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Dickel, Diane E.; Ypsilanti, Athena R.; Pla, Ramón; Zhu, Yiwen; Barozzi, Iros; Mannion, Brandon J.; Khin, Yupar S.; Fukuda-Yuzawa, Yoko; Plajzer-Frick, Ingrid; Pickle, Catherine S.; Lee, Elizabeth A.; Harrington, Anne N.; Pham, Quan T.; Garvin, Tyler H.; Kato, Momoe; Osterwalder, Marco; Akiyama, Jennifer A.; Afzal, Veena; Rubenstein, John L.R.; Pennacchio, Len A.; Visel, Axel
Cell, 01/2018, Volume: 172, Issue: 3Journal Article
Non-coding “ultraconserved” regions containing hundreds of consecutive bases of perfect sequence conservation across mammalian genomes can function as distant-acting enhancers. However, initial deletion studies in mice revealed that loss of such extraordinarily constrained sequences had no immediate impact on viability. Here, we show that ultraconserved enhancers are required for normal development. Focusing on some of the longest ultraconserved sites genome wide, located near the essential neuronal transcription factor Arx, we used genome editing to create an expanded series of knockout mice lacking individual or combinations of ultraconserved enhancers. Mice with single or pairwise deletions of ultraconserved enhancers were viable and fertile but in nearly all cases showed neurological or growth abnormalities, including substantial alterations of neuron populations and structural brain defects. Our results demonstrate the functional importance of ultraconserved enhancers and indicate that remarkably strong sequence conservation likely results from fitness deficits that appear subtle in a laboratory setting. Display omitted •The Arx locus has a high density of very long ultraconserved forebrain enhancers•Single or pairwise deletion of these enhancers results in viable mice in all cases•In most cases, individual enhancer loss results in developmental anomalies•Selection against these fitness deficits likely contributes to ultraconservation Although initial studies suggested that loss of ultraconserved enhancers had no impact on viability, these sequences are now shown to be required for normal development.
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