Volume 47 Issue 6, June 2015

A new study identifies PDE3A mutations as the cause of brachydactyly type E with hypertension. These mutations alter PDE3A activity by uncovering cryptic sites for phosphorylation by PKA and PKC, leading to enzyme hyperactivation that abnormally lowers cAMP levels.

The genetic drivers of osteosarcoma have been difficult to identify because of the genomic complexity consistently encountered in cancer cells at diagnosis. A new study uses Sleeping Beauty transposon mutagenesis to drive osteosarcomagenesis in the mouse and identify likely drivers of the disease in humans.

A new large-scale study reports the whole-genome sequences of nearly 2,000 Salmonella enterica serovar Typhi (S. Typhi) strains collected from 63 countries. A recent and dominant multidrug-resistant (MDR) lineage originating from South Asia, which is supplanting a bulk of ancestral drug-sensitive strains, is identified; the success of this lineage is likely driven by plasmid acquisitions and the chromosomal integration of resistance-conferring genes.

Olga Troyanskaya and colleagues present genome-wide functional interaction networks for 144 human tissues and cell types. They identify important disease-gene associations by combining data from GWAS and tissue-specific networks. They also developed a webserver, GIANT, that includes multi-gene query capability, network visualization and analysis tools.

Cisca Wijmenga and colleagues report fine mapping of the association signal in the MHC region in individuals with celiac disease. They identify five additional risk factors that are independent of HLA-DQ alleles and that account for 18% of the genetic risk for this disease.

Jean-Luc Battini, Giovanni Coppola and colleagues identify XPR1 mutations in several families with primary brain calcification. They further show that these mutations alter phosphate export activity, implicating defective phosphate homeostasis in the etiology of this disease.

Evan Eichler and colleagues analyze the relative impact of de novo and rare, inherited variants on autism risk. They show a statistically independent role for rare, inherited mutations and implicate several new candidate genes likely contributing to autism risk.

Samuli Ripatti and colleagues report the results of a genome-wide association study for circulating lipid levels based on 1000 Genomes Project imputation. Their results implicate several new loci, refine the association signals at many established loci and highlight the impact of low-frequency variants on lipid traits.

Nicholas Luscombe, Cameron Osborne and colleagues report the use of Capture Hi-C (CHi-C) to detect the long-range interactions of almost 22,000 promoters in 2 human cell types. They found that transcriptionally inactive genes interact with previously uncharacterized elements that may act as long-range silencers.

William Evans and colleagues find that the proinflammatory genes CASP1 and NLRP3 are expressed at higher levels in primary acute lymphoblastic leukemia cells that are resistant than in those that are sensitive to glucocorticoid treatment. They find that CASP1 mediates glucocorticoid resistance through cleavage of the glucocorticoid receptor.

Branden Moriarity, David Largaespada and colleagues report a Sleeping Beauty forward genetic screen in mice that identifies candidate genes and pathways for osteosarcoma tumor development and progression. They identify sites specifically associated with tumorigenesis and metastasis and find that several candidate oncogenes are involved in axon guidance.

Bin Han and colleagues report the draft genome sequence of the grass carp Ctenopharyngodon idellus, a major commercially farmed species of freshwater fish. Analyses of the grass carp genome identify lineage-specific duplications that may have contributed to the adaptation of this species to a vegetarian diet.

Vanessa Wong and colleagues report whole-genome sequencing of 1,832 Salmonella enterica serovar Typhi isolates from 63 endemic countries. They identify mutations that define the multidrug resistant (MDR) H58 lineage and report numerous inter- and intracontinental transmissions of this lineage as well as an ongoing MDR typhoid epidemic in Africa.

Eric Boerwinkle and colleagues carried out exome sequencing on 8,554 individuals and tested loss-of-function variants for association with 20 phenotypes related to common chronic diseases. They identified several new associations and illustrate the value of applying exome sequencing to a large sample of deeply phenotyped individuals.

Mohammad Akbari and colleagues report that rare truncating mutations in RECQL are associated with breast cancer susceptibility. RECQL encodes a helicase that helps prevent double-stranded DNA breaks by stabilizing stalled or regressed replication forks.

Friedrich Luft and colleagues identify missense mutations in PDE3A in six unrelated families with an autosomal dominant syndrome marked by severe hypertension and brachydactyly. They further show that the mutations result in gain of enzymatic function, leading to increased vascular smooth muscle cell proliferation and vessel wall hyperplasia.

Anthony Shum, Jordan Orange, James Lupski and colleagues show that mutations in the coatamer subunit gene COPA cause an autoimmune syndrome characterized by inflammatory arthritis and interstitial lung disease. They further show that the mutations disrupt ER-Golgi transport, leading to ER stress and altered T cell function.

Kerstin Kutsche, Marco Tartaglia and colleagues show that missense mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome, a disorder characterized by facial dysmorphism, intellectual disability, digit anomalies and hypertrichosis. Functional studies indicate that the KCNH1 mutations lead to altered channel activity.

Roland Kuiper and colleagues identify a homozygous germline nonsense mutation in the base-excision repair gene NTHL1 in three families with recessive inheritance of adenomatous polyposis.

Kajsa Paulsson and colleagues performed whole-genome and/or whole-exome sequencing of 51 cases of high hyperdiploid pediatric acute lymphoblastic leukemia, which is characterized by a massive nonrandom gain of chromosomes. They found that high hyperdiploidy arose early during leukemogenesis and was the main leukemogenic event.

Sarah Fortune, Meindert Lamers and colleagues show that, unlike Escherichia coli, Mycobacterium tuberculosis uses an exonuclease domain in polymerase DnaE1 to proofread DNA replication. Importantly, this proofreading mechanism renders mycobacteria sensitive to nucleoside analogs, a class of small molecules used to treat viral infections and cancer.

Gil McVean, Alexander Dilthey and colleagues present a graphical model-based method for accurate genomic assembly that uses the diversity present in multiple reference sequences, as represented by a population reference graph. The method is applied to simulated and empirical data from the human MHC region to demonstrate the improved accuracy of genomic inference.