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Genomics In The Journals: Sep 6, 2012

NEW YORK (GenomeWeb News) – In Nature Genetics, an international team led by investigators at the Children's Hospital of Philadelphia reports on findings from a genome-wide association study of neuroblastoma risk.

Using genotyping data for 2,101 individuals with neuroblastoma and 4,202 individuals without, the researchers identified a set of known neuroblastoma risk variants, as well as several new SNPs suspected of contributing to the childhood brain cancer. After validation studies on another 351 cases and 780 controls from Italy, the team verified significant neuroblastoma associations for two chromosome 6 SNPs: one falling in the tumor suppressor gene HACE1 and another within an oncogene, LIN28B.

In addition, SNPs in the latter gene appeared promising for predicting neuroblastoma progression. Variants of both genes seem to be linked to neuroblastoma in the African American population, too, the team found, though the protective version of the HACE1 allele was more common overall in that population.

"HACE1 and LIN28B are both known cancer-related genes, but this is the first study to link them to neuroblastoma," CHOP and University of Pennsylvania researcher Sharon Diskin, the study's first author, said in a statement.


In another Nature Genetics study, members of the Multiple Tissue Human Expression Resource, or MuTHER, consortium describe the gene regulatory variants they detected using genomic and transcriptomic data generated for multiple tissue types from twins.

The team brought together array-based gene expression and genotyping information for blood, skin, and fat tissue samples from more than 850 female twins who had been recruited through a program called Twins UK. These included adults between the ages of around 39 and 85 years old from 154 identical twin pairs and 232 sets of non-identical twins, along with several dozen singleton twins.

By comparing patterns in identical twins, who have more or less the same genome sequence, with those in non-identical twins, who are as genetically related as any other pair of siblings, the team was able to start teasing apart genetic and non-genetic influences on gene expression. In so doing, they also detected hundreds of candidate expression quantitative trait loci, including some suspected of contributing to disease risk. Roughly a third of the apparent regulatory variants detected fell near the affected gene, while the rest influenced the expression of genes from a distance.

"For the first time we are able to quantify the contribution of rare regulatory variants to gene expression levels," co-corresponding author Emmanouil Dermitzakis, a researcher with the University of Geneva's Institute of Genetics and Genomics, said in a statement. "This is a great step in elucidating the identity and contribution of such rare regulatory variants to complex disease risk."


Researchers from Canada and the Republic of Benin have tracked down new host variants that influence the course of infection for individuals with malaria caused by the Plasmodium falciparum parasite.

As they report in the early, online edition of the Proceedings of the National Academy of Sciences, the investigators got blood samples from almost 100 West African children infected with P. falciparum and 61 age-matched controls. From genome-wide, array-based transcript patterns and genotype profiles in the blood samples, the team tracked down genes suspected of contributing to malaria infection patterns. In addition to uncovering host genetic profiles associated with malaria susceptibility, these analyses — coupled with follow-up studies in mice infected with another Plasmodium species — offered clues to the biological pathways affected by malaria infection.

"These results suggest that host variation and its interplay with infection affect children's ability to cope with infection," University of Montreal researcher Philip Awadalla, the study's senior author, and colleagues wrote, "and suggest a polygenic model mounted at the transcriptional level for susceptibility."


Meanwhile, a PLoS Medicine study looks at the role that another malaria parasite has had on human genome evolution.

A team of researchers based in Papua New Guinea, Australia, Spain, the US, and Switzerland genotyped nearly 2,000 children from Papua New Guinea's Madang province, looking at the prevalence of a 27 base pair deletion in a red blood cell-related gene called SLC4A1 delta27 and its effects in the population. This polymorphism produces a blood cell disorder known as Southeast Asian ovalocytosis, or SAO, that can protect against a severe form of malaria caused by the P. falciparum parasite.

But the team wanted to find out whether this portion of the genome has also been influenced by a more widely distributed and less frequently fatal form of malaria caused by P. vivax. Indeed, through a series of analyses, the investigators showed that the SAO-causing polymorphism has ties to lower risk of P. vivax infection and reinfection, hinting that exposure to this malaria parasite has exerted selective pressure on the human genome.

"It has long been assumed that Plasmodium falciparum, the species that causes the most severe disease and most deaths from malaria, is the most important driver of this gene selection in humans," senior author Ivo Mueller, a researcher affiliated with Australia's Walter and Eliza Hall Institute, the Barcelona Centre for International Health Research, and the PNG Institute for Medical Research in Papua New Guinea, said in a statement.

"Our results suggest that P. vivax malaria, though until recently widely considered to be a 'benign' form of malaria, actually causes severe enough disease to provide evolutionary selection pressures in the Asia-Pacific," he explained.


Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.

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