Articles in 2012

Yinghao Sun and colleagues report a genome-wide association study for prostate cancer in Han Chinese men. They identify two new risk-associated loci at chromosomes 9q31 and 19q13.

Zubair Ahmed and colleagues identify homozygous mutations in CIB2, a gene that encodes a calcium- and integrin-binding protein, that cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. CIB2 is required for hair cell development and retinal photoreceptor cells in zebrafish and Drosophila melanogaster.

Harry Dietz and colleagues report the identification of mutations in SKI in Shprintzen-Goldberg syndrome, which shares features with Marfan syndrome and Loeys-Dietz syndrome. SKI encodes a known repressor of TGF-β activity, and this work provides evidence for paradoxical increased TGF-β signaling as the mechanism underlying these related syndromes.

Gordon Dougan and colleagues report whole-genome sequencing of a global collection of 179 Salmonella Typhimurium isolates, including 129 diverse sub-Saharan African isolates associated with invasive disease. They determine the phylogenetic structure of invasive Salmonella Typhimurium in sub-Saharan Africa and find that the majority are from two closely related highly conserved lineages, which emerged in the last 60 years in close temporal association with the current HIV epidemic.

Christopher Walsh and colleagues identify mutations in CHMP1A in human cerebellar hypoplasia and microcephaly. Cells lacking CHMP1A show decreased cell proliferation and decreased expression of BMI1, a negative regulator of stem cell proliferation.

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A new exome sequencing study of individuals with hepatocellular carcinoma (HCC) reveals imprints of mutagenic exposure and identifies new genes contributing to tumorigenesis. This work joins several recent publications reporting whole-genome, exome and RNA sequencing in HCC, which together provide a comprehensive genomic landscape and new insights into the etiology of liver cancer.

Gene expression is under partial genetic regulation, which may vary between different cell types and tissues. A new study finds that there is substantial but incomplete overlap among regulatory variants located near the regulated genes in three human tissues.

Genomic characterization efforts in small-cell lung cancer have been complicated by the paucity of high-quality surgical resection specimens for this aggressive lung cancer subtype that is usually diagnosed at unresectable stages in small biopsies or cytology specimens. Now, two papers report genomic analyses of small-cell lung cancer, highlighting subsets of tumors driven by amplification of FGFR1, SOX2 or MYC family members or by a MYCL1 fusion oncogene, among many other recurrent alterations.

Ross Levine, Lambert Busque and colleagues report the identification of recurrent somatic mutations in TET2 in elderly female individuals with clonal hematopoiesis. The mutations were identified in individuals without clinically apparent hematological malignancies.

Nick Orr and colleagues report a genome-wide association study for male breast cancer. They identify a new susceptibility locus at RAD51B and examine association evidence for known female breast cancer loci in these cohorts.

Yanick Crow and colleagues show that mutations in ADAR1 cause the autoimmune disorder Aicardi-Goutières syndrome, accompanied by upregulation of interferon-stimulated genes. ADAR1 encodes an enzyme that catalyzes the deamination of adeonosine to inosine in double-stranded RNA, and the findings suggest a possible role for RNA editing in limiting the accumulation of repeat-derived RNA species.

Mathieu Lupien, Jason Moore and colleagues show that breast cancer risk–associated SNPs commonly disrupt the binding of FOXA1 to chromatin, thereby directly affecting gene expression.

Evan Eichler and colleagues report an estimate of the mutation rate in humans that is based on the whole-genome sequences of five parent-offspring trios from a Hutterite population and genotyping data from an extended pedigree. They use a new approach for estimating the mutation rate over multiple generations that takes into account the extensive autozygosity in this founder population.

Yurii Aulchenko and colleagues report a variance components–based method, GRAMMAR-Gamma, for genome-wide association studies including a large number of individuals and genetic markers. They demonstrate, using simulations as well as human and Arabidopsis thaliana data sets, that their method provides unbiased estimates of SNP effect and increases computational efficiency, which may facilitate analysis of human whole-genome resequencing studies.