the brain.

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High-Resolution Analysis of Parent-of-Origin Allelic Expression in the Mouse Brain

The endosperm of flowering plants is a tissue that acquires resources from the maternal sporophyte and is in turn digested by the developing embryo in its own seed. In this respect, the endosperm takes the role filled by the female gametophyte in gymnosperms. Endosperm is a tissue unique to angiosperms. At fertilization, a male gametophyte (pollen tube) releases two sperm into the female gametophyte. One sperm fuses with the egg to form a diploid zygote, and the other sperm fuses with two female-gametophyte nuclei (known as polar nuclei) to form the triploid primary-endosperm nucleus. Therefore, the endosperm, which develops from this triploid nucleus, has an unusual genetic composition. Each nucleus contains one copy of the paternal contribution to the associated embryo and two copies of the maternal contribution. A minority of flowering plant species have endosperms of different genetic composition, but almost all share the characteristic that more of the endosperm genome is derived from the mother than from the father. Double fertilization and the formation of endosperm are often considered the major features that distinguish flowering plants from other seed plants. Because of this importance, many authors have suggested adaptive explanations for the unusual genetic constitution of endosperm. Heterozygote vigor (Brink and Cooper 1940) can explain the presence of a paternal contribution but not why the maternal contribution should be doubled. Polyploid vigor (Stebbins 1974) can explain the advantage of triploid over diploid endosperm but not the weighting toward the maternal contribution. In other words, the polyploid-vigor explanation does not explain why genome doubling should occur in the female gametophyte before fertilization, particularly given that endosperm cells often increase their ploidy by other means after fertilization (D'Amato 1984). More-recent hypotheses have treated the endosperm as a participant in conflicts of interest among mother, father, and offspring. Conflict arises because sibling offspring of one mother tend to compete with each other. Each offspring's prospects of survival and eventual reproduction are sensitive to the quantity of resources it obtains from the mother, and when some offspring obtain more resources, others tend to obtain less. Because the mother is equally related to (has an equal genetic investment in) each of her offspring, her inclusive fitness is greatest when all nonabortive offspring are provisioned equally (Smith and Fretwell 1974; Trivers 1974). However, each offspring is more closely related to itself than to its siblings. For this reason, individual offspring would benefit from some redistribution of the mother's resources toward themselves and away from their

/pdf/parent-specific-gene-expression-and-the-triploid-endosperm-3og99ufqit.pdf

David Haig

Papers

Genomic imprinting in mammalian development: a parental tug-of-war

Genetic conflicts in human pregnancy.

Does the Agent of Scrapie Replicate without Nucleic Acid

High-Resolution Analysis of Parent-of-Origin Allelic Expression in the Mouse Brain

Parent-Specific Gene-Expression and the Triploid Endosperm