Reviews & Analysis

Five genome-wide association studies of the timing of menarche and menopause have now taken us beyond the range of candidate gene and linkage studies. The list of new genetic associations identified for these two traits should shed light on the mechanisms of ovarian aging, as well as breast cancer and other diseases associated with reproductive lifespan.

A new study reports large-scale systematic resequencing of the coding exons of the X chromosome in males with X-linked mental retardation (XLMR), illustrating the challenge of sorting through large amounts of benign variation in order to identify disease-causing sequence changes.

A new study defines the flaky tail mouse as a model for human atopic dermatitis caused by a null mutation in the gene encoding filaggrin, a key component of the epidermal barrier. Research in these mice will help explain how a disrupted barrier contributes to the pathogenesis of atopic dermatitis and to asthma arising in the context of atopic skin disease.

Two studies show that the common recurrent gene fusion between TMPRSS2 and ERG promotes prostate cancer in both mouse and humans when PTEN is concurrently lost. In human prostate cancer, the presence of both these aberrations may be indicative of poor prognosis, suggesting that preclinical therapeutic research should target both of these pathways.

Myeloproliferative neoplasms are hematological malignancies frequently associated with somatically acquired mutation of the JAK2 gene. A new study shows that these mutations are preferentially found within a particular inherited JAK2 haplotype, implying the existence of a strong, but uncharacterized, interaction between somatic and germline genetics at this locus.

The small liver peptide hepcidin is a major regulator of systemic iron homeostasis in mammals, adapting iron absorption to the body's demands. Two new studies now identify BMP6 as the key endogenous regulator of hepcidin.

Prolongation of the electrocardiographic QT interval, a measure of cardiac repolarization, is associated with arrhythmogenic disorders and is a risk factor for sudden cardiac death. Two genome-wide association studies (GWAS) of variation in the QT interval in population-based cohorts now report association with variants in a subset of ion channel genes and other new associations.

Studies of rare genetic disorders in humans have yielded important insights into the function of the hypothalamic-pituitary-gonadal axis. A new study now establishes a fundamental role for the neurokinin B pathway in normal reproductive function.

The global patterning of histone lysine methylation has been scrutinized over the years in an effort to uncover unique features indicative of chromatin function. A study in Caenorhabditis elegans now shows that nucleosomes covering exons and introns on active genes are differentially marked by H3K36 trimethylation, suggesting a new mode of communication between chromatin and pre-mRNA processing.

FGF receptors have been implicated in a number of syndromes that involve skeletal disorders. A new study in mice has identified a spontaneous mutation in Fgf9 with reduced activity but increased diffusion through tissues resulting in a gain-of-function phenotype comparable to those due to activating mutations in genes encoding FGF receptors.

A new study identifies mutations in the HR gene as the cause of Marie Unna hereditary hypotrichosis (MUHH). The mutations seem to disrupt an unusual leader sequence–based mechanism of translational repression, making MUHH the first example of a disease linked to this form of repression.

Obesity genetics is making progress, as evidenced by the recent discovery of 15 new loci associated with body mass index. The function of the likely candidate genes in associated regions suggests a key role for the hypothalamus in the genetics of weight control.

Experimental reverse evolution, in which a population is readapted to an ancestral environment, can probe the nature and extent of evolutionary memory. A new study shows that standing genetic variation is key to this memory in experimental Drosophila populations, where selection drives rapid but incomplete convergence to ancestral genotypes.

An integrative genetical genomics study in Arabidopsis reports that six QTL hot spots have system-wide effects on a wide range of molecular and phenotypic traits, providing empirical evidence for phenotypic buffering.

Comparing levels of genetic variation between the X chromosome and autosomes can reveal the different demographic histories of males and females of a species. Taking this approach, two new studies report that the effective population sizes of men and women differ, but they disagree as to which sex outnumbered the other.

DNA methylation is an epigenetic mark directing stable, heritable gene silencing through development. A new study uncovers the importance of demethylation of the DNA methyltransferase-1 for maintenance of DNA methylation.

Three new studies identify nearly 20 new loci for serum lipid levels using predominantly a prospective cohort study design which also permits extensive and unbiased characterization of environmental exposures. Given the known, strong environmental influences on these traits, investigation of gene-environment interactions should be emphasized in attempts to understand the complete epidemiologic and genetic architecture of these complex traits.

The identification of targets of virally encoded microRNAs is essential to understanding their role in the viral life cycle. A new study reports the successful use of a microarray-based approach to identify a key target of a microRNA encoded by Kaposi's sarcoma–associated herpesvirus, with implications for microRNA target identification in other contexts as well.