The three-dimensional genome drives the evolution of asymmetric gene duplicates via enhancer capture-divergence.

Previous evolutionary models of duplicate gene evolution have overlooked the pivotal role of genome architecture. Here, we show that proximity-based regulatory recruitment by distally duplicated genes is an efficient mechanism for modulating tissue-specific production of preexisting proteins. By leveraging genomic asymmetries, we performed a coexpression analysis on tissue data to show the generality of enhancer capture-divergence (ECD) as a significant evolutionary driver of asymmetric, distally duplicated genes.

Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.

New genes (or young genes) are genetic novelties pivotal in mammalian evolution. However, their phenotypic impacts and evolutionary patterns over time remain elusive in humans due to the technical and ethical complexities of functional studies. Integrating gene age dating with Mendelian disease phenotyping, our research shows a gradual rise in disease gene proportion as gene age increases.

Hedgehog signaling activates a mammalian heterochronic gene regulatory network controlling differentiation timing across lineages.

Many developmental signaling pathways have been implicated in lineage-specific differentiation; however, mechanisms that explicitly control differentiation timing remain poorly defined in mammals. We report that murine Hedgehog signaling is a heterochronic pathway that determines the timing of progenitor differentiation. Hedgehog activity was necessary to prevent premature differentiation of second heart field (SHF) cardiac progenitors in mouse embryos, and the Hedgehog transcription factor GLI1 was sufficient to delay differentiation of cardiac progenitors in vitro.

Control of cardiomyocyte differentiation timing by intercellular signaling pathways.

Congenital Heart Disease (CHD), malformations of the heart present at birth, is the most common class of life-threatening birth defect (Hoffman (1995) [1], Gelb (2004) [2], Gelb (2014) [3]). A major research challenge is to elucidate the genetic determinants of CHD and mechanistically link CHD ontogeny to a molecular understanding of heart development. Although the embryonic origins of CHD are unclear in most cases, dysregulation of cardiovascular lineage specification, patterning, proliferation, migration or differentiation have been described (Olson (2004) [4], Olson (2006) [5], Srivastava (2006) [6], Dunwoodie (2007) [7], Bruneau (2008) [8]).

Hedgehog-FGF signaling axis patterns anterior mesoderm during gastrulation.

The mechanisms used by embryos to pattern tissues across their axes has fascinated developmental biologists since the founding of embryology. Here, using single-cell technology, we interrogate complex patterning defects and define a Hedgehog (Hh)-fibroblast growth factor (FGF) signaling axis required for anterior mesoderm lineage development during gastrulation. Single-cell transcriptome analysis of Hh-deficient mesoderm revealed selective deficits in anterior mesoderm populations, culminating in defects to anterior embryonic structures, including the pharyngeal arches, heart, and anterior somites.

Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation.

, an essential cardiogenic transcription factor, provides a model for dominant transcription factor mutations in human disease. Dominant GATA4 mutations cause congenital heart disease (CHD), specifically atrial and atrioventricular septal defects (ASDs and AVSDs). We found that second heart field (SHF)-specific heterozygote embryos recapitulated the AVSDs observed in germline heterozygote embryos.