Editing Zebrafish (section)

==Scientific research==
[[Image:Zfishchroma.jpg|thumb|upright|Zebrafish [[chromatophore]]s, shown here mediating [[camouflage|background adaptation]], are widely studied by scientists.]]
[[File:Zebrafish embryos.png|thumb|A zebrafish pigment mutant (bottom) produced by insertional [[mutagenesis]].<ref name=Parichy2006/> A wild-type embryo (top) is shown for comparison. The mutant lacks black [[pigment]] in its [[melanocyte]]s because it is unable to synthesize [[melanin]] properly.]]

''D. rerio'' is a common and useful scientific [[model organism]] for studies of [[vertebrate]] development and [[gene]] function. Its use as a laboratory animal was pioneered by the American [[molecular biologist]] [[George Streisinger]] and his colleagues at the [[University of Oregon]] in the 1970s and 1980s; Streisinger's zebrafish [[List of animals that have been cloned|clones]] were among the earliest successful vertebrate clones created.<ref name=StreiClone>{{cite web |url=http://www.neuro.uoregon.edu/k12/george_streisinger.html |title=In Memory of George Streisinger, "Founding Father" of Zebrafish Developmental and Genetic Research |publisher=[[University of Oregon]] |access-date=September 23, 2015 |archive-date=September 29, 2015 |archive-url=https://web.archive.org/web/20150929003619/http://www.neuro.uoregon.edu/k12/george_streisinger.html}}</ref> Its importance has been consolidated by successful large-scale forward [[genetic screen]]s (commonly referred to as the Tübingen/Boston screens). The fish has a dedicated online database of genetic, genomic, and developmental information, the [[Zebrafish Information Network]] (ZFIN). The Zebrafish International Resource Center (ZIRC) is a genetic resource repository with 29,250 [[alleles]] available for distribution to the research community. ''D. rerio'' is also one of the few fish species [[Animals in space|to have been sent into space]].

Research with ''D. rerio'' has yielded advances in the fields of [[developmental biology]], [[oncology]],<ref>{{cite journal |vauthors=Xiang J, Yang H, Che C, Zou H, Yang H, Wei Y, Quan J, Zhang H, Yang Z, Lin S |display-authors=6 |title=Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays |journal=[[PLOS ONE]] |volume=4 |issue=2 |pages=e4361 |year=2009 |pmid=19194508 |pmc=2633036 |doi=10.1371/journal.pone.0004361 |editor1-last=Isalan |doi-access=free |bibcode=2009PLoSO...4.4361X |editor1-first=Mark}}</ref> [[toxicology]],<ref name="Hill 6–19"/><ref>{{cite journal |vauthors=Bugel SM, Tanguay RL, Planchart A |title=Zebrafish: A marvel of high-throughput biology for 21st century toxicology |journal=Current Environmental Health Reports |volume=1 |issue=4 |pages=341–352 |date=September 2014 |pmid=25678986 |pmc=4321749 |doi=10.1007/s40572-014-0029-5 |bibcode=2014CEHR....1..341B}}</ref><ref>{{cite journal |vauthors=Dubińska-Magiera M, Daczewska M, Lewicka A, Migocka-Patrzałek M, Niedbalska-Tarnowska J, Jagla K |title=Zebrafish: A Model for the Study of Toxicants Affecting Muscle Development and Function |journal=International Journal of Molecular Sciences |volume=17 |issue=11 |page=1941 |date=November 2016 |pmid=27869769 |pmc=5133936 |doi=10.3390/ijms17111941 |doi-access=free}}</ref> reproductive studies, [[teratology]], [[genetics]], [[neurobiology]], [[environmental science]]s, [[stem cell]] research, [[regenerative medicine]],<ref>{{cite journal |vauthors=Major RJ, Poss KD |title=Zebrafish Heart Regeneration as a Model for Cardiac Tissue Repair |journal=Drug Discovery Today: Disease Models |volume=4 |issue=4 |pages=219–225 |year=2007 |pmid=19081827 |pmc=2597874 |doi=10.1016/j.ddmod.2007.09.002}}</ref><ref>{{cite web |url=https://www.voanews.com/a/adult-stem-cell-research-avoids-ethical-concerns-94507429/169472.html |title=Adult Stem Cell Research Avoids Ethical Concerns |publisher=Voice of America |date=19 May 2010 |access-date=21 June 2013 |archive-date=6 December 2014 |archive-url=https://web.archive.org/web/20141206163006/http://www.voanews.com/content/adult-stem-cell-research-avoids-ethical-concerns-94507429/169472.html |url-status=live}}</ref> [[Muscular dystrophy|muscular dystrophies]]<ref name="Model organisms in the fight agains">{{cite journal |vauthors=Plantié E, Migocka-Patrzałek M, Daczewska M, Jagla K |title=Model organisms in the fight against muscular dystrophy: lessons from drosophila and Zebrafish |journal=Molecules |volume=20 |issue=4 |pages=6237–6253 |date=April 2015 |pmid=25859781 |pmc=6272363 |doi=10.3390/molecules20046237 |doi-access=free}}</ref> and [[evolutionary theory]].<ref name=Parichy2006/>

===Model characteristics===
As a model biological system, the zebrafish possesses numerous advantages for scientists. Its [[genome]] has been [[whole genome sequencing|fully sequenced]], and it has well-understood, easily observable and testable developmental behaviors. Its [[embryogenesis|embryonic development]] is very rapid, and its embryos are relatively large, robust, and transparent, and able to develop outside their mother.<ref>{{cite journal |title=The Zebrafish Exposed |first1=Ralf |last1=Dahm |name-list-style=vanc |journal=American Scientist |volume=94 |issue=5 |year=2006 |pages=446–53 |url=http://www.americanscientist.org/issues/feature/the-zebrafish-exposed |doi=10.1511/2006.61.446 |access-date=2012-11-15 |archive-date=2017-04-18 |archive-url=https://web.archive.org/web/20170418051522/http://www.americanscientist.org/issues/feature/the-zebrafish-exposed}}</ref> Furthermore, well-characterized mutant strains are readily available.

Other advantages include the species' nearly constant size during early development, which enables simple [[staining]] techniques to be used, and the fact that its two-celled embryo can be fused into a single cell to create a [[homozygous]] embryo. The zebrafish embryos are transparent and they develop outside of the uterus, which allows scientists to study the details of development starting from fertilization and continuing throughout development. The zebrafish is also demonstrably similar to mammalian models and humans in toxicity testing, and exhibits a diurnal sleep cycle with similarities to mammalian sleep behavior.<ref>{{cite journal |vauthors=Jones R |title=Let sleeping zebrafish lie: a new model for sleep studies |journal=PLOS Biology |volume=5 |issue=10 |pages=e281 |date=October 2007 |pmid=20076649 |pmc=2020498 |doi=10.1371/journal.pbio.0050281 |doi-access=free}}</ref> However, zebrafish are not a universally ideal research model; there are a number of disadvantages to their scientific use, such as the absence of a standard diet<ref>{{cite journal |vauthors=Penglase S, Moren M, Hamre K |title=Lab animals: Standardize the diet for zebrafish model |journal=[[Nature (journal)|Nature]] |volume=491 |issue=7424 |page=333 |date=November 2012 |pmid=23151568 |doi=10.1038/491333a |doi-access=free |bibcode=2012Natur.491..333P}}</ref> and the presence of small but important differences between zebrafish and mammals in the roles of some genes related to human disorders.<ref>{{cite journal |vauthors=Jurynec MJ, Xia R, Mackrill JJ, Gunther D, Crawford T, Flanigan KM, Abramson JJ, Howard MT, Grunwald DJ |display-authors=6 |title=Selenoprotein N is required for ryanodine receptor calcium release channel activity in human and zebrafish muscle |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=105 |issue=34 |pages=12485–12490 |date=August 2008 |pmid=18713863 |pmc=2527938 |doi=10.1073/pnas.0806015105 |doi-access=free |bibcode=2008PNAS..10512485J}}</ref><ref>{{cite journal |vauthors=Rederstorff M, Castets P, Arbogast S, Lainé J, Vassilopoulos S, Beuvin M, Dubourg O, Vignaud A, Ferry A, Krol A, Allamand V, Guicheney P, Ferreiro A, Lescure A |display-authors=6 |title=Increased muscle stress-sensitivity induced by selenoprotein N inactivation in mouse: a mammalian model for SEPN1-related myopathy |journal=PLOS ONE |volume=6 |issue=8 |pages=e23094 |date=2011 |pmid=21858002 |pmc=3152547 |doi=10.1371/journal.pone.0023094 |doi-access=free |bibcode=2011PLoSO...623094R}}</ref>

===Regeneration===
Zebrafish have the ability to [[Regeneration (biology)|regenerate]] their heart and [[lateral line]] [[hair cell]]s during their larval stages.<ref name=Wade>{{cite news |title=Research Offers Clue Into How Hearts Can Regenerate in Some Species |last=Wade |first=Nicholas |work=The New York Times |date=March 24, 2010 |url=https://www.nytimes.com/2010/03/25/science/25heart.html |archive-url=https://ghostarchive.org/archive/20220101/https://www.nytimes.com/2010/03/25/science/25heart.html |archive-date=2022-01-01 |url-access=limited}}{{cbignore}}</ref><ref name="autogenerated1187">{{cite journal |vauthors=Lush ME, Piotrowski T |title=Sensory hair cell regeneration in the zebrafish lateral line |journal=Developmental Dynamics |volume=243 |issue=10 |pages=1187–1202 |date=October 2014 |pmid=25045019 |pmc=4177345 |doi=10.1002/dvdy.24167}}</ref> The cardiac regenerative process likely involves signaling pathways such as [[Notch signaling pathway|Notch]] and [[Wnt signaling pathway|Wnt]]; hemodynamic changes in the damaged heart are sensed by ventricular [[Endothelium|endothelial cells]] and their associated cardiac cilia by way of the mechanosensitive ion channel [[TRPV4]], subsequently facilitating the [[Notch signaling pathway]] via [[KLF2]] and activating various downstream effectors such as [[Bone morphogenetic protein 2|BMP-2]] and [[HER2/neu]].<ref>{{cite web |last1=Teske |first1=Christopher |title=An Evolving Role for Notch Signaling in Heart Regeneration of the Zebrafish Danio rerio |url=https://www.researchgate.net/publication/362704455 |website=Researchgate.com |access-date=4 October 2022 |archive-date=19 May 2024 |archive-url=https://web.archive.org/web/20240519141133/https://www.researchgate.net/publication/362704455_An_Evolving_Role_for_Notch_Signaling_in_Heart_Regeneration_of_the_Zebrafish_Danio_rerio |url-status=live}}</ref> In 2011, the [[British Heart Foundation]] ran an advertising campaign publicising its intention to study the applicability of this ability to humans, stating that it aimed to raise £50 million in research funding.<ref>{{cite web |url=https://www.youtube.com/watch?v=djFb8PGS34g |archive-url=https://ghostarchive.org/varchive/youtube/20211117/djFb8PGS34g |archive-date=2021-11-17 |url-status=live |title=Mending Broken Hearts (2011) British Heart Foundation TV ad |publisher=[[British Heart Foundation]] via YouTube |date=January 31, 2011 |access-date=November 15, 2012}}{{cbignore}}</ref><ref>{{cite web |url=http://www.bhf.org.uk/research/mending-broken-hearts-appeal/the-science.aspx?pid=p&sc_cid=MBH-EX-24&gclid=CL2w_L2hhqcCFcgf4QodBA25eA |title=British Heart Foundation – The science behind the appeal |publisher=Bhf.org.uk |date=February 16, 2007 |access-date=November 15, 2012 |archive-url=https://web.archive.org/web/20120310000952/http://www.bhf.org.uk/research/mending-broken-hearts-appeal/the-science.aspx?pid=p&sc_cid=MBH-EX-24&gclid=CL2w_L2hhqcCFcgf4QodBA25eA |archive-date=10 March 2012}}</ref>

Zebrafish have also been found to regenerate [[photoreceptor cells]] and [[retina]]l neurons following injury, which has been shown to be mediated by the dedifferentiation and proliferation of [[Muller glia|Müller glia]].<ref>{{cite journal |vauthors=Bernardos RL, Barthel LK, Meyers JR, Raymond PA |title=Late-stage neuronal progenitors in the retina are radial Müller glia that function as retinal stem cells |journal=The Journal of Neuroscience |volume=27 |issue=26 |pages=7028–7040 |date=June 2007 |pmid=17596452 |pmc=6672216 |doi=10.1523/JNEUROSCI.1624-07.2007}}</ref> Researchers frequently [[amputate]] the dorsal and ventral tail fins and analyze their regrowth to test for mutations. It has been found that [[Histone methylation|histone demethylation]] occurs at the site of the amputation, switching the zebrafish's cells to an "active", regenerative, stem cell-like state.<ref>{{cite journal |vauthors=Stewart S, Tsun ZY, Izpisua Belmonte JC |title=A histone demethylase is necessary for regeneration in zebrafish |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=106 |issue=47 |pages=19889–19894 |date=November 2009 |pmid=19897725 |pmc=2785262 |doi=10.1073/pnas.0904132106 |doi-access=free |bibcode=2009PNAS..10619889S |jstor=25593294}}</ref><ref>{{Cite web |url=https://www.sciencedaily.com/releases/2009/11/091102171419.htm |title=Organ Regeneration In Zebrafish: Unraveling The Mechanisms |website=ScienceDaily |access-date=2018-03-09 |archive-date=2018-02-05 |archive-url=https://web.archive.org/web/20180205130047/https://www.sciencedaily.com/releases/2009/11/091102171419.htm |url-status=live}}</ref> In 2012, Australian scientists published a study revealing that zebrafish use a specialised [[protein]], known as [[fibroblast growth factor]], to ensure their [[spinal cord]]s heal without [[glial scar]]ring after injury.<ref name=Regen2012>{{cite journal |vauthors=Goldshmit Y, Sztal TE, Jusuf PR, Hall TE, Nguyen-Chi M, Currie PD |title=Fgf-dependent glial cell bridges facilitate spinal cord regeneration in zebrafish |journal=The Journal of Neuroscience |volume=32 |issue=22 |pages=7477–7492 |date=May 2012 |pmid=22649227 |pmc=6703582 |doi=10.1523/JNEUROSCI.0758-12.2012}}</ref><ref>{{Cite web |url=http://www.sci-news.com/othersciences/biochemistry/article00366.html |title=Study Reveals Secret of Zebrafish &#124; Biochemistry &#124; Sci-News.com |website=Breaking Science News &#124; Sci-News.com |access-date=2012-06-02 |archive-date=2020-11-11 |archive-url=https://web.archive.org/web/20201111224203/http://www.sci-news.com/othersciences/biochemistry/article00366.html |url-status=live}}</ref> In addition, [[hair cell]]s of the posterior [[lateral line]] have also been found to regenerate following damage or developmental disruption.<ref name="autogenerated1187"/><ref name="autogenerated832">{{cite journal |vauthors=Head JR, Gacioch L, Pennisi M, Meyers JR |title=Activation of canonical Wnt/β-catenin signaling stimulates proliferation in neuromasts in the zebrafish posterior lateral line |journal=Developmental Dynamics |volume=242 |issue=7 |pages=832–846 |date=July 2013 |pmid=23606225 |doi=10.1002/dvdy.23973 |doi-access=free}}</ref> Study of gene expression during regeneration has allowed for the identification of several important signaling pathways involved in the process, such as [[Wnt signaling]] and [[Fibroblast growth factor]].<ref name="autogenerated832"/><ref>{{cite journal |vauthors=Steiner AB, Kim T, Cabot V, Hudspeth AJ |title=Dynamic gene expression by putative hair-cell progenitors during regeneration in the zebrafish lateral line |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=111 |issue=14 |pages=E1393–E1401 |date=April 2014 |pmid=24706895 |pmc=3986164 |doi=10.1073/pnas.1318692111 |doi-access=free |bibcode=2014PNAS..111E1393S}}</ref>

In probing disorders of the nervous system, including neurodegenerative diseases, movement disorders, psychiatric disorders and deafness, researchers are using the zebrafish to understand how the genetic defects underlying these conditions cause functional abnormalities in the human brain, spinal cord and sensory organs.<ref name="Kizil">{{cite journal |vauthors=Kizil C |title=Mechanisms of Pathology-Induced Neural Stem Cell Plasticity and Neural Regeneration in Adult Zebrafish Brain |journal=Current Pathobiology Reports |volume=6 |issue=1 |pages=71–77 |date=January 2018 |pmid=29938129 |pmc=5978899 |doi=10.1007/s40139-018-0158-x}}</ref><ref name="Cosacak">{{cite journal |vauthors=Cosacak MI, Bhattarai P, Reinhardt S, Petzold A, Dahl A, Zhang Y, Kizil C |title=Single-Cell Transcriptomics Analyses of Neural Stem Cell Heterogeneity and Contextual Plasticity in a Zebrafish Brain Model of Amyloid Toxicity |journal=Cell Reports |volume=27 |issue=4 |pages=1307–1318.e3 |date=April 2019 |pmid=31018142 |doi=10.1016/j.celrep.2019.03.090 |doi-access=free}}</ref><ref name="Bhattarai">{{cite journal |vauthors=Bhattarai P, Cosacak MI, Mashkaryan V, Demir S, Popova SD, Govindarajan N, Brandt K, Zhang Y, Chang W, Ampatzis K, Kizil C |display-authors=6 |title=Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer's model of adult zebrafish brain |journal=PLOS Biology |volume=18 |issue=1 |pages=e3000585 |date=January 2020 |pmid=31905199 |pmc=6964913 |doi=10.1371/journal.pbio.3000585 |doi-access=free}}</ref><ref name="Xi">{{cite journal |vauthors=Xi Y, Noble S, Ekker M |title=Modeling neurodegeneration in zebrafish |journal=Current Neurology and Neuroscience Reports |volume=11 |issue=3 |pages=274–282 |date=June 2011 |pmid=21271309 |pmc=3075402 |doi=10.1007/s11910-011-0182-2}}</ref> Researchers have also studied the zebrafish to gain new insights into the complexities of human musculoskeletal diseases, such as [[muscular dystrophy]].<ref>{{cite journal |vauthors=Bassett DI, Currie PD |title=The zebrafish as a model for muscular dystrophy and congenital myopathy |journal=Human Molecular Genetics |volume=12 |issue=Spec No 2 |pages=R265–R270 |date=October 2003 |pmid=14504264 |doi=10.1093/hmg/ddg279 |doi-access=free}}</ref> Another focus of zebrafish research is to understand how a gene called [[Hedgehog signaling pathway|Hedgehog]], a biological signal that underlies a number of human cancers, controls cell growth.

===Genetics===

====Background genetics====
[[Inbred strains]] and traditional outbred stocks have not been developed for laboratory zebrafish, and the genetic variability of wild-type lines among institutions may contribute to the [[replication crisis]] in biomedical research.<ref>{{cite journal |vauthors=Crim MJ, Lawrence C |title=A fish is not a mouse: understanding differences in background genetics is critical for reproducibility |journal=Lab Animal |volume=50 |issue=1 |pages=19–25 |date=January 2021 |pmid=33268901 |doi=10.1038/s41684-020-00683-x |issn=0093-7355 |s2cid=227259359}}</ref> Genetic differences in wild-type lines among populations maintained at different research institutions have been demonstrated using both [[Single-nucleotide polymorphism]]s<ref>{{cite journal |vauthors=Whiteley AR, Bhat A, Martins EP, Mayden RL, Arunachalam M, Uusi-Heikkilä S, Ahmed AT, Shrestha J, Clark M, Stemple D, Bernatchez L |display-authors=6 |title=Population genomics of wild and laboratory zebrafish (''Danio rerio'') |journal=Molecular Ecology |volume=20 |issue=20 |pages=4259–4276 |date=October 2011 |pmid=21923777 |pmc=3627301 |doi=10.1111/j.1365-294X.2011.05272.x |bibcode=2011MolEc..20.4259W}}</ref> and [[microsatellite]] analysis.<ref>{{cite journal |vauthors=Coe TS, Hamilton PB, Griffiths AM, Hodgson DJ, Wahab MA, Tyler CR |title=Genetic variation in strains of zebrafish (''Danio rerio'') and the implications for ecotoxicology studies |journal=Ecotoxicology |volume=18 |issue=1 |pages=144–150 |date=January 2009 |pmid=18795247 |doi=10.1007/s10646-008-0267-0 |bibcode=2009Ecotx..18..144C |s2cid=18370151}}</ref>

====Gene expression====
Due to their fast and short life cycles and relatively large clutch sizes, ''D. rerio'' or zebrafish are a useful model for genetic studies. A common [[reverse genetics]] technique is to [[gene knockdown|reduce gene expression]] or modify [[Splicing (genetics)|splicing]] using [[Morpholino]] [[antisense]] technology. Morpholino [[oligonucleotide]]s (MO) are stable, synthetic [[macromolecule]]s that contain the same [[nucleoside|bases]] as DNA or RNA; by binding to complementary RNA sequences, they can reduce the [[gene expression|expression]] of specific genes or block other processes from occurring on RNA. MO can be injected into one cell of an embryo after the 32-cell stage, reducing gene expression in only cells descended from that cell. However, cells in the early embryo (less than 32 cells) are permeable to large molecules,<ref name=blast2>{{cite journal |vauthors=Kimmel CB, Law RD |title=Cell lineage of zebrafish blastomeres. I. Cleavage pattern and cytoplasmic bridges between cells |journal=Developmental Biology |volume=108 |issue=1 |pages=78–85 |date=March 1985 |pmid=3972182 |doi=10.1016/0012-1606(85)90010-7}}</ref><ref name=blast4>{{cite journal |vauthors=Kimmel CB, Law RD |title=Cell lineage of zebrafish blastomeres. III. Clonal analyses of the blastula and gastrula stages |journal=Developmental Biology |volume=108 |issue=1 |pages=94–101 |date=March 1985 |pmid=3972184 |doi=10.1016/0012-1606(85)90012-0}}</ref> allowing diffusion between cells. Guidelines for using Morpholinos in zebrafish describe appropriate control strategies.<ref>{{cite journal |vauthors=Stainier DY, Raz E, Lawson ND, Ekker SC, Burdine RD, Eisen JS, Ingham PW, Schulte-Merker S, Yelon D, Weinstein BM, Mullins MC, Wilson SW, Ramakrishnan L, Amacher SL, Neuhauss SC, Meng A, Mochizuki N, Panula P, Moens CB |display-authors=6 |title=Guidelines for morpholino use in zebrafish |journal=PLOS Genetics |volume=13 |issue=10 |pages=e1007000 |date=October 2017 |pmid=29049395 |pmc=5648102 |doi=10.1371/journal.pgen.1007000 |doi-access=free}}</ref> Morpholinos are commonly [[microinjection|microinjected]] in 500pL directly into 1–2 cell stage zebrafish embryos. The morpholino is able to integrate into most cells of the embryo.<ref>{{cite journal |vauthors=Rosen JN, Sweeney MF, Mably JD |title=Microinjection of zebrafish embryos to analyze gene function |journal=Journal of Visualized Experiments |issue=25 |date=March 2009 |pmid=19274045 |pmc=2762901 |doi=10.3791/1115}}</ref>

A known problem with gene knockdowns is that, because the genome underwent a [[genome#Genome evolution|duplication]] after the divergence of [[ray-finned fish]]es and [[lobe-finned fish]]es, it is not always easy to silence the activity of one of the two gene [[paralog]]s reliably due to [[Complementation (genetics)|complementation]] by the other paralog.<ref>{{cite journal |vauthors=Leong IU, Lan CC, Skinner JR, Shelling AN, Love DR |title=In vivo testing of microRNA-mediated gene knockdown in zebrafish |journal=Journal of Biomedicine & Biotechnology |volume=2012 |page=350352 |year=2012 |pmid=22500088 |pmc=3303736 |doi=10.1155/2012/350352 |publisher=Hindawi |doi-access=free}}</ref> Despite the complications of the zebrafish [[genome]], a number of commercially available global platforms exist for analysis of both gene expression by [[expression profiling|microarrays]] and promoter regulation using [[ChIP-on-chip]].<ref>{{cite journal |vauthors=Tan PK, Downey TJ, Spitznagel EL, Xu P, Fu D, Dimitrov DS, Lempicki RA, Raaka BM, Cam MC |display-authors=6 |title=Evaluation of gene expression measurements from commercial microarray platforms |journal=Nucleic Acids Research |volume=31 |issue=19 |pages=5676–5684 |date=October 2003 |pmid=14500831 |pmc=206463 |doi=10.1093/nar/gkg763}}</ref>

====Genome sequencing====
The [[Wellcome Trust Sanger Institute]] started the zebrafish genome sequencing project in 2001, and the full genome sequence of the Tuebingen reference strain is publicly available at the [[National Center for Biotechnology Information]] (NCBI)'s [https://www.ncbi.nlm.nih.gov/genome?term=danio%20rerio Zebrafish Genome Page]. The zebrafish reference genome sequence is annotated as part of the [[Ensembl]] [http://www.ensembl.org/Danio_rerio/Info/Index project], and is maintained by the [[Genome Reference Consortium]].<ref>{{cite web |title=Genome Reference Consortium |url=https://www.ncbi.nlm.nih.gov/projects/genome/assembly/grc/ |publisher=GRC |access-date=October 23, 2012 |archive-date=October 5, 2016 |archive-url=https://web.archive.org/web/20161005062544/https://www.ncbi.nlm.nih.gov/projects/genome/assembly/grc/ |url-status=live}}</ref>

In 2009, researchers at the [[Institute of Genomics and Integrative Biology]] in Delhi, India, announced the sequencing of the genome of a wild zebrafish strain, containing an estimated 1.7 billion genetic letters.<ref>[http://www.indianexpress.com/news/Decoding-the-Genome-Mystery/485122 "Decoding the Genome Mystery"] {{Webarchive|url=https://web.archive.org/web/20090715190646/http://www.indianexpress.com/news/Decoding-the-Genome-Mystery/485122 |date=2009-07-15 }}. ''[[Indian Express]]''. July 5, 2009. Retrieved February 5, 2013.</ref><ref>[http://genome.igib.res.in/ FishMap Zv8] {{Webarchive|url=https://web.archive.org/web/20180719084933/http://genome.igib.res.in/ |date=2018-07-19 }}. [[Institute of Genomics and Integrative Biology]] (IGIB). Retrieved June 7, 2012.</ref> The genome of the wild zebrafish was sequenced at 39-fold coverage. Comparative analysis with the zebrafish reference genome revealed over 5 million single nucleotide variations and over 1.6 million insertion deletion variations. The zebrafish reference genome sequence of 1.4GB and over 26,000 protein coding genes was published by Kerstin Howe ''et al.'' in 2013.<ref name=howe2013>{{cite journal |vauthors=Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C, Muffato M, Collins JE, Humphray S, McLaren K, Matthews L, McLaren S, Sealy I, Caccamo M, Churcher C, Scott C, Barrett JC, Koch R, Rauch GJ, White S, Chow W, Kilian B, Quintais LT, Guerra-Assunção JA, Zhou Y, Gu Y, Yen J, Vogel JH, Eyre T, Redmond S, Banerjee R, Chi J, Fu B, Langley E, Maguire SF, Laird GK, Lloyd D, Kenyon E, Donaldson S, Sehra H, Almeida-King J, Loveland J, Trevanion S, Jones M, Quail M, Willey D, Hunt A, Burton J, Sims S, McLay K, Plumb B, Davis J, Clee C, Oliver K, Clark R, Riddle C, Elliot D, Eliott D, Threadgold G, Harden G, Ware D, Begum S, Mortimore B, Mortimer B, Kerry G, Heath P, Phillimore B, Tracey A, Corby N, Dunn M, Johnson C, Wood J, Clark S, Pelan S, Griffiths G, Smith M, Glithero R, Howden P, Barker N, Lloyd C, Stevens C, Harley J, Holt K, Panagiotidis G, Lovell J, Beasley H, Henderson C, Gordon D, Auger K, Wright D, Collins J, Raisen C, Dyer L, Leung K, Robertson L, Ambridge K, Leongamornlert D, McGuire S, Gilderthorp R, Griffiths C, Manthravadi D, Nichol S, Barker G, Whitehead S, Kay M, Brown J, Murnane C, Gray E, Humphries M, Sycamore N, Barker D, Saunders D, Wallis J, Babbage A, Hammond S, Mashreghi-Mohammadi M, Barr L, Martin S, Wray P, Ellington A, Matthews N, Ellwood M, Woodmansey R, Clark G, Cooper J, Cooper J, Tromans A, Grafham D, Skuce C, Pandian R, Andrews R, Harrison E, Kimberley A, Garnett J, Fosker N, Hall R, Garner P, Kelly D, Bird C, Palmer S, Gehring I, Berger A, Dooley CM, Ersan-Ürün Z, Eser C, Geiger H, Geisler M, Karotki L, Kirn A, Konantz J, Konantz M, Oberländer M, Rudolph-Geiger S, Teucke M, Lanz C, Raddatz G, Osoegawa K, Zhu B, Rapp A, Widaa S, Langford C, Yang F, Schuster SC, Carter NP, Harrow J, Ning Z, Herrero J, Searle SM, Enright A, Geisler R, Plasterk RH, Lee C, Westerfield M, de Jong PJ, Zon LI, Postlethwait JH, Nüsslein-Volhard C, Hubbard TJ, Roest Crollius H, Rogers J, Stemple DL |display-authors=6 |title=The zebrafish reference genome sequence and its relationship to the human genome |journal=[[Nature (journal)|Nature]] |volume=496 |issue=7446 |pages=498–503 |date=April 2013 |pmid=23594743 |pmc=3703927 |doi=10.1038/nature12111 |bibcode=2013Natur.496..498H}}</ref>

====Mitochondrial DNA====
In October 2001, researchers from the [[University of Oklahoma]] published ''D. rerio's'' complete [[mitochondrial DNA]] sequence.<ref name=2001Journal>{{cite journal |vauthors=Broughton RE, Milam JE, Roe BA |title=The complete sequence of the zebrafish (''Danio rerio'') mitochondrial genome and evolutionary patterns in vertebrate mitochondrial DNA |journal=Genome Research |volume=11 |issue=11 |pages=1958–1967 |date=November 2001 |pmid=11691861 |pmc=311132 |doi=10.1101/gr.156801}}</ref> Its length is 16,596 base pairs. This is within 100 base pairs of other related species of fish, and it is notably only 18 pairs longer than the goldfish (''Carassius auratus'') and 21 longer than the [[carp]] (''Cyprinus carpio''). Its gene order and content are identical to the common [[vertebrate]] form of mitochondrial DNA. It contains 13 [[protein]]-coding genes and a noncoding control region containing the [[origin of replication]] for the heavy strand. In between a grouping of five [[tRNA]] genes, a sequence resembling vertebrate origin of light strand replication is found. It is difficult to draw evolutionary conclusions because it is difficult to determine whether base pair changes have adaptive significance via comparisons with other vertebrates' [[nucleotide]] sequences.<ref name=2001Journal/>

====Developmental genetics====
[[T-box]]es and [[homeobox]]es are vital in ''Danio'' similarly to other vertebrates.<ref name="Schier-Talbot-2005">{{cite journal |last1=Schier |first1=Alexander F. |last2=Talbot |first2=William S. |title=Molecular Genetics of Axis Formation in Zebrafish |journal=[[Annual Review of Genetics]] |publisher=[[Annual Reviews (publisher)|Annual Reviews]] |volume=39 |issue=1 |date=2005-12-01 |issn=0066-4197 |doi=10.1146/annurev.genet.37.110801.143752 |pages=561–613 |pmid=16285872}}</ref><ref name="Naiche-et-al-2005">{{cite journal |last1=Naiche |first1=L.A. |last2=Harrelson |first2=Zachary |last3=Kelly |first3=Robert G. |last4=Papaioannou |first4=Virginia E. |title=T-Box Genes in Vertebrate Development |journal=[[Annual Review of Genetics]] |publisher=[[Annual Reviews (publisher)|Annual Reviews]] |volume=39 |issue=1 |date=2005-12-01 |issn=0066-4197 |doi=10.1146/annurev.genet.39.073003.105925 |pages=219–239 |pmid=16285859}}</ref> The Bruce et al. team are known for this area, and in Bruce et al. 2003 & Bruce et al. 2005 uncover the role of two of these elements in [[oocyte]]s of this species.<ref name="Schier-Talbot-2005" /><ref name="Naiche-et-al-2005" /> By interfering via a [[dominance (genetics)|dominant]] nonfunctional [[allele]] and a [[morpholino]] they find the T-box transcription activator [[Eomesodermin]] and its target ''[[mtx2]]'' – a [[transcription factor]] – are vital to [[epiboly]].<ref name="Schier-Talbot-2005" /><ref name="Naiche-et-al-2005" /> (In Bruce et al. 2003 they failed to support the possibility that Eomesodermin behaves like [[Vegt (development)|Vegt]].<ref name="Schier-Talbot-2005" /> Neither they nor anyone else has been able to locate any [[mutation]] which – in the mother – will prevent initiation of the [[mesoderm]] or [[endoderm]] development processes in this species.)<ref name="Schier-Talbot-2005" />

====Pigmentation genes====
In 1999, the ''nacre'' mutation was identified in the zebrafish ortholog of the mammalian ''MITF'' transcription factor.<ref>{{cite journal |vauthors=Lister JA, Robertson CP, Lepage T, Johnson SL, Raible DW |title=nacre encodes a zebrafish microphthalmia-related protein that regulates neural-crest-derived pigment cell fate |journal=Development |volume=126 |issue=17 |pages=3757–3767 |date=September 1999 |pmid=10433906 |doi=10.1242/dev.126.17.3757}}</ref> Mutations in human ''[[MITF]]'' result in eye defects and loss of pigment, a type of [[Waardenburg Syndrome]]. In December 2005, a study of the ''golden'' strain identified the gene responsible for its unusual pigmentation as [[SLC24A5]], a [[solute]] carrier that appeared to be required for [[melanin]] production, and confirmed its function with a Morpholino knockdown. The [[Orthologue|orthologous]] gene was then characterized in humans and a one base pair difference was found to strongly segregate fair-skinned Europeans and dark-skinned Africans.<ref>{{cite journal |vauthors=Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O'donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC |display-authors=6 |title=SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans |journal=Science |volume=310 |issue=5755 |pages=1782–1786 |date=December 2005 |pmid=16357253 |doi=10.1126/science.1116238 |s2cid=2245002 |bibcode=2005Sci...310.1782L}}</ref> <!-- this article is on fish, not on studies...This study featured on the cover of the [[academic journal]] [[Science (journal)|''Science'']] and demonstrates the power of zebrafish as a model organism in the relatively new field of [[comparative genomics]].--> Zebrafish with the ''nacre'' mutation have since been bred with fish with a ''roy orbison (roy)'' mutation to make Casper strain fish that have no melanophores or iridophores, and are transparent into adulthood. These fish are characterized by uniformly pigmented eyes and translucent skin.<ref name=zviv>{{cite journal |vauthors=White RM, Sessa A, Burke C, Bowman T, LeBlanc J, Ceol C, Bourque C, Dovey M, Goessling W, Burns CE, Zon LI |display-authors=6 |title=Transparent adult zebrafish as a tool for in vivo transplantation analysis |journal=Cell Stem Cell |volume=2 |issue=2 |pages=183–189 |date=February 2008 |pmid=18371439 |pmc=2292119 |doi=10.1016/j.stem.2007.11.002}}</ref><ref>{{Cite web |url=https://www.livescience.com/2267-scientists-create-fish-watch-cancer-grow.html |title=Scientists Create See-Through Fish, Watch Cancer Grow |author1=Jeanna Bryner |date=February 6, 2008 |website=livescience.com |access-date=January 23, 2022 |archive-date=May 19, 2024 |archive-url=https://web.archive.org/web/20240519141106/https://www.livescience.com/2267-scientists-create-fish-watch-cancer-grow.html |url-status=live}}</ref>

====Transgenesis====
[[Transgene]]sis is a popular approach to study the function of genes in zebrafish. Construction of transgenic zebrafish is rather easy by a method using the ''Tol2'' transposon system. ''Tol2'' element which encodes a gene for a fully functional transposase capable of catalyzing transposition in the zebrafish germ lineage. ''Tol2'' is the only natural DNA transposable element in vertebrates from which an autonomous member has been identified.<ref>{{cite journal |vauthors=Kawakami K, Takeda H, Kawakami N, Kobayashi M, Matsuda N, Mishina M |title=A transposon-mediated gene trap approach identifies developmentally regulated genes in zebrafish |journal=Developmental Cell |volume=7 |issue=1 |pages=133–144 |date=July 2004 |pmid=15239961 |doi=10.1016/j.devcel.2004.06.005 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Parinov S, Kondrichin I, Korzh V, Emelyanov A |title=Tol2 transposon-mediated enhancer trap to identify developmentally regulated zebrafish genes in vivo |journal=Developmental Dynamics |volume=231 |issue=2 |pages=449–459 |date=October 2004 |pmid=15366023 |doi=10.1002/dvdy.20157 |doi-access=free}}</ref> Examples include the artificial interaction produced between [[Lymphoid enhancer-binding factor 1|LEF1]] and [[Catenin beta-1]]/β-catenin/''CTNNB1''. Dorsky et al. 2002 investigated the developmental role of [[Wnt signaling pathway|Wnt]] by transgenically expressing a Lef1/β-catenin reporter.<ref name="Barolo-Posakony-2002">{{cite journal |vauthors=Barolo S, Posakony JW |title=Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling |journal=Genes & Development |volume=16 |issue=10 |pages=1167–1181 |date=May 2002 |pmid=12023297 |doi=10.1101/gad.976502 |publisher=[[Cold Spring Harbor Laboratory Press]] & [[The Genetics Society]] |s2cid=14376483 |doi-access=free}}</ref> The Tol2 transposon system was used to develop transgenic zebrafish as sensitive biosensors for heavy metal detection. This involved creating a transgenic zebrafish line expressing a fluorescent protein under the control of a heavy metal-responsive promoter, enabling the detection of low concentrations of cadmium (Cd2+) and zinc (Zn2+).<ref name="Herath_et_al_2024">{{cite journal |vauthors=Herath HM etal |title=Innovative transgenic zebrafish biosensor for heavy metal detection |journal=Environmental Pollution |page=125547 |date=2024 |volume=366 |doi=10.1016/j.envpol.2024.125547 |pmid=39694312}}</ref>


There are well-established protocols for editing zebrafish genes using [[CRISPR gene editing|CRISPR-Cas9]]<ref>{{Cite journal |last1=Vejnar |first1=Charles E. |last2=Moreno-Mateos |first2=Miguel A. |last3=Cifuentes |first3=Daniel |last4=Bazzini |first4=Ariel A. |last5=Giraldez |first5=Antonio J. |date=October 2016 |title=Optimized CRISPR–Cas9 System for Genome Editing in Zebrafish |url=http://www.cshprotocols.org/lookup/doi/10.1101/pdb.prot086850 |journal=Cold Spring Harbor Protocols |language=en |volume=2016 |issue=10 |pages=pdb.prot086850 |doi=10.1101/pdb.prot086850 |pmid=27698232 |issn=1940-3402 |access-date=2022-12-05 |archive-date=2024-05-19 |archive-url=https://web.archive.org/web/20240519141211/https://cshprotocols.cshlp.org/content/2016/10/pdb.prot086850 |url-status=live}}</ref> and this tool has been used to generate genetically modified models.

====Transparent adult bodies====
In 2008, researchers at [[Boston Children's Hospital]] developed a new strain of zebrafish, named Casper, whose adult bodies had transparent skin.<ref name=zviv/> This allows for detailed visualization of cellular activity, circulation, [[metastasis]] and many other phenomena.<ref name=zviv/> In 2019 researchers published a crossing of a ''prkdc<sup>-/-</sup>'' and a ''IL2rga<sup>-/-</sup>'' strain that produced transparent, immunodeficient offspring, lacking [[natural killer cell]]s as well as [[B cell|B]]- and [[T cell|T-cells]]. This strain can be adapted to {{convert|37|C|F}} warm water and the absence of an immune system makes the use of patient derived [[Xenotransplantation|xenografts]] possible.<ref>{{cite journal |vauthors=Yan C, Brunson DC, Tang Q, Do D, Iftimia NA, Moore JC, Hayes MN, Welker AM, Garcia EG, Dubash TD, Hong X, Drapkin BJ, Myers DT, Phat S, Volorio A, Marvin DL, Ligorio M, Dershowitz L, McCarthy KM, Karabacak MN, Fletcher JA, Sgroi DC, Iafrate JA, Maheswaran S, Dyson NJ, Haber DA, Rawls JF, Langenau DM |display-authors=6 |title=Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish |journal=Cell |volume=177 |issue=7 |pages=1903–1914.e14 |date=June 2019 |pmid=31031007 |pmc=6570580 |doi=10.1016/j.cell.2019.04.004}}</ref> In January 2013, Japanese scientists genetically modified a transparent zebrafish specimen to produce a visible glow during periods of intense brain activity.<ref name=ithinkz>{{cite news |url=http://www.popsci.com/science/article/2013-01/watch-zebrafish-think-about-food |title=Researchers Capture A Zebrafish's Thought Process On Video |website=Popular Science |date=January 31, 2013 |access-date=February 4, 2013 |archive-date=October 3, 2016 |archive-url=https://web.archive.org/web/20161003135509/http://www.popsci.com/science/article/2013-01/watch-zebrafish-think-about-food |url-status=live}}</ref>

In January 2007, Chinese researchers at [[Fudan University]] genetically modified zebrafish to detect [[oestrogen]] pollution in lakes and rivers, which is linked to male infertility. The researchers cloned oestrogen-sensitive genes and injected them into the fertile eggs of zebrafish. The modified fish turned green if placed into water that was polluted by oestrogen.<ref name=ChinaOest>[https://web.archive.org/web/20080225200714/http://news.xinhuanet.com/english/2007-01/12/content_5597696.htm "Fudan scientists turn fish into estrogen alerts"]. [[Xinhua]]. January 12, 2007. Retrieved November 15, 2012.</ref>

====RNA splicing====
In 2015, researchers at [[Brown University]] discovered that 10% of zebrafish genes do not need to rely on the [[U2AF2]] [[protein]] to initiate [[RNA splicing]]. These genes have the DNA base pairs AC and TG as repeated sequences at the ends of each [[intron]]. On the 3'ss (3' splicing site), the base pairs [[adenine]] and [[cytosine]] alternate and repeat, and on the 5'ss (5' splicing site), their complements [[thymine]] and [[guanine]] alternate and repeat as well. They found that there was less reliance on U2AF2 protein than in humans, in which the protein is required for the splicing process to occur. The pattern of repeating base pairs around introns that alters RNA [[nucleic acid secondary structure|secondary structure]] was found in other [[teleost]]s, but not in [[tetrapod]]s. This indicates that an evolutionary change in tetrapods may have led to humans relying on the U2AF2 protein for RNA splicing while these genes in zebrafish undergo splicing regardless of the presence of the protein.<ref name="BrownRNA">{{cite journal |vauthors=Lin CL, Taggart AJ, Lim KH, Cygan KJ, Ferraris L, Creton R, Huang YT, Fairbrother WG |display-authors=6 |title=RNA structure replaces the need for U2AF2 in splicing |journal=Genome Research |volume=26 |issue=1 |pages=12–23 |date=January 2016 |pmid=26566657 |pmc=4691745 |doi=10.1101/gr.181008.114}}</ref>

====Orthology====
''D. rerio'' has three [[transferrin]]s, all of which cluster closely with other [[vertebrate]]s.<ref name="Gabaldon-Koonin-2013">{{cite journal |vauthors=Gabaldón T, Koonin EV |title=Functional and evolutionary implications of gene orthology |journal=[[Nature Reviews Genetics]] |volume=14 |issue=5 |pages=360–366 |date=May 2013 |pmid=23552219 |pmc=5877793 |doi=10.1038/nrg3456}}</ref>

===Inbreeding depression===
When close relatives mate, progeny may exhibit the detrimental effects of [[inbreeding depression]]. Inbreeding depression is predominantly caused by the [[Zygosity#homozygous|homozygous]] expression of recessive deleterious alleles.<ref name="pmid19834483">{{cite journal |vauthors=Charlesworth D, Willis JH |title=The genetics of inbreeding depression |journal=[[Nature Reviews Genetics]] |volume=10 |issue=11 |pages=783–796 |date=November 2009 |pmid=19834483 |doi=10.1038/nrg2664 |s2cid=771357}}</ref> For zebrafish, inbreeding depression might be expected to be more severe in stressful environments, including those caused by [[Human impact on the environment|anthropogenic pollution]]. Exposure of zebrafish to environmental stress induced by the chemical clotrimazole, an imidazole fungicide used in agriculture and in veterinary and human medicine, amplified the effects of inbreeding on key reproductive traits.<ref name="pmid23798977">{{cite journal |vauthors=Bickley LK, Brown AR, Hosken DJ, Hamilton PB, Le Page G, Paull GC, Owen SF, Tyler CR |display-authors=6 |title=Interactive effects of inbreeding and endocrine disruption on reproduction in a model laboratory fish |journal=Evolutionary Applications |volume=6 |issue=2 |pages=279–289 |date=February 2013 |pmid=23798977 |pmc=3689353 |doi=10.1111/j.1752-4571.2012.00288.x |bibcode=2013EvApp...6..279B}}</ref> Embryo viability was significantly reduced in inbred exposed fish and there was a tendency for inbred males to sire fewer offspring.

===Aquaculture research===
Zebrafish are common models for research into [[fish farming]], including [[fish pathogen|pathogens]]<ref name="Llewellyn-et-al-2014">{{cite journal |last1=Llewellyn |first1=Martin S. |last2=Boutin |first2=Sébastien |last3=Hoseinifar |first3=Seyed Hossein |last4=Derome |first4=Nicolas |title=Teleost microbiomes: the state of the art in their characterization, manipulation and importance in aquaculture and fisheries |journal=[[Frontiers in Microbiology]] |publisher=[[Frontiers Media|Frontiers]] |volume=5 |date=2014-06-02 |page=207 |issn=1664-302X |doi=10.3389/fmicb.2014.00207 |s2cid=13050990 |pmid=24917852 |pmc=4040438 |doi-access=free}}<!--- Published by Frontiers but very highly cited including by Ringø et al., 2016, Ghanbari et al., 2015, Wang et al., 2018, etc. ---></ref><ref name="Dahm-Geisler-2006">{{cite journal |last1=Dahm |first1=Ralf |last2=Geisler |first2=Robert |title=Learning from Small Fry: The Zebrafish as a Genetic Model Organism for Aquaculture Fish Species |journal=Marine Biotechnology |publisher=[[European Society for Marine Biotechnology]] (ESMB) + [[Japanese Society for Marine Biotechnology]] (JSMB) + [[Australia New Zealand Marine Biotechnology Society]] (ANZMBS) ([[Springer Science+Business Media|Springer]]) |volume=8 |issue=4 |date=2006-04-25 |issn=1436-2228 |doi=10.1007/s10126-006-5139-0 |pages=329–345 |s2cid=23994075 |pmid=16670967 |bibcode=2006MarBt...8..329D}}</ref><ref name="Ribas-Piferrer-2014">{{cite journal |last1=Ribas |first1=Laia |last2=Piferrer |first2=Francesc |title=The zebrafish (''Danio rerio'') as a model organism, with emphasis on applications for finfish aquaculture research |journal=[[Reviews in Aquaculture]] |publisher=[[Wiley publishing|Wiley]] |volume=6 |issue=4 |date=2013-07-31 |issn=1753-5123 |doi=10.1111/raq.12041 |pages=209–240 |s2cid=84107971}}</ref> and [[fish parasite|parasites]]<ref name="Llewellyn-et-al-2014" /><ref name="Ribas-Piferrer-2014" /> causing yield loss or spreading to adjacent wild populations.

This usefulness is less than it might be due to ''Danio''{{'}}s [[taxonomic]] distance from the most common aquaculture species.<ref name="Dahm-Geisler-2006" /> Because the most common are [[salmonid]]s and [[cod]] in the [[Protacanthopterygii]] and [[sea bass]], [[sea bream]],
[[tilapia]], and [[flatfish]], in the [[Percomorpha]], zebrafish results may not be perfectly applicable.<ref name="Dahm-Geisler-2006" /> Various other [[model species|models]] {{endash}} Goldfish (''[[Carassius auratus]]''), Medaka (''[[Oryzias latipes]]''), Stickleback (''[[Gasterosteus aculeatus]]''), Roach (''[[Rutilus rutilus]]''), Pufferfish (''[[Takifugu rubripes]]''), Swordtail (''[[Xiphophorus hellerii]]'') {{endash}} are less used normally but would be closer to particular target species.<ref name="Ribas-Piferrer-2014" />

The only exception are the [[Carp]] (including Grass Carp, ''[[Ctenopharyngodon idella]]'')<ref name="Dahm-Geisler-2006" /> and Milkfish (''[[Chanos chanos]]'')<ref name="Ribas-Piferrer-2014" /> which are quite close, both being in the [[Cyprinidae]]. However it should also be noted that ''Danio'' consistently proves to be a useful model for mammals in many cases and there is dramatically more [[genetic distance]] between them than between ''Danio'' and any farmed fish.<ref name="Dahm-Geisler-2006" />

=== Neurochemistry ===
In a [[glucocorticoid receptor]]-defective mutant with reduced [[exploration|exploratory behavior]], [[fluoxetine]] rescued the normal exploratory behavior.<ref name="Affective-Disorder" /> This demonstrates relationships between glucocorticoids, fluoxetine, and exploration in this fish.<ref name="Affective-Disorder">
   {{Unbulleted list citebundle
      |{{*}} {{cite journal |year=2015 |issue=1 |volume=16 |issn=1527-8204 |journal=[[Annual Review of Genomics and Human Genetics]] |publisher=[[Annual Reviews (publisher)|Annual Reviews]] |pages=173–197 |last1=McCammon |first1=Jasmine M. |last2=Sive |first2=Hazel |author2-link=Hazel Sive |s2cid=19597664 |pmid=26002061 |doi=10.1146/annurev-genom-090314-050048 |title=Addressing the Genetics of Human Mental Health Disorders in Model Organisms}}
      |{{*}} {{cite journal |issn=1359-4184 |journal=[[Molecular Psychiatry]] |year=2012 |issue=6 |volume=18 |publisher=[[Nature Portfolio]]/[[Macmillan Publishers Limited]] |id=NIHMSID: NIHMS368312 |pages=681–691 |first9=H. |first1=L. |first2=A. |first3=P. J. |first4=S. H. |first5=D. |first6=H. A. |first7=M. J. M. |first8=K. R. |last9=Baier |last8=Yamamoto |last7=Schaaf |last6=Ingraham |last5=Strasser |last4=Meijsing |last3=Schoonheim |last2=Muto |last1=Ziv |s2cid=11962425 |pmid=22641177 |pmc=4065652 |doi=10.1038/mp.2012.64 |title=An affective disorder in zebrafish with mutation of the glucocorticoid receptor}}
   }}
</ref>

===DNA repair===

Zebrafish have been used as a model for studying DNA repair pathways.<ref name="Dey2023">{{Cite journal |last1=Dey |first1=Abhipsha |last2=Flajšhans |first2=Martin |last3=Pšenička |first3=Martin |last4=Gazo |first4=Ievgeniia |date=2023-03-01 |title=DNA repair genes play a variety of roles in the development of fish embryos |journal=Frontiers in Cell and Developmental Biology |volume=11 |doi=10.3389/fcell.2023.1119229 |doi-access=free |issn=2296-634X |pmc=10014602 |pmid=36936683}}</ref> Embryos of externally fertilized fish species, such as zebrafish during their development, are directly exposed to environmental conditions such as pollutants and [[reactive oxygen species]] that may cause [[DNA damage (naturally occurring)|damage to their DNA]].<ref name = Dey2023/> To cope with such DNA damages, a variety of different [[DNA repair]] pathways are expressed during development.<ref name = Dey2023/> Zebrafish have, in recent years, proven to be a useful model for assessing environmental pollutants that might cause DNA damage.<ref>{{Cite journal |last1=Canedo |first1=Aryelle |last2=Rocha |first2=Thiago Lopes |date=March 2021 |title=Zebrafish (Danio rerio) using as model for genotoxicity and DNA repair assessments: Historical review, current status and trends |url=https://linkinghub.elsevier.com/retrieve/pii/S0048969720376154 |journal=Science of the Total Environment |language=en |volume=762 |page=144084 |doi=10.1016/j.scitotenv.2020.144084 |pmid=33383303 |bibcode=2021ScTEn.76244084C}}</ref>