Sciences of the USA 1418 -1421 ͉ PNAS

The discovery of the block-like structure of linkage disequilibrium (LD) in human populations holds the promise of delineating the etiology of common diseases. However, understanding the magnitude, mechanism, and utility of between-population LD sharing is critical for future genome-wide association studies. In this study, substantial LD sharing between six non-African populations was observed, although much less between African-American and non-African, based on 20,000 SNPs of chromosome 21. We also demonstrated the respective roles of recombination and demographic events in shaping LD sharing. Furthermore, we showed that the haplotype-tagged SNPs chosen from one population are portable to the others in East Asia. Therefore, we concluded that the magnitude of LD sharing between human populations justifies the use of representative populations for selecting haplotypetagged SNPs in genome-wide association studies of complex diseases. bottleneck ͉ genetic distance ͉ association study ͉ common disease ͉ genetic variant C omprehensive testing of the association between genetic variations in the human genome and common diseases holds the promise of delineating the genetic architecture of these diseases (1-5). Substantial sharing of the boundaries and specific haplotypes of linkage disequilibrium (LD) blocks between populations was observed (6). However, variations of haplotype and LD across populations were also reported, raising concerns on its practical hindrance for genomewide testing of association (7-9). Conflicting observations on the magnitude of LD sharing between human populations, therefore, call for a careful examination of the following three questions, which are fundamental in developing strategies for genomewide testing of association. First, measurement of LD sharing between populations should be made independent of the definition of LD blocks, which introduce inconsistent block boundaries (10). Second, the mechanisms that shape LD sharing between populations are yet to be fully explored although the roles of recombination hotspots and demographic events have been implicated To address the aforementioned questions, we typed Ͼ20,000 SNPs on chromosome 21 in seven populations: three representative continental populations [African-American (AFR), European (EUR), and Han Chinese (HAN)] and four other major East Asian (EA) populations. This design allows a close examination of LD sharing between continental groups as well as those within East Asia. In this report, we measured the LD sharing between populations independent of the definition of LD block; and we showed that bottleneck events play a critical role in shaping the LD sharing between Africans and nonAfricans, but much less so between non-Africans. An important question for applying HapMap results to disease studies is how tagSNPs selected from a HapMap population will be ported to disease studies performed in other populations. In this study, we showed that tagSNPs selected from representative continental populations are indeed portable to the others in the same continent for association studies, at least in East Asia, with reasonable efficiency. In addition, we proposed a simple guideline that allows a quick evaluation of the portability of tagSNPs between populations by typing a small number of SNPs. Results Overall 26,112 SNPs were selected and typed in this study, and the data from 19,060 SNPs passed the quality control criteria and were used for further analyses. The SNPs and quality control criteria for SNP selection are described in Materials and Methods. Seven world populations, including EUR, AFR, and five EA populations, were studied. The five EA populations, i.e., HAN, Miao (HMJ), Zhuang (CCY), Wa (WBM), and Uighur (UIG), represent five major linguistic families spoken in East Asia. Preservation of LD between populations, i.e., LD sharing (S, or S AB when the population A was given as reference), is measured by the proportion of SNP pairs in LD in one population (population A or the reference) that are also in LD in another (population B). In this study, LD sharing was estimated without invoking the inference of haplotype blocks; therefore, the measure is independent of the definition of haplotype blocks. LD between two loci was measured in r 2 (16). Detail for the measure of LD sharing is described in Materials and Methods. LD sharing between EAs ranges from 63-74% for r 2 Ն 0.1 and 70-84% for r 2 Ն 0.5 (se

Multivalent HA DNA Vaccination Protects against Highly Pathogenic H5N1 Avian Influenza Infection in Chickens and Mice

Sustained outbreaks of highly pathogenic avian influenza (HPAI) H5N1 in avian species increase the risk of reassortment and adaptation to humans. The ability to contain its spread in chickens would reduce this threat and help maintain the capacity for egg-based vaccine production. While vaccines offer the potential to control avian disease, a major concern of current vaccines is their potency and inability to protect against evolving avian influenza viruses.The ability of DNA vaccines encoding hemagglutinin (HA) proteins from different HPAI H5N1 serotypes was evaluated for its ability to elicit neutralizing antibodies and to protect against homologous and heterologous HPAI H5N1 strain challenge in mice and chickens after DNA immunization by needle and syringe or with a pressure injection device. These vaccines elicited antibodies that neutralized multiple strains of HPAI H5N1 when given in combinations containing up to 10 HAs. The response was dose-dependent, and breadth was determined by the choice of the influenza virus HA in the vaccine. Monovalent and trivalent HA vaccines were tested first in mice and conferred protection against lethal H5N1 A/Vietnam/1203/2004 challenge 68 weeks after vaccination. In chickens, protection was observed against heterologous strains of HPAI H5N1 after vaccination with a trivalent H5 serotype DNA vaccine with doses as low as 5 microg DNA given twice either by intramuscular needle injection or with a needle-free device.DNA vaccines offer a generic approach to influenza virus immunization applicable to multiple animal species. In addition, the ability to substitute plasmids encoding different strains enables rapid adaptation of the vaccine to newly evolving field isolates

Minimum Aberration Blocking Schemes for 128-Run Designs

Several criteria have been proposed for ranking blocked fractional factorial designs. For large fractional factorial designs, the most appropriate minimum aberration criterion was one proposed by Cheng and Wu (2002). We justify this assertion and propose a novel construction method to overcome the computational challenge encountered in large fractional factorial designs. Tables of minimum aberration blocked designs are presented for N=128 runs and n=8–64 factors

Discovery of a low order drug-cell response surface for applications in personalized medicine

The cell is a complex system involving numerous components, which may often interact in a non-linear dynamic manner. Diseases at the cellular level are thus likely to involve multiple cellular constituents and pathways. As some drugs, or drug combinations, may act synergistically on these multiple pathways, they might be more effective than the respective single target agents. Optimizing a drug mixture for a given disease in a particular patient is particularly challenging due to both the difficulty in the selection of the drug mixture components to start out with, and the all-important doses of these drugs to be applied. For n concentrations of m drugs, in principle, n(m) combinations will have to be tested. As this may lead to a costly and time-consuming investigation for each individual patient, we have developed a Feedback System Control (FSC) technique which can rapidly select the optimal drug-dose combination from the often millions of possible combinations. By testing this FSC technique in a number of experimental systems representing different disease states, we found that the response of cells to multiple drugs is well described by a low order, rather smooth, drug-mixture-input/drug-effect-output multidimensional surface. The main consequences of this are that optimal drug combinations can be found in a surprisingly small number of tests, and that translation from in vitro to in vivo is simplified. This points to the possibility of personalized optimal drug mixtures in the near future. This unexpectedly simple input-output relationship may also lead to a simple solution for handling the issue of human diversity in cancer therapeutics