Volume 44 Issue 1, January 2012

Recent studies, including two in this issue, report heterozygous missense mutations in the U2AF1 and SF3B1 genes that encode spliceosome subunits. U2AF1 is frequently mutated in myeloid hematopoietic malignancies, especially in myelodysplastic syndrome (MDS), and SF3B1 is frequently mutated in both MDS and chronic lymphocytic leukemia (CLL).

A new study reports the development of the 'morbidostat', a device that allows for continuous culture of bacteria under a constant drug selection pressure using computer feedback control of antibiotic concentration. This device, together with bacterial whole-genome sequencing, allowed the authors to follow the evolution of resistance-conferring mutations in Escherichia coli populations in real time, providing support for deterministic evolution of resistance in some situations.

DNA methylation is an epigenetic mark stably directing gene expression throughout development. A new study uncovers a role for the DNA methyltransferase Dnmt3a in silencing self-renewal genes in hematopoietic stem cells (HSCs) to permit efficient hematopoietic differentiation.

Huanming Yang, Zhiming Cai, Jun Wang and colleagues report whole-exome sequencing of 10 clear cell renal cell carcinomas followed by a screen of ~1,100 genes in a total of 98 tumors. They found 12 new disease-associated genes and detected frequent alterations in the ubiquitin-mediated proteolysis pathway.

Andrew Hattersley and colleagues report an exome sequencing study that identifies de novo heterozygous inactivating mutations in GATA6 as a common cause of pancreatic agenesis. This suggests an essential function for GATA6 in human pancreas development.

Margaret Goodell, Wei Li and colleagues report conditional ablation of the Dnmt3a DNA methyltransferase in hematopoietic stem cells (HSCs) in mice. They show that Dnmt3a is critical for epigenetic silencing of HSC regulatory genes and for HSC differentiation.

Bin Han and colleagues report low-coverage sequencing for 950 diverse rice accessions. They develop a framework for haplotype-based de novo assembly, phenotyped the 950 lines for 11 agronomic traits and used this information to conduct genome-wide association studies. They identify 32 new loci associated with these traits.

Peter Laird and colleagues performed whole-genome bisulfite sequencing in a human colorectal tumor and a matched normal sample. They find regions of methylation variation that coincide with domains associated with the nuclear lamina.

Carlos López-Otín, Elías Campo and colleagues report exome sequencing of tumor and normal samples from 105 individuals with chronic lymphocytic leukemia (CLL). They identify 1,246 somatic mutations predicted to affect gene function and 78 genes with recurrent predicted functional mutations. They find recurrent mutations in the gene encoding the SF3B1 splicing factor, which was mutated in 10% of the CLL samples.

Matthew Walter and colleagues report the whole-genome sequencing of a secondary acute myeloid leukemia sample and a matched normal tissue sample. Further analysis of additional subjects identified recurrent mutations in U2AF1 in 13/150 (8.7%) individuals with myelodysplastic syndrome.

Richard Houlston, Gareth Morgan, Kari Hemminki and colleagues report the results of a genome-wide association study of multiple myeloma. They identify two regions influencing susceptibility to this hematological malignancy.

Dongxin Lin and colleagues report a genome-wide association study for pancreatic cancer in Chinese populations. The authors identify five new genetic loci associated with risk of pancreatic cancer.

Yoon Shin Cho, Mark Seielstad and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes in individuals of east Asian ancestry. They identify eight new loci associated with type 2 diabetes.

Jieruo Gu, Jianjun Liu and colleagues report the results of a genome-wide association study of ankylosing spondylitis in Han Chinese. They identify two new susceptibility loci for this inflammatory disease and confirm strong associations with variants in the HLA-B region.

Hakon Hakonarson and colleagues report a genome-wide copy number variation study in 3,506 cases of attention-deficit hyperactivity disorder. The authors identify a statistically significant enrichment of CNVs impacting metabotropic glutamate receptor genes.

Valérie Cormier-Daire and colleagues report the identification of mutations in SMAD4 that cause Myhre syndrome, a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. All of the mutations alter a single codon in the Mad Homology 2 domain of SMAD4.

Len Pennacchio, Axel Visel and colleagues use an epigenomic approach to identify a large number of candidate enhancers from human heart tissue. This work will facilitate further studies into the role of enhancers in human cardiac development and disease.

Dirk Schübeler, Michael Stadler and colleagues show that the c-Jun NH₂-terminal kinase (JNK) binds directly to active promoters during the differentiation of stem cells to neurons and targets histone H3 serine 10 for phosphorylation.

Roy Kishony and colleagues develop a device for the continuous culture of bacterial populations under constant antibiotic selection pressure. They use this morbidostat, together with whole-genome sequencing of E. coli strains, to follow evolutionary paths leading to high levels of resistance to three individual drugs.

Sebastien Gagneux and colleagues identify a set of compensatory mutations in the RNA polymerase of rifampicin-resistant M. tuberculosis by comparing the whole-genome sequences of ten paired clinical isolates and strains evolved in vitro. These mutations are associated with high competitive fitness in vitro and occur with increased clinical frequency in affected populations with a high burden of drug-resistant tuberculosis.