Optimized Southern Blot Helps to Determine C9orf72 Repeat-Expansion Size
Although C9orf72 hexanucleotide repeat expansions are associated with diseases such as frontaltemporal lobar degeneration (FLTD) and amyotrophic lateral sclerosis (ALS), defining a role for C9orf72 expansions has proven complicated: the number of repeats is difficult to quantify, rendering correlations between the number of repeat expansions and a phenotype ambiguous. Now, Beck et al. utilize an optimized Southern blot protocol to determine the frequency of large repeats in disease and control cohorts. They show that large repeat expansions are present in 7.5% of FLTD cases, 1.2% of Alzheimer cases, 8.1% of ALS cases, 0.2% of cases of sporadic Creutzfeldt-Jakob disease, 1.7% of Huntington Disease-like cases, and 2% of cases involving other neurodegenerative diseases. Notably, these expansions were also detected in 1/691 healthy individuals. Because of the high number of carriers and the frequency of expansions in several neurodegenerative diseases, a reliable method for quantifying expansion size, such as the optimized Southern blot used in this work, will be increasingly important as a diagnostic and investigative tool.

A SNP Slows Migration
Although GWASs have provided hints about the underpinnings of complex traits, experimental follow-up will be necessary before researchers can get a handle on the underlying biology. In this issue, Pu et al. present studies of rs3825807, a SNP inversely associated with coronary artery disease. This polymorphism causes a nonsynonymous alteration in the prodomain of ADAMTS7, a protease that cleaves thrombospondin-5, a protein that is produced by vascular smooth-muscle cells (VSMC) and which inhibits the cells' own migration. Cells expressing this variant display reduced thrombospondin-5 cleavage and reduced migratory ability. Although the specific mechanism by which reduced VSMC migration protects an individual from atherosclerosis remains unclear, this study provides an example of how to use GWAS data as a starting point for in vivo characterization.

Zooming in on CNVs
Microdeletions affecting NRXN1 occur with high frequency and confer risk for neurodevelopmental abnormalities, including autism spectrum disorder (ASD) and schizophrenia. Owing to the variability of the size and location of the deletions, however, the mechanism(s) that target this region have remained unknown. Now, Chen et al. analyze the breakpoints of more than 30 NRXN1 deletions and propose that the presence of short inverted repeats predisposes this region to genomic instability. Although the authors’ analysis was limited to deletions affecting NRXN1, these results should be of considerable interest to investigators who hope to better understand the mechanisms that underlie complex patterns of copy-number variation and their related genomic disorders.

A New Look at the Y
Efforts to uncover the origins of anatomically modern humans have relied, in large part, on analyses of mtDNA and the nonrecombining portion of the Y chromosome. These studies have led to a well-accepted model that places the origin of our most recent common ancestors in sub-Saharan Africa. Unsatisfyingly, however, estimates of timing based on female- and male-specific sequences differ by ~100,000 years. Now, Mendez et al. report on a new root to the Y chromosome phylogenetic tree, a lineage they term A00, which is estimated to be much older than previously identified mtDNA lineages. This work is sure to send many investigators back into the lab, where they will need not only to consider new models for Y chromosome diversity but also to reassess exactly who our earliest ancestors were.

ONECUT Ahead
Hemophilia B, also known as "royal disease" because of its prevalence in descendants of England’s Queen Victoria, is caused by mutations in coagulation factor IX (F9). In this issue, Funnell et al. demonstrate that a cluster of mutations in the F9 promoter disrupts binding of the ONECUT1 and ONECUT2 transcription factors. The ONECUT proteins join HNF4 and C/EBPα as known regulators of F9 expression, thus expanding our knowledge of this liver-restricted transcriptional program. Of interest to those with an appreciation of history, these findings also solve a puzzle that has stymied geneticists for many years.

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