Volume 44 Issue 7, July 2012

Three new studies report large-scale resequencing and comparative genomic analysis of diverse maize varieties. The authors conducted a comprehensive characterization of sequence variation in maize genomes and identified signals of selection in maize domestication and breeding.

A new study shows that alteration of poly(dA:dT) tracts in promoters offers a broadly applicable genetic mechanism for predictably tuning gene expression with high resolution. By systematically manipulating these tracts in a controlled yeast system, the authors demonstrate quantitative mechanistic relationships linking regulatory DNA sequences, nucleosome occupancy, transcription factor binding and gene expression.

Loss-of-function mutations in the gene encoding the cyclin-dependent kinase inhibitor CDKN1C cause Beckwith-Wiedemann syndrome and cancer. A new study now identifies potentially gain-of-function missense mutations in CDKN1C that cause the undergrowth-associated IMAGe syndrome.

Adrian Clark and colleagues report mutations in the NNT gene encoding nicotinamide nucleotide transhydrogenase in familial glucocorticoid deficiency (FGD).

Eran Segal and colleagues measure the promoter activities of 70 different constructed promoter variants and find that poly(dA:dT) tracts significantly affect transcriptional outcome. They suggest that this is mediated by altering nucleosome organization and that these sequences can be manipulated to fine tune regulation of gene expression.

James Brugarolas and colleagues identify recurrent BAP1 mutations in clear cell renal cell carcinoma (ccRCC). They show that BAP1 binds to HCF-1 and suppresses cell proliferation, and they find that BAP1 loss is associated with high tumor grade.

Hidewaki Nakagawa and colleagues report the whole-genome sequencing of 27 hepatocellular carcinomas. They find that chromatin regulators were mutated in approximately 50% of tumors.

John Luk and colleagues report the sequencing of 81 hepatitis B virus (HBV)-positive and 7 HBV-negative hepatocellular carcinomas and matched normal tissues. They confirm recurrent integration events of HBV at TERT and MLL4 and report recurrent events at the CCNE1 gene.

Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. They report three loci newly associated with colorectal cancer, bringing the total number of common susceptibility loci to 20.

Arn van den Maagdenberg and colleagues report a genome-wide association analysis for migraine without aura, the most common form of migraine. They identify two loci that are newly associated with migraine without aura.

Christian Hafner and colleagues identify postzygotic HRAS and KRAS mutations as the cause of nevus sebaceous and Schimmelpenning syndrome. Their functional studies suggest that the HRAS p.Gly13Arg alteration, found in 91% of lesions, results in activation of the MAPK and PI3K-Akt signaling pathways.

Eric Vilain and colleagues identify missense mutations in the imprinted gene CDKN1C, encoding the p57KIP2 cyclin dependent kinase inhibitor, in individuals with IMAGe syndrome. IMAGe syndrome is a developmental disorder characterized by intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies.

Edwin Cuppen, Gijs van Haaften and colleagues report the identification of mutations in ABCC9 in individuals with Cantú syndrome, which is characterized by congenital hypertrichosis, distinctive facial features, cardiomegaly and osteochondrodyplasia. ABCC9 encodes an ATP-dependent potassium channel.

Ron Wevers, Saskia Wortmann and colleagues show that mutations in SERAC1 cause a recessive syndrome characterized by deafness, encephalopathy, progressive spasticity and dystonia. Their findings suggest a role for SERAC1 in phosphatidylglycerol remodeling and intracellular cholesterol trafficking.

The nucleotide diversity present in maize exceeds that in humans by an order of magnitude, and it has been challenging to characterize the high levels of diversity in this important crop. Doreen Ware and colleagues have identified 55 million SNPs in 103 domesticated and pre-domestication Zea mays varieties, as well as in a representative from the sister genus Tripsacum.

Jeff Ross-Ibarra and colleagues report a population genomic analysis of maize evolution. They analyze genome-wide evidence for selection during the initial domestication of wild maize and during the improvement of landraces to modern inbred breeds. Their findings suggest stronger selection during domestication compared to improvement.

Jinsheng Lai and colleagues report the resequencing of 278 inbred maize lines and perform a genome-wide analysis of genetic changes during modern breeding. Using SNP imputation, the authors also perform a genome-wide association study for cob color, silk color and date to anthesis. The authors identified association signals with significant P values near known targets.

Alan Lloyd and colleagues report the mapping of a gene encoding a novel cytochrome P450, CYP76AD1, to the classic R locus in beet that is responsible for red versus yellow pigment.

Matthew Stephens and Xiang Zhou report an efficient exact method for accounting for population stratification and relatedness in genome-wide association analyses. Their method, genome-wide efficient mixed-model association (GEMMA) is implemented in freely available software.

Magnus Nordborg and colleagues report a multi-locus mixed-model method (MLMM) for genome-wide association studies in structured populations. Their simulations show that MLMM offers increased power and a reduced false discovery rate, and applications to both human and Arabidopsis thaliana data sets identify new associations and allelic heterogeneity.