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Familiarity with developments in all areas of genetics—from the trained intuition of dysmorphology to algorithms for SNP calling in next-generation sequencing—is extraordinarily productive in research and clinical translation. Actively organized conferences modeled on the recent European Society of Human Genetics (ESHG) meeting in Nuremberg go a long way in preparing the field for future success.
A combination of in vitro and in vivo models with validation in human tumors has identified AXL activation as a new mechanism of acquired resistance to EGFR inhibitors in non–small cell lung cancer. The identification of this mechanism, alongside the current development of specific AXL inhibitors, provides the rationale for further studies that may improve treatment for EGFR inhibitor–resistant patients.
Two new studies report mutations in FAN1 and three other genome-stability genes that tie the DNA damage response to progressive kidney failure and the dysfunction of several other organs. These findings provide clues to the underlying causes of tissue decline and may add a series of genes to the growing list of genome maintenance factors that protect against premature aging.
Two new studies show that haploinsufficiency for TGFB2 causes a familial syndrome of thoracic aortic aneurysms and dissections with other clinical features that overlap the Marfan, Loeys-Dietz spectrum of syndromes. Their finding of loss-of-function mutations in yet another transforming growth factor (TGF)-β pathway gene reinforces the seeming paradox of observed increases in the downstream TGF-β signaling pathway.
Peter Donnelly and colleagues report an analysis considering the inclusion of non-confounding covariates within genome-wide association studies and provide software that can be used to assess the impact on power within a particular study. They find that, when the disease prevalence is low, including known covariates, such as sex or established genetic associations, can reduce the power to detect new associations.
Trever Bivona and colleagues identify the upregulation of the AXL kinase in human non–small cell lung cancer with acquired resistance to erlotinib. Inhibition of AXL restores sensitivity to erlotinib in in vitro and in vivo tumor models. The authors suggest AXL as a potential therapeutic target that may prevent or overcome acquired resistance in patients with EGFR-mutant lung cancer.
Shaoguang Li and colleagues show that the Blk pathway functions as a tumor suppressor in cancer stem cells of chronic myeloid leukemia but has no effect on normal hematopoietic stem cells. These results support the feasibility of selectively targeting leukemic stem cells without harming the normal stem cell compartment.
Evan Eichler and colleagues explore the structural diversity and ancestral origins of the 17q21.31 inversion region. They find that complex duplication architectures have arisen independently on both inversion haplotypes and have recently reached high frequencies among Europeans, either through extraordinary genetic drift or selective sweeps.
Steven McCarroll and colleagues use a population genetics approach to identify nine different structural forms of the 17q21.31 inversion region. They show that duplications have arisen independently on both ancestral forms of the inversion and have reached high frequencies in Europeans.
Michael Bamshad and colleagues report an exome sequencing study of extreme phenotypes to identify genetic variants that modify the risk for chronic Pseudomonas aeruginosa airway infection in individuals with cystic fibrosis.
Dongfeng Gu and colleagues report a genome-wide association study for coronary artery disease in Han Chinese individuals. They identify four loci newly associated with coronary artery disease.
Hongbing Shen and colleagues identify three new susceptibility loci for lung cancer in the Chinese population. Their follow-up analyses suggest that two of these loci interact multiplicatively with smoking dose to influence lung cancer risk.
Takashi Kohno and colleagues identify two new susceptibility loci for lung adenocarcinoma in the Japanese population. They also replicate previously identified risk loci near TERT and TP63.
Yukinori Okada and colleagues report a meta-analysis of genome-wide association studies for kidney function–related traits in 71,149 individuals from east Asia. They identify 17 loci newly associated with the concentrations of blood urea nitrogen, serum creatinine and uric acid, and with glomerular filtration rate (eGFRcrea), several of which are also associated with chronic kidney disease.
Friedhelm Hildebrandt, Agata Smogorzewska and colleagues show that mutations in the DNA repair gene FAN1 cause karyomegalic interstitial nephritis. These findings implicate deficient DNA damage response signaling in the pathophysiology of renal fibrosis.
Dianna Milewicz and colleagues report the identification of loss-of-function mutations in TGFB2 in individuals with familial thoracic aortic aneurysm and acute aortic dissection associated with mild systemic features of the Marfan syndrome.
Bart Loeys and colleagues identify mutations or deletions of TGFB2 in individuals with thoracic aortic aneurysm and other features of Loeys-Dietz syndrome. TGFB2 encodes the transforming growth factor-β2 ligand.
Leslie Biesecker and colleagues report an exome sequencing study identifying somatic activating mutations in PIK3CA as the cause of a new progressive segmental overgrowth disorder. They identify mutations in PIK3CA in ten additional individuals with overlapping syndromes.
William Dobyns and colleagues report de novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA in the sporadic overgrowth syndromes megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) and megalencephaly-capillary malformation (MCAP).
Joseph Gleeson and colleagues report exome sequencing of 20 individuals with hemimegalencephaly (HME), identifying de novo somatic mutations in the PIK3CA, AKT3 and MTOR genes.
Jianquan Liu and colleagues report the draft genome sequence of the domestic yak, Bos grunniens. Their comparative analyses with low-altitude cattle provide insights into high-altitude adaptation in the yak.
Xiangdong Fu and colleagues map variants in OsSPL16 that influence grain width and yield in a cross between a slender-grain Basmati and a wide-grain indica variety of rice. The authors show that higher expression of OsSPL16 promotes cell division and grain filling and can lead to improvements in grain quality and yield.
Gonçalo Abecasis, Jonathan Marchini and colleagues report a pre-phasing strategy for genotype imputation in GWAS, which they show maintains accuracy while substantially lowering computational costs. Their approach has been implemented in both MACH and IMPUTE 2.0 software.
