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

Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

“Bioinformatics” 특집을 내면서

Genetics and analysis of quantitative traits

Gene expression is central to the genotype-phenotype relationship in all organisms, and it is an important component of the genetic basis for evolutionary change in diverse aspects of phenotype. However, the evolution of transcriptional regulation remains understudied and poorly understood. Here we review the evolutionary dynamics of promoter, or cis-regulatory, sequences and the evolutionary mechanisms that shape them. Existing evidence indicates that populations harbor extensive genetic variation in promoter sequences, that a substantial fraction of this variation has consequences for both biochemical and organismal phenotype, and that some of this functional variation is sorted by selection. As with protein-coding sequences, rates and patterns of promoter sequence evolution differ considerably among loci and among clades for reasons that are not well understood. Studying the evolution of transcriptional regulation poses empirical and conceptual challenges beyond those typically encountered in analyses of coding sequence evolution: promoter organization is much less regular than that of coding sequences, and sequences required for the transcription of each locus reside at multiple other loci in the genome. Because of the strong context-dependence of transcriptional regulation, sequence inspection alone provides limited information about promoter function. Understanding the functional consequences of sequence differences among promoters generally requires biochemical and in vivo functional assays. Despite these challenges, important insights have already been gained into the evolution of transcriptional regulation, and the pace of discovery is accelerating.

/pdf/the-evolution-of-transcriptional-regulation-in-eukaryotes-16fy43qset.pdf

The Evolution of Transcriptional Regulation in Eukaryotes

A new field of genetic analysis of global gene expression has emerged in recent years, driven by the realization that traditional techniques of linkage and association analysis can be applied to thousands of transcript levels measured by microarrays. Genetic dissection of transcript abundance has shed light on the architecture of quantitative traits, provided a new approach for connecting DNA sequence variation with phenotypic variation, and improved our understanding of transcriptional regulation and regulatory variation.

Genetics of global gene expression.

The search for the alleles that matter, the quantitative trait nucleotides (QTNs) that underlie heritable variation within populations and divergence among them, is a popular pursuit. But what is the question to which QTNs are the answer? Although their pursuit is often invoked as a means of addressing the molecular basis of phenotypic evolution or of estimating the roles of evolutionary forces, the QTNs that are accessible to experimentalists, QTNs of relatively large effect, may be uninformative about these issues if large-effect variants are unrepresentative of the alleles that matter. Although 20th century evolutionary biology generally viewed large-effect variants as atypical, the field has recently undergone a quiet realignment toward a view of readily discoverable large-effect alleles as the primary molecular substrates for evolution. I argue that neither theory nor data justify this realignment. Models and experimental findings covering broad swaths of evolutionary phenomena suggest that evolution often acts via large numbers of small-effect polygenes, individually undetectable. Moreover, these small-effect variants are different in kind, at the molecular level, from the large-effect alleles accessible to experimentalists. Although discoverable QTNs address some fundamental evolutionary questions, they are essentially misleading about many others.

/pdf/the-qtn-program-and-the-alleles-that-matter-for-evolution-20ux8399mc.pdf

The QTN Program and the Alleles That Matter for Evolution: All That’s Gold Does Not Glitter

Cryptic genetic variation (CGV) is invisible under normal conditions, but it can fuel evolution when circumstances change In theory, CGV can represent a massive cache of adaptive potential or a pool of deleterious alleles that are in need of constant suppression CGV emerges from both neutral and selective processes, and it may inform about how human populations respond to change CGV facilitates adaptation in experimental settings, but does it have an important role in the real world? Here, we review the empirical support for widespread CGV in natural populations, including its potential role in emerging human diseases and the growing evidence of its contribution to evolution

Cryptic genetic variation: evolution's hidden substrate

Recombination rate and linkage disequilibrium, the latter a function of population genomic processes, are the critical parameters for mapping by linkage and association, and their patterns in Caenorhabditis elegans are poorly understood. We performed high-density SNP genotyping on a large panel of recombinant inbred advanced intercross lines (RIAILs) of C. elegans to characterize the landscape of recombination and, on a panel of wild strains, to characterize population genomic patterns. We confirmed that C. elegans autosomes exhibit discrete domains of nearly constant recombination rate, and we show, for the first time, that the pattern holds for the X chromosome as well. The terminal domains of each chromosome, spanning about 7% of the genome, exhibit effectively no recombination. The RIAILs exhibit a 5.3-fold expansion of the genetic map. With median marker spacing of 61 kb, they are a powerful resource for mapping quantitative trait loci in C. elegans. Among 125 wild isolates, we identified only 41 distinct haplotypes. The patterns of genotypic similarity suggest that some presumed wild strains are laboratory contaminants. The Hawaiian strain, CB4856, exhibits genetic isolation from the remainder of the global population, whose members exhibit ample evidence of intercrossing and recombining. The population effective recombination rate, estimated from the pattern of linkage disequilibrium, is correlated with the estimated meiotic recombination rate, but its magnitude implies that the effective rate of outcrossing is extremely low, corroborating reports of selection against recombinant genotypes. Despite the low population, effective recombination rate and extensive linkage disequilibrium among chromosomes, which are techniques that account for background levels of genomic similarity, permit association mapping in wild C. elegans strains.

https://escholarship.org/content/qt1n7317b5/qt1n7317b5.pdf?t=qaelyy

Matthew V. Rockman

Papers

The Evolution of Transcriptional Regulation in Eukaryotes

Genetics of global gene expression.

The QTN Program and the Alleles That Matter for Evolution: All That’s Gold Does Not Glitter

Cryptic genetic variation: evolution's hidden substrate

Recombinational landscape and population genomics of Caenorhabditis elegans.