Gene Clusters, Molecular Evolution and Disease: A Speculation

Traditionally eukaryotic genes are considered independently expressed under the control of their promoters and cis-regulatory domains. However, recent studies in worms, flies, mice and humans have shown that genes co-habiting a chromatin domain or “genomic neighborhood” are frequently co-expressed. Often these co-expressed genes neither constitute part of an operon nor function within the same biological pathway. The mechanisms underlying the partitioning of the genome into transcriptional genomic neighborhoods are poorly defined. However, cross-species analyses find that the linkage among the co-expressed genes of these clusters is significantly conserved and that the expression patterns of genes within clusters have coevolved with the clusters. Such selection could be mediated by chromatin interactions with the nuclear matrix and long-range remodeling of chromatin structure. In the context of human disease, we propose that dysregulation of gene expression across genomic neighborhoods will cause highly pleiotropic diseases. Candidate genomic neighborhood diseases include the nuclear laminopathies, chromosomal translocations and genomic instability disorders, imprinting disorders of errant insulator function, syndromes from impaired cohesin complex assembly, as well as diseases of global covalent histone modifications and DNA methylation. The alteration of transcriptional genomic neighborhoods provides an exciting and novel model for studying epigenetic alterations as quantitative traits in complex common human diseases

Association of migraine-like headaches with Schimke immuno-osseous dysplasia

Schimke immuno-osseous dysplasia (SIOD) is characterized by spondyloepiphyseal. dysplasia, nephropathy, and T-cell deficiency. SIOD is caused by mutations in the putative chromatin remodeling protein SAL&RCAL1. We report an 8-year-old boy with SIOD and recurrent, severe, refractory migraine-like headaches. Through a retrospective questionnaire-based study, we found that refractory and severely disabling migraine-like headaches occur in nearly half of SIOD patients. We have also found that the vasodilator minoxidil provided symptomatic relief for one patient. We hypothesize that these headaches may arise from an intrinsic vascular, neuroimmune, or neurovascular defect resulting from loss of SMARCAL1 function