News & Views in 2010

Sequence conservation of noncoding DNA across species can indicate functional conservation. However, a new study demonstrates notable differences between human and mouse stem cell regulatory networks, suggesting caution in generalizing from sequence to functional conservation.

Two studies describe how regulatory variation at the rice gene OsSPL14 can lead to altered plant morphology and improve grain yield. These studies support the possibility of improving rice yield through changing plant architecture.

A new study reports the whole-genome sequences of 21 Mycobacterium tuberculosis complex strains, selected to represent geographically diverse isolates. Comparative genomic analyses identify surprising conservation of epitopes recognized by human T cells.

A new study has identified rare de novo mutations in SHANK2 in individuals with autism and/or mental retardation. SHANK2 encodes a scaffolding protein present in excitatory synapses. This finding sheds some light on the pathophysiology of social and cognitive disability.

A new study reports biallelic mutations in RAD51C in a Fanconi anemia–like disorder, while a second study reports monoallelic mutations in the same gene associated with increased breast cancer risk. These findings strengthen the link between Fanconi anemia and breast cancer–associated pathways.

Maps of human genome copy number variation (CNV) are maturing into useful resources for complex disease genetics. Four new studies increase the resolution of CNV maps and seek to locate human phenotypic variation on these maps.

Three large consortia present comprehensive analyses that identify genetic factors influencing smoking initiation, intensity and cessation. The genetic architecture of these three phases of smoking behavior appears to be largely distinct.

Enhancers and transcription factor binding sites that control cell-specific transcription in higher eukaryotes can be found up to hundreds of kilobases from the promoters that they control, making their identification challenging. A new study uses a model based on histone modifications and chromatin dynamics to predict functional elements involved in androgen receptor response.

Human hemoglobin variants are known to protect the host against severe malaria due to P. falciparum. A new study demonstrates that such genetic variation may also be associated with increased transmission of this pathogen from the human host to the Anopheles vector.

A genome-wide association study reports more than a dozen new susceptibility loci for celiac disease. Analysis of eQTL data from these and previously established risk loci sheds light on the genetic pathways underlying this common autoimmune disease.

A genome-wide association study has identified a new genetic susceptibility factor for a subtype of frontotemporal lobar dementia characterized by TDP-43 inclusions. The work illustrates how high-quality phenotyping can increase power to detect risk alleles for rare heterogeneous diseases.

A new study has identified a large number of open chromatin regions harboring active regulatory elements in human pancreatic islets. A type 2 diabetes–associated SNP in TCF7L2 was found to be located in a region of allele-specific open chromatin and shows allele-specific enhancer activity, suggesting a potential mechanism for this disease association.

A new study reports an elevated frequency of second-site genomic alterations among children with severe developmental delay who carry a recurrent microdeletion at chromosome 16p12.1. The work highlights the complex relationship between genotype and phenotype and provides a model to explain the clinical variability associated with this and other common microdeletion syndromes.

Scapuloperoneal spinal muscular atrophy and Charcot-Marie-Tooth disease type 2C are inherited neurodegenerative diseases characterized by sensory defects and muscle weakness. Three new studies demonstrate that they are allelic disorders caused by mutations in the vanilloid transient receptor potential cation-channel gene TRPV4.

A new study now reports recurrent somatic mutation of EZH2, a histone methyltransferase that modifies H3K27, in diffuse large B-cell lymphoma (DLBCL). There is now evidence for both increased and decreased activity of enzymes controlling H3K27 methylation in cancer, suggesting that a precise balance of this methylation is critical for normal cell growth.

Advances in analytical biochemistry have recently made it possible to obtain global snapshots of metabolism. A new study couples such technology with genome-wide genetic analysis to explore inherited variation in human metabolism.

A new study provides compelling evidence that transcriptional regulation and three-dimensional genomic architecture are linked. The alpha- and beta-globin loci associate with hundreds of active genes across the genome at transcription factories in erythroid cells, and specialized Klf1-containing transcription factories mediate the association of Klf1-regulated genes.

Massively parallel sequencing of the exomes of four individuals with Miller syndrome, combined with filtering to exclude benign and unrelated variants, has identified causative mutations in DHODH. This approach will accelerate discovery of the genetic bases of hundreds of other rare mendelian disorders.

Two studies report genome-wide association studies for lung function, using cross-sectional spirometric measurements in healthy individuals. They identify six genetic loci newly associated to natural variation in lung function, which may have implications for the related airway diseases of asthma and chronic obstructive pulmonary disease.