Putting science over supposition in the arena of personalized genomics

Colleen McBride and colleagues argue that progress on a multifaceted research agenda is necessary to reap the full benefits and avoid the potential pitfalls of the emerging area of personalized genomics. They also outline one element of this agenda, the Multiplex Initiative, which has been underway since 2006.     

Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation

Allele-specific DNA methylation (ASM) is a hallmark of imprinted genes, but ASM in the larger nonimprinted fraction of the genome is less well characterized. Using methylation-sensitive SNP analysis (MSNP), we surveyed the human genome at 50K and 250K resolution, identifying ASM as recurrent genotype call conversions from heterozygosity to homozygosity when genomic DNAs were predigested with the methylation-sensitive restriction enzyme HpaII. Using independent assays, we confirmed ASM at 16 SNP-tagged loci distributed across various chromosomes. At 12 of these loci (75%), the ASM tracked strongly with the sequence of adjacent SNPs. Further analysis showed allele-specific mRNA expression at two loci from this methylation-based screen--the vanin and CYP2A6-CYP2A7 gene clusters--both implicated in traits of medical importance. This recurrent phenomenon of sequence-dependent ASM has practical implications for mapping and interpreting associations of noncoding SNPs and haplotypes with human phenotypes.     

The genetics of health

Recent experience with several high-profile drugs demonstrates the great challenges in developing effective and safe therapeutics. A complementary approach to the popular paradigm of disease genetics is based on inherited factors that reduce the incidence and severity of disease among individuals who are genetically predisposed to disease. We propose testing specifically for modifier genes and protective alleles among at-risk individuals and studying the efficacy of therapeutics based on the genetics of health.     

Testing for the usefulness of forecasts

Ashley (Journal of Forecasting 1983; 2 (3): 211–223) proposes a criterion (known as Ashley's index) to judge whether the external macroeconomic variables are well forecast to serve as explanatory variables in forecasting models, which is crucial for policy makers. In this article, we try to extend Ashley's work by providing three testing procedures, including a ratio‐based test, a difference‐based test, and the Bayesian approach. The Bayesian approach has the advantage of allowing the flexibility of adapting all possible information content within a decision‐making environment such as the change of variable's definition due to the evolving system of national accounts. We demonstrate the proposed methods by applying six macroeconomic forecasts in the Survey of Professional Forecasters. Researchers or practitioners can thus formally test whether the external information is helpful. Copyright © 2010 John Wiley & Sons, Ltd.     

Early development of the razorback sucker, Xyrauchen texanus (Abbott)

  Fertilized ova of razorback sucker, Xyrauchen texanus, were adhesive for 3 to 4 hours after fertilization. Cleavage was completed at 24 hours, gastrulation occurred at 34 hours, and blood circulation was established at 117 hours. Hatching occurred from 5.2 to 5.5 days after fertilization. Larvae were from 6.8 to 7.3 mm TL at hatching. Yolk was assimilated at 13 days (10 mm TL). All fins were formed and had ossified rays at 64 days (27 mm TL). The unique nuchal keel appeared about 200 days after fertilization.     

Larger ectoparasites of the Idaho ground squirrel ( Spermophilus brunneus )

We sampled both subspecies of the Idaho ground squirrel ( Spermophilus brunneus ) to document the larger ectoparasites of this rare endemic. S. b. brunneus was host (+ = new host record, ? = new Idaho record) to 4 flea species ( Neopsylla inopina + , Oropsylla idahoensis + , O. tuberculata , and Thrassis pandorae +), 1 tick ( Ixodes sculptus +), and an eyeworm (Nematoda: Rhabditis orbitalis ? + , also 1st records from Seiuridae); S. b. endemicus was host to a louse species ( Neohaematopinus laeviusculus +), 5 flea taxa ( Rhadinopsylla sp. + , O. t. tuberculata, Thrassis f. francisi + , T. f. barnest + , and T. f. rockwoodi ), and a mite ( Androlaelaps fahrenholzi +). Spermophilus brunneus had fewer known ectoparasite species than other congeners. Although all of their parasites had many other hosts, S. b. endemicus and S. b. brunneus shared only a single parasite species in common, whereas all but one of their ectoparasites also occurred on the closely related Townsend's ground squirrel ( S. townsendii ). The proportion of parasitized individuals and the parasite loads per individual were significantly lower in S. b. brunneus , which lives in small, isolated populations, than in S. b. endemicus , which has larger, less fragmented populations, suggesting a relationship between host population structure, parasite loads, and parasite species diversity. All but one of the flea species have been linked to plague transmission.     

HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus

Early treatment of acute HIV-1 infection followed by treatment interruptions has shown promise for enhancing immune control of infection. A subsequent loss of control, however, allows the correlates of protective immunity to be assessed. Here we show that sudden breakthrough of plasma viraemia occurred after prolonged immune containment in an individual infected with HIV-1 at a time when 25 distinct CD8+ T-cell epitopes in the viral proteins Gag, RT, Integrase, Env, Nef, Vpr, Vif and Rev were being targeted. Sequencing of the virus in plasma and cells showed that superinfection with a second clade-B virus was coincident with the loss of immune control. This sudden increase in viraemia was associated with a decline in half of the CD8+ T-cell responses. The declining CD8+ T-cell responses were coupled with sequence changes relative to the initial virus that resulted in impaired recognition. Our data show that HIV-1 superinfection can occur in the setting of a strong and broadly directed virus-specific CD8+ T-cell response. The lack of cross-protective immunity for closely related HIV-1 strains, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development.     

Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox

The potential use of smallpox as a biological weapon has led to the production and stockpiling of smallpox vaccine and the immunization of some healthcare workers. Another public health goal is the licensing of a safer vaccine that could benefit the millions of people advised not to take the current one because they or their contacts have increased susceptibility to severe vaccine side effects. As vaccines can no longer be tested for their ability to prevent smallpox, licensing will necessarily include comparative immunogenicity and protection studies in non-human primates. Here we compare the highly attenuated modified vaccinia virus Ankara (MVA) with the licensed Dryvax vaccine in a monkey model. After two doses of MVA or one dose of MVA followed by Dryvax, antibody binding and neutralizing titres and T-cell responses were equivalent or higher than those induced by Dryvax alone. After challenge with monkeypox virus, unimmunized animals developed more than 500 pustular skin lesions and became gravely ill or died, whereas vaccinated animals were healthy and asymptomatic, except for a small number of transient skin lesions in animals immunized only with MVA.