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Genomics in the Journals: Aug 14, 2014

NEW YORK (GenomeWeb) – In Nature Genetics, researchers from Korea, Singapore, and the US described alterations in a gene called NUDT15 that seem to influence the risk of developing a condition called leukopenia — characterized by a potentially life-threatening drop in white blood cell count — in individuals with Crohn's disease who've been treated with thiopurine drugs.

Using array-based genotyping profiles for 340 Korean individuals with Crohn's disease — including 33 individuals who'd experienced thiopurine-related leukopenia and 307 who had not — the team identified four variants with potential ties to the adverse treatment outcome.

With the help of additional SNPs identified through imputation, researchers found four more sites in the genome that appeared to coincide with leukopenia risk in Crohn's patients taking thiopurine drugs.

Within the full risk locus set, the team noted that a chromosome 13 site in and around NUDT15 showed the most pronounced association with thiopurine-related leukopenia risk. And through follow-up testing on another 33 Crohn's patients with early leukopenia and 325 unaffected controls, it verified thiopurine-related leukopenia associations for one SNP in particular at this site.

That variant, which fell in NUDT15, was subsequently linked to late leukopenia as well as leukopenia occurring in European Crohn's patients treated with thiopurine, though the associated variant appeared to be found with far lower frequency in individuals of European descent.


A Danish- and American-led team used a genome-wide association study to track down variants contributing to a congenital condition in males known as hypospadias — work they presented in another Nature Genetics paper.

Starting with genotyping profiles for more than 1,000 Danish individuals with hypospadias and almost 5,500 without, the researchers searched for variants that were especially common in individuals with hypospadias, which is characterized by the presence of a urethral opening under the penis.

The team then took the top four-dozen SNPs forward for replication testing in nearly 2,000 more Danish, Dutch, or Swedish individuals with hypospadias and more than 1,800 controls from the same populations.

Following this validation stage of the study, the researchers were left with 18 hypospadias-associated regions that tended to fall in and around genes such as HOXA4, IRX5, and IRX6 that are known for their roles in embryonic development.

Moreover, they determined that some of the same genes implicated in the GWAS showed enhanced expression in foreskin tissue samples tested for subsequent stages of the study, supporting the notion that they may have hypospadias-related functions.


Microbial communities in the human gut develop after birth through a series of transitions partly influenced by an infant's gestational age, according to a study in the Proceedings of the National Academy of Sciences.

Washington University researchers used 16S ribosomal RNA gene sequencing on stool DNA to identify members of microbial communities found in the guts of 58 infants born prematurely.

By comparing the microbial make-up in more than 900 stool samples collected from the infants over time, the study's authors saw a "choreographed succession" of microbes in the infant gut.

In particular, they noted that bacteria from Bacilli classes tended to give way to bugs from Gammaproteobacteria and then Clostridia classes, arriving at gut microbial communities that are largely comprised of anaerobic microbes within 33 to 36 weeks after conception.

"Sometimes the abrupt changes [in bacterial community composition] were in the same direction as the overall progression, and at other times they weren't," noted Washington University's Phillip Tarr, a co-corresponding author on the study.

Despite that type of unpredictability, though, he explained that the overall population proportion ultimately shifted so that bacteria from the three main bacterial classes were represented at each stage of the microbiome progression.

Factors such as antibiotic exposure, mode of delivery, and foods consumed had relatively modest impacts on the microbial community members found in the infants' guts, he and his colleagues noted, though the speed of gut microbial change appeared to be influenced by gestational age.


A Cell study illustrated the power of compressing molecular networks to focus in on core biological functions of interest within the network and gain clues about the function of poorly characterized genes or proteins.

Researchers from the Baylor College of Medicine and other centers in the US demonstrated that biological networks composed of information from hundreds of genomes can be compressed by removing redundant relationships to get at core features of interest.

Specifically, the team took a compression network-based look at so-called "supergenomic" information in the malaria-causing parasite Plasmodium falciparum. By identifying clusters of orthologous groups of proteins, or COGs, from 373 genomes and weeding out redundant information in these network members, it established a more complete functional understanding for the P. falciparum antigen EXP1.

The investigators' results indicated that the protein acts as an enzyme on the P. falciparum membrane, helping to degrade a cytotoxic compound called hematin that gets produced during the parasite's infection of host blood. That, in turn, suggested that EXP1 is likely susceptible to a malaria treatment called artesunate, which is known to act on related metabolic processes.

The Scan

Ancient Greek Army Ancestry Highlights Mercenary Role in Historical Migrations

By profiling genomic patterns in 5th century samples from in and around Himera, researchers saw diverse ancestry in Greek army representatives in the region, as they report in PNAS.

Estonian Biobank Team Digs into Results Return Strategies, Experiences

Researchers in the European Journal of Human Genetics outline a procedure developed for individual return of results for the population biobank, along with participant experiences conveyed in survey data.

Rare Recessive Disease Insights Found in Individual Genomes

Researchers predict in Genome Medicine cross-population deletions and autosomal recessive disease impacts by analyzing recurrent nonallelic homologous recombination-related deletions.

Genetic Tests Lead to Potential Prognostic Variants in Dutch Children With Dilated Cardiomyopathy

Researchers in Circulation: Genomic and Precision Medicine found that the presence of pathogenic or likely pathogenic variants was linked to increased risk of death and poorer outcomes in children with pediatric dilated cardiomyopathy.