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Genomics in the Journals: Nov 21, 2013

NEW YORK (GenomeWeb News) – In Nature Communications, researchers from the University of Cambridge, the Zoological Society of London's Institute of Zoology, and elsewhere reported on connections between fruit bats in Africa in the context of zoonotic virus carriage and transmission.

Using a combination of mitochondrial and nuclear DNA sequence profiling, urine analysis, and bat blood antibody testing, the team assessed relationships and viral carriage across almost 2,100 bats from straw-colored fruit bat, Eidolon helvum, populations in various parts of Africa.

The analysis indicated that the straw-colored fruit bat is capable of more widespread mixing across the continent than was previously appreciated, researchers reported, though island populations of E. helvum appear to remain relatively genetically distinct.

From antibodies and DNA sequences detected in the bat's blood and pooled urine samples, meanwhile, they picked up signs of widespread straw-colored fruit bat exposure to the Lagos bat virus and henipaviruses in Africa. In contrast to the bat mating patterns, such viral exposures stretched to remote island locales too, the study's authors noted, hinting that "factors other than population size and connectivity may be responsible for viral persistence."

"Understanding the viral persistence and the potential for [zoonotic virus] spillover in African bat populations in the face of extensive hunting, logging, and human population growth is of central importance for both public health and conservation," they concluded, "especially as these processes can be expected to increase over time."

Members of the Clarification of Optimal Anticoagulation through Genetics, or COAG, consortium published a New England Journal of Medicine study assessing the value of using CYP2C9 and VKORC1 genotypes in warfarin dosing schemes.

The researchers enrolled 1,015 patients in the study. For the first five days of treatment with the anticoagulant, those patients were randomly assigned to groups receiving warfarin doses decided with an algorithm informed by genotype data or with a clinically guided algorithm.

The team then tracked the percentage of time that each individual received a warfarin dose that was within the appropriate therapeutic range over the course of four weeks. In the genotype-guided group, patients spent 45.2 percent of the time in the therapeutic range, on the mean, compared to 45.4 percent in the group dosed using the clinically guided algorithm.

Along with a lack of improved dosing with the inclusion of genotyping data, the researchers saw that African American patients were especially unlikely to remain in the proper therapeutic range — and took longer to get there — when given warfarin based on a genotype-guided algorithm rather than clinically guided doses of the blood clot drug.

In Cell, researchers from the University of Iceland and elsewhere outlined the role of a non-protein-coding variant associated with a particular pigmentation pattern and propensity for freckles. The work followed from past genome-wide association studies fingering variants in and around the inferon regulatory factor 4, or IRF4, transcription factor gene in pigmentation, hair, and eye color.

The team began by fine-mapping the IRF4 locus with the help of whole-genome sequence data on 2,230 individuals from Iceland. The search led to some 16,280 variants in the vicinity of IRF4, which were subsequently screened in 95,085 genotyped Icleanders.

Among them was a SNP in an IRF4 intron that was found at higher-than-usual frequency in individuals with brown hair, blue eyes, pale skin, and freckles, researchers reported. Their results suggest that that SNP falls within an enhancer sequence influencing IRF4 expression.

Moreover, the team's follow-up experiments in zebrafish and mouse models suggest that the presence of the freckle- and pigmentation-associated allele alters the way that the IRF4 enhancer sequence interacts with another transcription factor, TFAP2A, and with a previously identified melanocyte-related regulatory gene called MITF. That, in turn, appears to change the combined action of IRF4 and MITF on a pathway containing a tyrosinase enzyme needed for melanin synthesis.

"Genome-wide association studies are uncovering many genomic variants that are associated with human traits and most of them are found in non-protein-coding regions of the genome," the National Human Genome Research Institute's William Pavan, a co-author on the study, said in a statement.

"Exploring the biological pathways and molecular mechanisms that involve variants in these under-explored portions of the genome is a challenging part of our work," Pavan said. "This is one of a few cases where scientists have been able to associate a variant in a non-coding genomic region with a functional mechanism."