Volume 42 Issue 1, January 2010

Massively parallel sequencing of the exomes of four individuals with Miller syndrome, combined with filtering to exclude benign and unrelated variants, has identified causative mutations in DHODH. This approach will accelerate discovery of the genetic bases of hundreds of other rare mendelian disorders.

Two studies report genome-wide association studies for lung function, using cross-sectional spirometric measurements in healthy individuals. They identify six genetic loci newly associated to natural variation in lung function, which may have implications for the related airway diseases of asthma and chronic obstructive pulmonary disease.

A new study provides compelling evidence that transcriptional regulation and three-dimensional genomic architecture are linked. The alpha- and beta-globin loci associate with hundreds of active genes across the genome at transcription factories in erythroid cells, and specialized Klf1-containing transcription factories mediate the association of Klf1-regulated genes.

David Hinds and colleagues report that a non-synonymous variant in PNPLA3 is associated with alcoholic liver disease and liver cirrhosis. This result follows previously reported associations of this variant with nonalcoholic fatty liver disease.

Elisabeth Mangold and colleagues report a genome-wide association study for non-syndromic cleft lip with or without cleft palate.

Martin Zenker, Marco Tartaglia, Reza Ahmadian and colleagues report the identification of a restricted spectrum of NRAS mutations in individuals with Noonan syndrome. Functional testing revealed that the mutations confer enhanced stimulus-dependent MAPK activation.

Michael Bamshad, Jay Shendure and colleagues report the first application of exome resequencing to identify the cause of a mendelian disorder. They sequenced the exomes of four individuals with Miller syndrome in three independent families and identify mutations in DHODH, a key enzyme in the pyrimidine de novo biosynthesis pathway, as causal for the disorder.

Martin Tobin and colleagues present genome-wide association studies for pulmonary function as part of the SpiroMeta consortium.

Stephanie London and colleagues from the CHARGE Consortium report genome-wide association studies for pulmonary function.

Peter Fraser and colleagues report a genome-wide analysis of transcription interactions involving the globin genes in mouse erythroid cells. They demonstrate that the transcription factor Klf1 mediates preferential co-associations between genes it regulates.

Greg Gibson and colleagues report an analysis of gene expression variation in relation to environmental geography and ethnicity in blood leukocyte samples from individuals in rural and urban southern Morocco. The study determined the contributions of geography and ethnicity to associations between genotypes and transcript abundance.

Chris Wallace and colleagues report the identification of a new locus on chromosome 14q32.3 that alters susceptibility to type 1 diabetes with a parent-of-origin effect. The region contains imprinted genes including DLK1 and MEG3.

Martin Pollak and colleagues show that missense mutations in the diaphanous inhibitory domain of INF2 cause focal segmental glomerular sclerosis. INF2 encodes a member of the formin family of actin-regulating proteins, highlighting an important role for actin dynamics in podocyte function.

Germline mutations in PARK2 are a well-known cause of the neurodegenerative disorder Parkinson's disease. Here, Timothy Chan and colleagues report somatic mutations and intragenic deletions of PARK2 in glioblastoma, colon cancer and lung cancer.

Liang Zhu and colleagues report that inactivation of Skp2, a target of the pRb tumor suppressor, completely prevented tumorigenesis in tumor-prone mice with loss of one Rb1 allele. This work nominates Skp2 as a drug target to combat Rb1-deficient tumors.

Nicholas Hastie and colleagues show that Wt1 is required for the epithelial-to-mesenchymal (EMT) transition in the developing epicardium and the formation of mesenchymal cardiovascular progenitors. Wt1 directly regulates the transcription of Snail and E-cadherin, two well-known mediators of EMT.