Volume 47 Issue 7, July 2015

Paul Flicek and colleagues provide an update on the European Genome-phenome Archive (EGA), a service of the European Bioinformatics Institute (EMBL-EBI) and the Center for Genome Regulation (CRG). The authors describe the EGA policies and infrastructure, how access decisions are made, methods for data submission and future plans for expansion of this database.

Crossing over, or reciprocal recombination, is essential for accurate segregation of homologous chromosomes at the first meiotic division, resulting in gametes containing the correct chromosome number. A new study in human oocytes analyzes the genome-wide recombination and segregation patterns in all the products of female meiosis, providing experimental support for existing theories about the origin of human aneuploidies and highlighting a novel reverse segregation mechanism of chromosome segregation during meiosis.

All cells of an adult plant are ultimately derived from divisions that occur in small groups of cells distributed throughout the plant, termed meristems. A new study shows that carbohydrate post-translational modification of a peptide signal influences meristem and, as a consequence, fruit size in tomato.

How the human brain rapidly builds up its lipid content during brain growth and maintains its lipids in adulthood has remained elusive. Two new studies show that inactivating mutations in MFSD2A, known to be expressed specifically at the blood-brain barrier, lead to microcephaly, thereby offering a simple and surprising solution to an old enigma.

Danielle Posthuma, Peter Visscher and colleagues report a meta-analysis of 17,804 traits based on virtually all twin studies from the last 50 years. For a majority of traits, twin resemblance seems solely due to additive genetic variation and lacks evidence for a substantial influence of shared environment or non-additive genetic variation.

Michael Snyder and colleagues analyze whole-genome sequencing data from eight cancer subtypes and identify recurrent mutations in regulatory regions. They find evidence for positive selection of mutations in transcription factor binding sites near cancer-related genes.

Gilean McVean and colleagues report the results of a large-scale clinical genome sequencing project spanning a broad spectrum of disorders. They identify factors influencing successful genetic diagnosis and highlight the challenges of interpreting findings for genetically heterogeneous disorders.

Eva Hoffman, Alan Handyside and colleagues generate genome-wide maps of crossovers and chromosome segregation patterns by recovering all three products of single female human meioses. They detect a reverse chromosome segregation pattern and selection for higher recombination rates in the female germ line and report chromosomal drive against non-recombinant chromatids at meiosis II.

Paul Boutros, Robert Bristow and colleagues report a molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer. They find that multifocal tumors are highly heterogeneous, and they identify a novel recurrent amplification of MYCL1.

José Martín-Subero and colleagues report the whole-genome bisulfite sequencing of ten blood cell subpopulations representing the cellular stages during B cell differentiation. They find that early stages are characterized by enhancer demethylation and that neoplasms derived from B cell lineages undergo methylation changes in regions with dynamic methylation during normal differentiation.

Susanne Kohl and colleagues report mutations in ATF6, a regulator of the unfolded protein response pathway, that cause a familial form of achromatopsia. Their results indicate a role for ATF6 in foveal development rather than a direct role in the cone phototransduction pathway.

Andrea Ventura and colleagues characterize an allelic series of genetically engineered mice harboring targeted deletions of individual members of the miR-17~92 cluster. They find evidence of functional cooperation and specialization among members of this cluster and show that the miR-17 seed family influences axial patterning.

Da-Zhi Wang and colleagues knock out Trbp in mouse cardiomyocytes in vivo and investigate its requirement for normal heart function. They find that Trbp is necessary for the biogenesis of miR-208a, which targets and represses Sox6.

Zachary Lippman and colleagues report mutations in the tomato ortholog of CLV1 and a gene encoding a hydroxyproline O-arabinosyltransferase enzyme that modifies CLV3, both of which cause fasciated flowers and fruits owing to increased meristem size. They also find that a natural mutation in CLV3 was a major target of selection during tomato domestication.

Yao Zhao, Yongyong Shi and colleagues performed a genome-wide association study on sporadic pituitary adenoma in the Han Chinese population. They identify three new susceptibility loci.

Yukinori Okada, Michiaki Kubo and colleagues report the construction of a new HLA imputation reference panel for the Japanese population. They apply this resource to analyze the association of the HLA region with Graves' disease and find that variants in multiple class I and class II HLA genes contribute independently to disease risk.

Geoffrey Woods, Jan Senderek and colleagues show that biallelic mutations in PRDM12 cause congenital insensitivity to pain. They further show that PRDM12 is expressed in nociceptors and their progenitors and participates in sensory neuron development in Xenopus.

Joseph Gleeson, David Silver and colleagues show that inactivating mutations in MFSD2A, which encodes an essential transporter of long-chain fatty acids in brain, cause a lethal microcephaly syndrome. These results establish a link between the activity of this transporter and human brain growth.

Andrew Crosby, David Silver and colleagues show that a partially inactivating mutation in MFSD2A causes a non-lethal microcephaly syndrome with symptoms that include intellectual disability, spasticity and absent speech. Their findings indicate an essential role for lysophosphatidylcholine uptake in human brain development and function.

Lauri Aaltonen, Jussi Taipale and colleagues report frequent mutation of CTCF- and cohesin-binding sites (CBSs) in multiple cancer types. They find that the frequency of CBS mutations in microsatellite-stable colorectal cancer is 1.5 times higher than that of other known cancer mutational targets.

Shamil Sunyaev, Paul de Bakker and colleagues report an analysis of 11,020 de novo mutations from the whole-genome sequences of Dutch families sequenced as part of the Genome of the Netherlands project. They identify correlations related to paternal age and genic content and develop an empirical human mutation rate map.

Hong-Xuan Lin, Ji-Ping Gao, Jun-Xiang Shan and colleagues show that natural variation in a proteasome α2 subunit gene contributes to thermotolerance in African rice. Their follow-up studies suggest that the variant allele protects cells from heat stress by enhancing the elimination of cytotoxic denatured proteins and maintaining heat-response processes.

Chengcai Chu and colleagues show that genetic variation in NRT1.1B/OsNPF6.5 contributes to nitrate-use divergence between two main subspecies of Asian cultivated rice. Their findings may help to improve nitrogen-use efficiency in plant production.

Mary Fortune, Chris Wallace and colleagues report a new method that allows statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls. They apply their method to type 1 diabetes, rheumatoid arthritis, celiac disease and multiple sclerosis and highlight the complexity in genetic variation underlying these distinct autoimmune diseases.