Volume 41 Issue 4, April 2009

Myeloproliferative neoplasms are hematological malignancies frequently associated with somatically acquired mutation of the JAK2 gene. A new study shows that these mutations are preferentially found within a particular inherited JAK2 haplotype, implying the existence of a strong, but uncharacterized, interaction between somatic and germline genetics at this locus.

The small liver peptide hepcidin is a major regulator of systemic iron homeostasis in mammals, adapting iron absorption to the body's demands. Two new studies now identify BMP6 as the key endogenous regulator of hepcidin.

Prolongation of the electrocardiographic QT interval, a measure of cardiac repolarization, is associated with arrhythmogenic disorders and is a risk factor for sudden cardiac death. Two genome-wide association studies (GWAS) of variation in the QT interval in population-based cohorts now report association with variants in a subset of ion channel genes and other new associations.

John Stamatoyannopoulos, Shamil Sunyaev and colleagues report a correlation between mutation rate and replication timing in the human genome, observing an increased mutation rate in later-replicating regions.

Stefan Schulte-Merker and colleagues report that ccbe1, a predicted secreted protein, is required for embryonic lymphangiogenesis in zebrafish. Ccbe1 acts at the same stage as Vegfc, and is required for lymphangioblast budding and angiogenic sprouting from the venous endothelium.

Christopher Newton-Cheh and colleagues from the QTGEN consortium report genetic associations to the QT interval duration, a measure of cardiac repolarization which is a risk factor for sudden cardiac death, in three genome-wide association studies from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study.

Arne Pfeufer, Aravinda Chakravarti and colleagues from the QTSCD consortium report genetic associations influencing the QT interval duration, a measure of cardiac repolarization which is a risk factor for sudden cardiac death, in five genome-wide association studies.

Thomas Drake and colleagues report the results of knockout or transgene introduction for nine obesity candidate genes in mice. Eight of the nine mutations result in significant changes in obesity-related traits, validating their previously developed approach for identifying candidate genes involved in particular phenotypes. They further identify related metabolic pathways that are altered by manipulation of the eight genes.

Alexandre Reymond, Henrik Kaessman and colleagues report a high-resolution survey of copy number variation in mice and assess the impact of such variation on gene expression across multiple tissues and strains. They conclude that CNVs substantially influence global transcription, including long-range cis effects extending up to several hundred kilobases.

Timothy Graubert and colleagues report a high-resolution survey of copy number variation in mouse inbred strains and assess the impact of such variation on gene expression. They find that up to 26% of strain-dependent expression variation in hematopoietic stem/progenitor cells is associated with copy number variation.

Eran Segal and colleagues report that promoters driving expression of cellular respiration genes in aerobic yeast species encode relatively open chromatin, whereas promoters associated with the same genes in anaerobic yeast species encode relatively closed chromatin. These results suggest that phenotypic diversity may in part be influenced by changes in the DNA-encoded nucleosome organization of promoters.

Nick Cross and colleagues report that the JAK2^V617F somatic mutation that drives the development of chronic myeloproliferative neoplasms is associated with the presence of a specific inherited haplotype in JAK2.

Robert Kralovics and colleagues report that the JAK2^V617F somatic mutation that drives the development of chronic myeloproliferative neoplasms is associated with the presence of a specific inherited haplotype in JAK2.

Ross Levine and colleagues report that the JAK2^V617F somatic mutation that drives the development of chronic myeloproliferative neoplasms is associated with the presence of a specific inherited SNP in JAK2.

Julius Gudmundsson and colleagues report the association of two SNPs on chromosomes 9 and 14 with thyroid cancer in European populations. The variants are near FOXE1 and NKX2-1, both good biological candidates, and individuals who are homozygous for both risk variants have a 5.7-fold greater risk of thyroid cancer.

Michael Taylor and colleagues identify copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, indicating that defective control of the histone code contributes to the pathogenesis of medulloblastoma.

Elisabeth Mangold and colleagues carried out a genome-wide association study for nonsyndromic cleft lip with or without cleft palate, and report a locus on 8q24.21 that is strongly associated with this phenotype.

Marie-Paule Roth and colleagues report that targeted disruption of Bmp6 in mice leads to a rapid and massive accumulation of iron in several tissues, showing that it is critical for iron homeostasis.

Jodie Babitt and colleagues report that Bmp6-null mice have a phenotype that resembles hereditary hemochromatosis, with increased serum iron concentration and tissue iron overload. Administration of Bmp6 increases hepcidin expression and reduces serum iron, suggesting that Bmp6 is a key endogenous regulator or iron metabolism in vivo

Wei Yan and colleagues report that many X-linked microRNAs escape meiotic sex chromosome inactivation (MSCI) during spermatogenesis. The authors speculate that such miRNAs may contribute to the process of MSCI or may regulate autosomal mRNAs during the latter stages of meiosis.

Xiangdong Fu and colleagues report characterization of a major rice grain yield QTL at the DEP1 locus.

Jung Kyoon Choi and Young-Joon Kim analyze published genome-wide datasets and show that a nucleosome is commonly positioned at a critical gene regulatory region flanking promoters that respond variably to external signals. The preference for nucleosome binding at this position is encoded by the DNA sequence itself.