SUMMARY Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.

These 62 patients with the Kabuki make-up syndrome (KMS) were collected in a collaborative study among 33 institutions and analyzed clinically, cytogenetically, and epidemiologically to delineate the phenotypic spectrum of KMS and to learn about its cause. Among various manifestations observed, most patients had the following five cardinal manifestations: 1) a peculiar face (100%) characterized by eversion of the lower lateral eyelid; arched eyebrows, with sparse or dispersed lateral one-third; a depressed nasal tip; and prominent ears; 2) skeletal anomalies (92%), including brachydactyly V and a deformed spinal column, with or without sagittal cleft vertebrae; 3) dermatoglyphic abnormalities (93%), including increased digital ulnar loop and hypothenar loop patterns, absence of the digital triradius c and/or d, and presence of fingertip pads; 4) mild to moderate mental retardation (92%); and 5) postnatal growth deficiency (83%). Thus the core of the phenotypic spectrum of KMS is rather narrow and clearly defined. Many other inconsistent anomalies were observed. Important among them were early breast development in infant girls (23%), and congenital heart defects (31%), such as a single ventricle with a common atrium, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of aorta, patent ductus arteriosus, aneurysm of aorta, transposition of great vessels, and right bundle branch block. Of the 62 KMS patients, 58 were Japanese, an indication that the syndrome is fairly common in Japan. It was estimated that its prevalence in Japanese newborn infants is 1/32,000. All the KMS cases in this study were sporadic, the sex ratio was even, there was no correlation with birth order, the consanguinity rate among the parents was not high, and no incriminated agent was found that was taken by the mothers during early pregnancy. Three of the 62 patients had a Y chromosome abnormality involving a possible common breakpoint (Yp11.2). This could indicate another possibility, i.e., that the KMS gene is on Yp11.2 and that the disease is pseudoautosomal dominant. These findings are compatible with an autosomal dominant disorder in which every patient represents a fresh mutation. The mutation rate was calculated at 15.6 X 10(6).

A new and more robust evolutionary synthesis is emerging that attempts to explain macroevolution as well as microevolutionary events. This new synthesis emphasizes three morphological areas of biology that had been marginalized by the Modern Synthesis of genetics and evolution: embryology, macroevolution, and homology. The foundations for this new synthesis have been provided by new findings from developmental genetics and from the reinterpretation of the fossil record. In this nascent synthesis, macroevolutionary questions are not seen as being soluble by population genetics, and the developmental actions of genes involved with growth and cell specification are seen as being critical for the formation of higher taxa. In addition to discovering the remarkable homologies of homeobox genes and their domains of expression, developmental genetics has recently proposed homologies of process that supplement the older homologies of structure. Homologous developmental pathways, such those involving the wnt genes, are seen in numerous embryonic processes, and they are seen occurring in discrete regions, the morphogenetic fields. These fields (which exemplify the modular nature of developing embryos) are proposed to mediate between genotype and phenotype. Just as the cell (and not its genome) functions as the unit of organic structure and function, so the morphogenetic field (and not the genes or the cells) is seen as a major unit of ontogeny whose changes bring about changes in evolution.

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