Reviews & Analysis

Sequencing of the genome of a second strain of Mycobacterium leprae and the development of a genome-wide typing scheme have provided deeper understanding of the evolution and epidemiology of the leprosy bacillus. A new study confirms that leprosy has a single clone origin and has spread around the globe, following human migration and trade over the last several thousand years.

In the largest Parkinson's disease genome-wide association studies to date, common variants in three familiar genes—SNCA, MAPT and LRRK2—and two new loci are found to increase disease susceptibility. The studies suggest genetic heterogeneity for Parkinson's disease risk in different human populations and lend support to the idea of a common pathway for Parkinson's and Alzheimer's diseases.

The success of bone marrow transplantation depends on whether transplanted immune cells respond in graft versus host disease. A new study identifies a common gene deletion that is associated with immune response following transplantation.

Four genome-wide association studies report associations to a range of clinically relevant hematological traits. The candidate genes identified include many that are known to be important in iron homeostasis and red blood cell maturation.

Two new studies report improved statistics to predict whether an individual participated in a genome-wide association study based on aggregate allele or genotype frequency information. They demonstrate that it may be possible to release summary statistics for a subset of genetic markers in a study while maintaining individual privacy.

Epigenetic marks, such as DNA methylation and histone modifications, undergo dynamic changes during cellular differentiation and development. A new study demonstrates that DNA methylation by Dnmt1 protects essential stem cell properties in both hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) by silencing differentiation programs that interfere with self-renewal and multipotency.

Two genome-wide association studies together report three new susceptibility loci for late-onset Alzheimer’s disease. CLU, PICALM and CR1 may be involved in amyloid-β clearance from the brain.

Adult mammalian tissues are maintained by multipotent stem cells, many of which are highly responsive to soluble Wnt proteins. A new study reports the requirement of two Tcf family members, Tcf3 and Tcf4, in the development and maintenance of epithelial stem cells in skin through Wnt-dependent and -independent processes.

Three new studies report genetic variants near IL28B, which encodes interferon-λ3 (interleukin 28B), are associated with response to treatment of chronic hepatitis C virus infection with interferon-alfa/ribavirin combination therapy. This renews interest in how interferons suppress viremia and could lead to improved clinical decisions for chronic HCV infection treatment based on individual genotype.

Although genome-wide analyses have identified somatic alterations contributing to the pathogenesis of pediatric acute lymphoblastic leukemia (ALL), few studies have identified germline variants conferring risk of this disease. Two reports now provide the first genome-wide glimpse into the role of inherited alleles in ALL pathogenesis.

The discovery that a cocktail of transcription factors can reprogram somatic cells into induced pluripotent stem (iPS) cells keeps revealing new secrets of cell fate specification. A new study with hematopoietic cells shows that progenitor cells are far more susceptible than differentiated cells to reprogramming.

Making causative connections between genotypic and phenotypic variation is a major challenge for geneticists engaged in the study of human disease. A study drawing this connection for a type 1 diabetes risk locus now demonstrates the importance of focusing on specific quantitative traits and studying them in normal subjects.

A new study reports the first mouse model for ATR-mutated Seckel syndrome. The mice show phenotypes recapitulating the human disorder and provide insights into how reduced ATR function affects normal embryonic development by increasing replicative stress, ultimately resulting in an accelerated aging phenotype postnatally.

Two new reports highlight the power of genome-wide association (GWA) studies to guide the functional annotation of genetic variants contributing to common diseases. The studies show that a common risk variant for colorectal cancer on chromosome 8q24 affects TCF4 binding to an enhancer that interacts with the MYC promoter, providing a mechanistic explanation for the association of this variant with disease risk.

Chromatin marks, including histone modifications and variants, have become important tools for characterizing epigenomes, yet how they might interact with one another to facilitate gene expression and regulation has remained unclear. A new study maps unstable nucleosomes containing both H3.3 and H2A.Z histone variants to human promoters and regulatory elements and suggests that transient occupancy by double-variant nucleosomes is a general feature of eukaryotic gene regulation.

Two genome-wide association studies for testicular cancer report associations at three new loci, including two candidate genes previously implicated in testicular development, KITLG (ligand for the receptor tyrosine kinase) and SPRY4 (sprouty 4). These studies are notable for the high effect sizes detected and the biological plausibility of the candidate genes.

The genetic basis of myelodysplasia has long been enigmatic, with few common targets of mutation known. A new study reports common mutations in the TET2 gene in myelodysplasia and related myeloid malignancies, suggesting that TET2 has an important role in hematopoiesis and in the pathogenesis of this disease.

MicroRNAs (miRNAs) and the pathways that regulate their expression have critical functions during normal development. A new study demonstrates that select cancer cells have appropriated one developmental mechanism of miRNA regulation, the inhibition of let-7 biogenesis by the Lin-28 and Lin-28B RNA binding proteins, to rid themselves of an antitumorigenic miRNA.

The etiology of the sleep disorder narcolepsy has not been firmly established, although an autoimmune pathogenesis has been proposed and is supported by a strong genetic association with the HLA. A new genome-wide association study provides further support for the autoimmune basis of narcolepsy by uncovering a robust association at the T-cell receptor alpha locus.

Tubulins are key structural components of all cells. A new study reveals roles in brain development for a specific β-tubulin isoform and highlights potential for functional diversity in the β-tubulin gene family.