News & Views in 2015

Two new studies show how highly divergent modes of male reproduction in a wading bird are controlled by alternate alleles at a single locus encompassing a 4.5-Mb inversion in the genome. The locus is an example of a 'supergene' controlling multiple complex phenotypes.

The plant circadian clock is a complex network of genes crucial for plant survival. A new study finds that domestication gradually slowed down the circadian clock of tomato via selection on two major genes—one that delayed phasing of the clock with daylight, whereas the other induced a longer period.

Iron is essential in multiple cellular processes and is especially critical for cellular respiration and division. A new study identified a mutation affecting the iron import receptor TfR1 as the cause of a human primary immunodeficiency, illuminating the importance of iron in immune cell function.

Characterizations of durable resistance genes in crop plants are coming to the fore. A new study characterizing the wheat gene Lr67 shows that how a plant manages sugar transport affects the ability of a broad group of fungal pathogens to colonize their host.

Large sample sizes, high-resolution arrays and comprehensive imputation are pushing genetic fine-mapping of complex trait loci to its limits without, in most cases, pinpointing a unique variant-gene combination. Superimposing these results on sophisticated maps of functional chromatin elements promises to break this logjam, as a new study of type 2 diabetes compellingly demonstrates.

The genome sequence assembly of the highly heterozygous Ananas comosus and its varieties is an impressive technical achievement. The sequence opens the door to a greater understanding of pineapple morphology and evolution.

Whole-exome sequencing has revolutionized the identification of genes with dominant disease-associated variants for rare clinically and genetically heterogeneous disorders, but the identification of genes with recessive disease-associated variants has been less successful. A new study now provides a framework integrating Mendelian variant filtering with statistical assessments of patients' genotypes and phenotypes, thereby catalyzing the discovery of novel mutations associated with recessive disease.

Three new studies have identified new genes and sequence variants implicated in blood lipids, inflammatory markers, hemoglobin levels and adult height variation in Sardinia. These reports highlight the usefulness of large-scale genotype imputation based on whole-genome sequencing, particularly in isolated populations, in studying the genetics of complex human phenotypes.

Adult T cell leukemia/lymphoma (ATL) is a neoplasm linked to human T-lymphotropic virus type-1 (HTLV-1) infection and is refractory to current combination chemotherapy. A large genomic and transcriptomic study of ATL now provides detailed insight into the molecular lesions implicated in the development of this T cell malignancy.

Pancreatic cancers consist of a heterogeneous amalgam of assorted cell types, making it challenging to develop a classification system that groups these tumors according to common molecular features. A new study tackles this important issue using bioinformatics approaches to decipher gene expression signatures derived specifically from either tumor cells or nonmalignant stromal cells that predict patient outcome and may inform personalized treatments.

Adeno-associated virus (AAV) vectors have been widely adopted for use in gene therapy. A new study raises concerns regarding this approach, reporting that chromosomal insertions of AAV serotype 2 seem to activate proto-oncogenes in human hepatocellular carcinoma.

The three-dimensional organization of the genome has an important role in orchestrating gene expression, but its regulation is poorly understood. Now, a new study uncovers a major role for Polycomb components of the PRC1 complex in organizing physical networks of genes that are co-repressed to maintain pluripotency.

The identification of gene-regulatory polymorphisms that influence cancer susceptibility can identify key oncogenic pathways. A new study links a germline variant to Ewing sarcoma disease susceptibility and EWSR1-FLI1–mediated gene activation.

High-throughput analysis of the phenotypes of mouse genetic knockouts presents several challenges, such as systematic measurement biases that can vary with time. A report from the EUMODIC consortium presents data from 320 genetic knockouts generated using standardized phenotyping pipelines and new statistical analyses aimed at increasing reproducibility across centers.

A new study has conducted a comprehensive exome and transcriptome analysis of a large number of intrahepatic, perihilar and distal cholangiocarcinomas and gallbladder cancers in Japanese patients. This study identifies many new alterations, confirms genetic differences in these distinct subtypes of biliary tract cancer and demonstrates that approximately 40% of described genetic aberrations are potentially targetable.

A major challenge in human genetics is pinpointing which non-coding genetic variants affect gene expression and disease risk. A new study in this issue describes a broadly applicable approach for this task that explicitly models cell type–specific regulatory motifs and generates variant effect predictions that are more accurate and interpretable than those of alternative tools.

Relapsed neuroblastoma is common, frequently lethal and poorly studied and poses a major treatment challenge. Two new studies shed light on the genomic landscape of recurrent neuroblastoma and demonstrate profound differences between the disease at diagnosis and relapse.

Copy number variation (CNV) at several genomic loci has been associated with different human traits and diseases, but in many cases the findings could not be replicated. A new study provides insights into the degree of variation present at the amylase locus and calls into question a previous association between amylase copy number and body mass index.

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.

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.