Genetic diversity and regulatory features of human-specific NOTCH2NL duplications

Taylor D. Real; Prajna Hebbar; DongAhn Yoo; Francesca Antonacci; Ivana Pačar; Danilo Dubocanin; Mark Diekhans; Gregory J Mikol; Oyeronke G. Popoola; Benjamin J. Mallory; Mitchell Robert Vollger; Philip C. Dishuck; Xavi Guitart; Allison N. Rozanski; Katherine M. Munson; Kendra Hoekzema; Jane Ranchalis; Shane J. Neph; Adriana Estela Sedeño-Cortés; Benedict Paten; Sofie R. Salama; Andrew B. Stergachis; Evan E. Eichler

doi:10.1016/j.xgen.2026.101194

GenomicsCell GenomicsMar 30, 2026

Peer-reviewed journal article

Genetic diversity and regulatory features of human-specific NOTCH2NL duplications

Taylor D. Real iD, Prajna Hebbar iD, DongAhn Yoo iD, Francesca Antonacci iD, Ivana Pačar iD, Danilo Dubocanin iD, Mark Diekhans iD, Gregory J Mikol, Oyeronke G. Popoola, Benjamin J. Mallory iD, Mitchell Robert Vollger iD, Philip C. Dishuck iD, Xavi Guitart iD, Allison N. Rozanski iD, Katherine M. Munson iD, Kendra Hoekzema iD, Jane Ranchalis, Shane J. Neph iD, Adriana Estela Sedeño-Cortés iD, Benedict Paten iD, Sofie R. Salama iD, Andrew B. Stergachis iD, Evan E. Eichler iD

Abstract

NOTCH2NL (NOTCH2-N-terminus-like) genes arose from ape-specific chromosome 1 segmental duplications implicated in human brain cortical expansion, including an incomplete NOTCH2 gene. Genetic characterization of these loci and their regulation is complicated because they are embedded in large, nearly identical duplications that predispose to recurrent microdeletion syndromes. Using near-complete long-read assemblies generated from 70 human and 12 ape haploid genomes, we show independent recurrent duplication among apes with protein-coding copies emerging in humans 2.2-3.7 million years ago. We distinguish NOTCH2NL paralogs present in every human haplotype (NOTCH2NLA) from copy number variable ones. We also characterize large-scale structural variation, including gene conversion, for 28% of haplotypes leading to a previously undescribed paralog, NOTCH2tv. Finally, we apply Fiber-seq and long-read transcript sequencing to human dorsal forebrain organoids to characterize the regulatory landscape and find that the most fixed paralogs, NOTCH2 and NOTCH2NLA, harbor the greatest number of paralog-specific elements potentially driving their regulation.

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