Abstract

Haploinsufficency (HI), wherein a single functional copy of a gene is insufficient to maintain normal function, is a major cause of dominant disease. Human disease studies have identified several hundred haploinsufficient genes affecting a range of phenotypes. In this mini-review we review the topic of HI with reference to brain and human neuropsychiatric diseases, providing clinical, genetic, and pathological implications of the mechanism. Further,the genetic implications of HI (“stuck”) genes from evolutionary and genetic lenses are reviewed along with potential clinical applications. In summary, the study of HI assumes significance since its spectrum extends to the realm of biophysics, gene expression, chromosome biology, quantitative traits, and evolutionary biology.

• 1.   Adam F Johnson, Ha T Nguyen 1, Reiner A Veitia. Causes and effects of haploinsufficiency.Biol Rev CambPhilos Soc. 2019 Oct;94(5):1774-1785. doi: 10.1111/brv.12527. Epub 2019 May 31.
• 2.   M Andrew Uhl 1, Matt Biery, Nancy Craig, Alexander D Johnson.Haploinsufficiency-based large-scale forward genetic analysis of filamentous growth in the diploid human fungal pathogen C.albicans.EMBO J. 2003 Jun 2;22(11):2668-78. doi: 10.1093/emboj/cdg256.
• 3.   Carla Navarro-Quiles, Samuel Daniel Lup, Tamara Munoz-Nortes,HectorCandela,JoseLuisMicol.The genetic and molecular basis of haploinsufficiency in flowering plants.Trends Plant Sci. 2024 Jan;29(1):72- 85. doi: 10.1016/j.tplants.2023.07.009. Epub 2023 Aug 24.
• 4.   T Stearns, D Botstein. Unlinked noncomplementation: isolation of new conditionallethal mutations in each of the tubulin genes of Saccharomyces cerevisiae.Genetics. 1988 Jun;119(2):249-60. doi: 10.1093/genetics/119.2.249.
• 5.   DianaMBravo-Estupinan,KarolAguilar-Guerrero, Steve Quiros, Man-Sai Acon, Christian MarinMuller, Miguel Ibanez-Hernandez, Rodrigo A Mora-Rodriguez.Gene dosage compensation: Origins, criteria to identify compensated genes, and mechanisms including sensor loops as an emerging systems-level property in cancer.Cancer Med. 2023 Dec;12(24):22130-22155. doi: 10.1002/cam4.6719. Epub 2023 Nov 21.
• 6.   MathijsWillemsen, Frederik Staels, Margaux Gerbaux, Julika Neumann, Rik Schrijvers, Isabelle Meyts, Stephanie Humblet-Baron, Adrian Liston.DNA replication-associated inborn errors of immunity.J Allergy ClinImmunol .023 Feb;151(2):345-360. doi: 10.1016/j.jaci.2022.11.003. Epub 2022 Nov 15.
• 7.   Tamara Potapova, Gary J Gorbsky.The Consequences of Chromosome Segregation Errors in Mitosis and Meiosis.
• 8.   Margaux L A Hujoel, Robert E Handsaker, Maxwell A Sherman, Nolan Kamitaki, Alison R Barton, Ronen E Mukame, ChikashiTerao, Steven A McCarroll, Po-Ru Loh.Protein-altering variants at copy number-variable regions influence diverse human phenotypes.Nat Genet. 2024 Apr;56(4):569- 578. doi: 10.1038/s41588-024-01684-z. Epub 2024 Mar 28.Biology (Basel). 2017 Feb 8;6(1):12. doi: 10.3390/biology6010012.
• 9.   Zeman MK, CimprichKA.Causes and consequences of replication stress.Nat Cell Biol. 2014 Jan;16(1):2-9. doi: 10.1038/ncb2897.
• 10.   https://my.clevelandclinic.org/).
• 11.   https://www.nature.com/scitable/).
• 12.   Encyclopedia of Dairy Sciences (Second Edition), 2011.
• 13.   Hosea R, Hillary S, Naqvi S, Wu S, KasimV.The two sides of chromosomal instability: drivers and brakes in cancer.SignalTransduct Target Ther. 2024 Mar 29;9(1):75. doi: 10.1038/s41392-024-01767-7.
• 14.   Anthony Levasseur 1, Pierre Pontarotti.The role of duplications in the evolution of genomes highlights the need for evolutionary-based approaches in comparative genomics.Biol Direct. 2011 Feb 18:6:11. doi: 10.1186/1745-6150-6-11.
• 15.   Ekaterina Khrameeva, Ilia Kurochkin, Dingding Han, Patricia Guijarro, Sabina Kanton, MalgorzataSantel, Zhengzong Qian, Shen Rong, et al., .Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains. Genome Res. 2020 May;30(5):776-789.
• 16.   https://portal.brain-map.org/.
• 17.   TamirTuller, Martin Kupiec, EytanRuppin. Evolutionary rate and gene expression across different brain regions. Genome Biol. 2008; 9(9):R142.
• 18.   Margarida Cardoso-Moreira, Jean Halbert, Delphine Valloton, Britta Velten, Chunyan Chen, Yi Shao, AngelicaLiechti, Kelly Ascencao, Coralie Rummel, Svetlana Ovchinnikova, Pavel V Mazin, IoannisXenarios, Keith Harshman, Matthew Mort, David N Cooper, Carmen Sandi, Michael J Soares, Paula G Ferreira, Sandra Afonso, Miguel Carneiro, James M A Turner, John L VandeBerg, Amir Fallahshahroudi, Per Jensen, Rüdiger Behr, Steven Lisgo, Susan Lindsay, Philipp Khaitovich, Wolfgang Huber 4, Julie Baker, Simon Anders, Yong E Zhang, Henrik Kaessmann. Gene expression across mammalian organ development. Comparative Study Nature. 2019 Jul; 571(7766):505-509. https:// hupo.org/human-proteome-project.
• 19.   Roman Zug.Developmental disorders caused by haploinsufficiency of transcriptional regulators: a perspective based on cell fate determination. Biol Open. 2022 Jan 28;11(1):bio058896. doi: 10.1242/ bio.058896.
• 20.   Robin van der Lee 1, SolenneCorreard, Wyeth W Wasserman.Deregulated Regulators: DiseaseCausing cis Variants in Transcription Factor GenesTrends Genet. 2020 Jul;36(7):523-539. doi: 10.1016/j.tig.2020.04.006. Epub 2020 May 22.
• 21.   Beth A Firulli 1, Dayana Krawchuk, Victoria E Centonze, Neil Vargesson, David M Virshup, Simon J Conway, Peter Cserjesi, Ed Laufer, Anthony B Firulli.Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities.Nat Genet. 2005 Apr;37(4):373- 81. doi: 10.1038/ng1525. Epub 2005 Feb.
• 22.   Rainer G Ruf, Pin-Xian Xu, Derek Silvius, Edgar A Otto, Frank Beekmann, Ulla T Muerb, Shrawan Kumar, Thomas J Neuhaus, M et al., SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.Proc Natl AcadSci USA.
• 23.   2004 May 25;101(21):8090-5. doi: 10.1073/ pnas.0308475101. Epub 2004 May 12.27.
• 24.   Roman Zug.Developmental disorders caused by haploinsufficiency of transcriptional regulators: a perspective based on cell fate determinationBiol Open. 2022 Jan 15;11(1):bio058896. doi: 10.1242/ bio.058896. Epub 2022 Jan 28.
• 25.   Matthew B Johnson, Yuka Imamura Kawasawa, Christopher E Mason, ZeljkaKrsnik, Giovanni Coppola,DarkoBogdanovic,DanielHGeschwind, Shrikant M Mane, Matthew W State, NenadSestan. Functional and evolutionary insights into human brain development through global transcriptome analysis. Neuron. 2009 May 28; 62(4):494-509.
• 26.   Byoung-Il Bae, DivyaJayaraman, Christopher A Walsh .Genetic changes shaping the human brain. Review Dev Cell. 2015 Feb 23; 32(4):423-34.
• 27.   Daniel Jutzi, Marc-David Ruepp.Alternative Splicing in Human Biology and Disease. MethodsMol Biol. 2022:2537:1-19. doi: 10.1007/978- 1-0716-2521-7_1.
• 28.   Donny D Licatalosi, Robert B Darnell. Splicing regulation in neurologic disease. Review Neuron. 2006 Oct 5; 52(1):93-101.
• 29.   E Reble, A Dineen, C L Barr.The contribution of alternative splicing to genetic risk for psychiatric disorders. Review Genes Brain Behav. 2018 Mar; 17(3):e12430.
• 30.   Erin E Duffy, Benjamin Finander, GiHun Choi, Ava C Carter, Iva Pritisanac, Aqsa Alam, Victor Luria, Amir Karger, William Phu, et al., .Developmental dynamics of RNA translation in the human brain. Nat Neurosci. 2022 Oct; 25(10):1353-1365.
• 31.   Mihoko Shimada, Yosuke Omae, AkiyoshiKakita, RamilGabdulkhaev, Yuki Hitomi, TakuMiyagawa, Makoto Honda, Akihiro Fujimoto, Katsushi Tokunaga.Identification of region-specific gene isoforms in the human brain using long-read transcriptome sequencing .Sci Adv. 2024 Jan 26;10(4):eadj5279.
• 32.   Maurizio S Riga, Mercedes Perez-Fernandez, Lluis Miquel-Rio, Veronica Paz, Leticia Campa, Magdalena Martinez-Losa, Francisco J Esteban, Luis F Callado, Javier Meana, Francesc Artigas, AnaliaBortolozzi, Manuel Alvarez-Dolado .Scn1a haploinsufficiency in the prefrontal cortex leads to cognitive impairment and depressive phenotype. Brain. 2024 Dec 3; 147(12):4169-4184.
• 33.   K MaravetBaig, Szu-Chi Su, Sunni L Mumford, Emma Giuliani, Sinnie Sin Man Ng, Charles Armstrong 2, Margaret F Keil, KamariaCayton Vaught, Nils Olsen, Elyse Pettiford, Irina Burd, James H Segars .Mice deficient in AKAP13 (BRX) develop compulsive-like behavior and increased body weight .Brain Res Bull. 2018 Jun: 140:72-79.
• 34.   Renaud Pourpre, Laurent Naudon, Hamid Meziane 3, Goran Lakisic 1, Luc Jouneau 4, Hugo Varet 5 6, Rachel Legendre 5 6, Olivia Wendling 3, Mohammed Selloum 3, Caroline Proux 6, JeanYves Coppée 6, Yann Herault, Helene Bierne.
• 35.   Matthew L Bosworth, Anthony R Isles, Lawrence S Wilkinson, Trevor Humby.Sex-dependent effects of Setd1a haploinsufficiency on development and adult behaviour. PLoS One. 2024 Aug 14; 19(8):e0298717.
• 36.   Tomonori Hara, An-A Kazuno, Tomoko Toyota, Junko Ueda, TakehikoShuno, Jun Mukai, Taka-Aki Sato 6, Naomichi Matsumoto, Takeo Yoshikawa, Atsushi Takata.A case of bipolar I disorder with a loss-of-function variant of schizophrenia risk gene SETD1A: possible expansion of the relevant clinical spectrum supported by a meta-analysis. Meta-Analysis Psychiatry ClinNeurosci. 2024 Jun; 78(6):374-375.
• 37.   An-Li Wang, Owen Y Chao, Susanne Nikolaus, Valeria Lamounier-Zepter, Cornelis P Hollenberg, GertLubec, Svenja V Trossbach, Carsten Korth, Joseph P Huston.Disrupted-in-schizophrenia 1 Protein Misassembly Impairs Cognitive Flexibility and Social Behaviors in a Transgenic Rat Model. Neuroscience. 2022 Jun 15:493:41-51. doi: 10.1016/j. neuroscience.2022.04.013. Epub 2022 Apr 21.
• 38.   Sophie Waldron, Rachel Pass, SimonasGriesius, Jack R Mellor, Emma S J Robinson, Kerrie L Thomas 2, Lawrence S Wilkinson, Trevor Humby, Jeremy Hall, Dominic M Dwyer .Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder. Genes Brain Behav. 2022 Apr; 21(4):e12797.
• 39.   Kazuhiro Ishii, Ken-Ichiro Kubo, Kazunori Nakajima .Reelin and Neuropsychiatric Disorders.. Review Front Cell Neurosci. 2016 Oct 18:10:229.
• 40.   Richard Paylor, Beate Glaser, Annalisa Mupo, Paris Ataliotis, Corinne Spencer, Angela Sobotka, Chelsey Sparks, Chul-Hee Choi, John Oghalai, Sarah Curran, Kieran C Murphy, Stephen Monks, Nigel Williams, Michael C O’Donovan, Michael J Owen, Peter J Scambler, Elizabeth Lindsay.. Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome.Proc Natl AcadSci U S A. 2006 May 16; 103(20):7729-34.
• 41.   Kazuo Nakajima, Mizuho Ishiwata, Adam Z Weitemier, Hirotaka Shoji, HiromuMonai, Hiroyuki Miyamoto, Kazuhiro Yamakawa, Tsuyoshi Miyakawa, Thomas J McHugh, Tadafumi Kato. Brain-specific heterozygous loss-of-function of ATP2A2, endoplasmic reticulum Ca2+ pump responsible for Darier’s disease, causes behavioral abnormalities and a hyper-dopaminergic state. HumMol Genet. 2021 Aug 28; 30(18):1762-1772.
• 42.   Susan E Maloney, Katherine B McCullough, Sneha M Chaturvedi, Din Selmanovic, Rebecca Chase, Jiayang Chen, Doris Wu, Jorge L Granadillo, Kristen L Kroll, Joseph D Dougherty .A survey of hypothalamic phenotypes identifies molecular and behavioral consequences of MYT1L haploinsufficiency in male and female mice. bioRxiv [Preprint]. 2024 Nov 25:2024.11.25.625294.
• 43.   Junyeop Daniel Roh, Mihyun Bae, Hyosang Kim, Yeji Yang, Yeunkeum Lee, Yisul Cho, Suho Lee, Yan Li, Esther Yang, Hyunjee Jang, Hyeonji Kim, Hyun Kim, Hyojin Kang, Jacob Ellegood, Jason P Lerch, Yong Chul Bae, Jin Young Kim, Eunjoon Kim .Lithium normalizes ASD-related neuronal, synaptic, and behavioral phenotypes in DYRK1Aknockin mice. Mol Psychiatry 2024 Dec 5.
• 44.   Kristina M Yim Marybeth Baumgartner, Martina Krenzer, Maria F Rosales Larios, Guillermina HillTeran, Timothy Nottoli, Rebecca A Muhle, James P Noonan .Cell type-specific dysregulation of gene expression due to Chdhaploinsufficiency during mouse cortical development. bioRxiv[Preprint]. 2024 Aug 15:2024.08.14.608000.
• 45.   Summer A Morrill, Angelika Amon. Whyhaploinsufficiencypersists.Proc Natl AcadSci U S A. 2019 Jun 11; 116(24):11866-11871.
• 46.   Michaela de Clare, Pinar Pir, Stephen G Oliver. Haploinsufficiency and the sex chromosomes from yeasts to humans.BMC Biol. 2011 Feb 28:9:15. Doi: 10.1186/1741-7007-9-15.
• 47.   Liang Yang, JialiLyu, Xi Li, GaigaiGuo, Xueya Zhou, Taoyu Chen, Yi Lin, Tingting Li. Phase separation as a possible mechanism for dosage sensitivity. Genome Biol. 2024 Jan 15;25(1):17. doi: 10.1186/ s13059-023-03128-z.
• 48.   GiorgiaSimonetti, Samantha Bruno, Antonella Padella, Elena Tenti, Giovanni Martinelli. Aneuploidy: Cancer strength or vulnerability?Int J Cancer. 2018 Oct 31;144(1):8–25. doi: 10.1002/ ijc.31718.
• 49.   James A Birchler, Reiner A Veitia.Gene balance hypothesis: connecting issues of dosage sensitivity across biological disciplines. Review Proc Natl AcadSci U S A. 2012 Sep 11; 109(37):14746-53.
• 50.   Uri Ben-David, Angelika Amon .Context is everything: aneuploidy in cancer.Review Nat Rev Genet. 2020 Jan; 21(1):44-62.
• 51.   Christopher M Jakobson, Jose Aguilar-Rodriguez, Daniel F Jarosz.Hsp90 shapes adaptation by controlling the fitness consequences of regulatory variation. bioRxiv [Preprint]. 2023 Nov 2:2023.10.30.564848
• 52.   Angela Stoddart, Anthony A Fernald, Elizabeth M Davis, Megan E McNerney, Michelle M Le Beau 4.EGR1 Haploinsufficiency Confers a Fitness Advantage to Hematopoietic Stem Cells Following Chemotherapy. ExpHematol. 2022 Nov:115: 54-67.
• 53.   Fyodor A Kondrashov, Eugene V Koonin.A common framework for understanding the origin of genetic dominance and evolutionary fates of gene duplications.Review Trends Genet. 2004 Jul; 20(7):287-90.
• 54.   Rebecca Kingdom, Caroline F Wright. Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts. Front Genet. 2022 Jul 25;13:920390. doi: 10.3389/fgene.2022.920390.
• 55.   Robert Ahrends, Asuka Ota, Kyle M Kovary, Takamasa Kudo, ByungOuk Park, Mary N Terue. Controlling low rates of cell differentiation through noise and ultrahigh feedback.Science. 2014 Jun 20;344(6190):1384-9. doi: 10.1126/ science.1252079.
• 56.   AnupamDey, DebashisBarik.Parallel arrangements of positive feedback loops limit cell-to-cell variability in differentiation.PLoS One. 2017 Nov 29;12(11):e0188623. doi: 10.1371/journal. pone.0188623. eCollection 2017.
• 57.   Ipsita Agarwal, Zachary L Fuller, Simon R Myers, Molly Przeworski .Relating pathogenic loss-offunction mutations in humans to their evolutionary fitness costs. Elife. 2023 Jan 17:12:e83172.
• 58.   Matthew Norris,imon Lovell, Daniela Delneri. Characterization and prediction of haploinsufficiency using systems-level gene properties in yeast. G3 (Bethesda). 2013 Nov 6; 3(11):1965-77.
• 59.   Kevin A Bird,J Chris Pires,RobertVanBuren, ZhiyongXiong, Patrick P Edger.Dosage-sensitivity shapes how genes transcriptionally respond to allopolyploidy and homoeologous exchange in resynthesized Brassica napus.Genetics.
• 60.   M Felicia Basilicata, Claudia Isabelle Keller Valsecchi. The good, the bad, and the ugly: Evolutionary and pathological aspects of gene dosage alterations.PLoS Genet. 2021 Dec 9;17(12):e1009906. doi: 10.1371/ journal.pgen.1009906. eCollection 2021 Dec.
• 61.   Elena F Evans,Zeenat A Shyr, Bryan J Traynor, Wei Zheng .Therapeutic development approaches to treat haploinsufficiency diseases: restoring protein levels. Review Drug Discov Today. 2024 Dec; 29(12):104201.
• 62.   Sheng Wang, Jian Peng.Network-assisted target identification for haploinsufficiency and homozygous profiling screens.PLoSComput Bio. 2017 Jun 2;13(6):e1005553. doi: 10.1371/journal. pcbi.1005553. eCollection 2017 Jun.
• 63.   Virginia E Glazier, JurajKramara, TomyeOllinger, Norma V Solis, Robert Zarnowski, Rohan S Wakade, Min-Ju Kim, Gabriel J Weigel 2, ShenHuan Liang, Richard J Bennett, Melanie Wellington, David R Andes, Mark A Stamnes, Scott G Filler 3, Damian J Krysan.The Candida albicans reference strain SC5314 contains a rare, dominant allele of the transcription factor Rob1 that modulates filamentation, biofilm formation, and oral commensalism.mBio. 2023 Oct 31;14(5):e0152123. doi: 10.1128/mbio.01521-23. Epub 2023 Sep 22.

Data Sharing Statement

Funding