PT  - JOURNAL ARTICLE
AU  - Ian T Fiddes
AU  - Gerrald A Lodewijk
AU  - Meghan Mooring
AU  - Colleen M Bosworth
AU  - Adam D Ewing
AU  - Gary L Mantalas
AU  - Adam M Novak
AU  - Anouk van den Bout
AU  - Alex Bishara
AU  - Jimi L Rosenkrantz
AU  - Ryan Lorig-Roach
AU  - Andrew R Field
AU  - Maximillian Haeussler
AU  - Lotte Russo
AU  - Aparna Bhaduri
AU  - Tomasz J. Nowakowski
AU  - Alex A. Pollen
AU  - Max L. Dougherty
AU  - Xander Nuttle
AU  - Marie-Claude Addor
AU  - Simon Zwolinski
AU  - Sol Katzman
AU  - Arnold Kreigstein
AU  - Evan E. Eichler
AU  - Sofie R Salama
AU  - Frank MJ Jacobs
AU  - David Haussler
TI  - Human-specific <em>NOTCH</em>-like genes in a region linked to neurodevelopmental disorders affect cortical neurogenesis
AID  - 10.1101/221226
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 221226
4099  - http://biorxiv.org/content/early/2017/12/11/221226.short
4100  - http://biorxiv.org/content/early/2017/12/11/221226.full
AB  - Genetic changes causing dramatic brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and a determinant of neuronal number in the mammalian cortex. We find three paralogs of human-specific NOTCH2NL are highly expressed in radial glia cells. Functional analysis reveals different alleles of NOTCH2NL have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, NOTCH2NL ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation. NOTCH2NL genes provide the breakpoints in typical cases of 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism, and deletions with microcephaly and schizophrenia. Thus, the emergence of hominin-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger hominin neocortex accompanied by loss of genomic stability at the 1q21. 1 locus and a resulting recurrent neurodevelopmental disorder.