Perfect and imperfect views of ultraconserved sequences

  • 1.

    Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    CAS 
    PubMed 

    Google Scholar
     

  • 2.

    International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 431, 931–945 (2004).


    Google Scholar
     

  • 3.

    Mouse Genome Sequencing Consortium. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).


    Google Scholar
     

  • 4.

    Jacob, H. J. & Kwitek, A. E. Rat genetics: attaching physiology and pharmacology to the genome. Nat. Rev. Genet. 3, 33–42 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 5.

    Gibbs, R. A. et al. Genome sequence of the brown Norway rat yields insights into mammalian evolution. Nature 428, 493–521 (2004).

    CAS 
    PubMed 

    Google Scholar
     

  • 6.

    Aparicio, S. et al. Whole-genome shotgun assembly and analysis of the genome of Fugu rubripes. Science 297, 1301–1310 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 7.

    International Chicken Genome Sequencing Consortium. Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432, 695–716 (2004).


    Google Scholar
     

  • 8.

    Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005).

    CAS 
    PubMed 

    Google Scholar
     

  • 9.

    Chimpanzee Sequencing and Analysis Consortium. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005).


    Google Scholar
     

  • 10.

    Bejerano, G. et al. Ultraconserved elements in the human genome. Science 304, 1321–1325 (2004). This is the first work to describe ultraconserved elements in the human genome.

    CAS 
    PubMed 

    Google Scholar
     

  • 11.

    Hecker, N. & Hiller, M. A genome alignment of 120 mammals highlights ultraconserved element variability and placenta-associated enhancers. Gigascience 9, giz159 (2020).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 12.

    McLean, C. & Bejerano, G. Dispensability of mammalian DNA. Genome Res. 18, 1743–1751 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 13.

    Ovcharenko, I. Widespread ultraconservation divergence in primates. Mol. Biol. Evol. 25, 1668–1676 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 14.

    Navratilova, P. et al. Systematic human/zebrafish comparative identification of cis-regulatory activity around vertebrate developmental transcription factor genes. Dev. Biol. 327, 526–540 (2009).

    CAS 
    PubMed 

    Google Scholar
     

  • 15.

    de la Calle-Mustienes, E. et al. A functional survey of the enhancer activity of conserved non-coding sequences from vertebrate Iroquois cluster gene deserts. Genome Res. 15, 1061–1072 (2005). This paper describes the first detailed experimental analysis of an ultraconserved enhancer.

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 16.

    Drake, J. A. et al. Conserved noncoding sequences are selectively constrained and not mutation cold spots. Nat. Genet. 38, 223–227 (2006). This study uses nascent human population sequencing data from the International HapMap Project to show that extremely conserved non-coding elements display higher rates of depletion for common human variants than rare variants, consistent with negative selection acting to maintain sequence conservation at these sites.

    CAS 
    PubMed 

    Google Scholar
     

  • 17.

    Habic, A. et al. Genetic variations of ultraconserved elements in the human genome. OMICS 23, 549–559 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 18.

    Derti, A., Roth, F. P., Church, G. M. & Wu, C.-T. Mammalian ultraconserved elements are strongly depleted among segmental duplications and copy number variants. Nat. Genet. 38, 1216–1220 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 19.

    Chiang, C. W. K. et al. Ultraconserved elements: analyses of dosage sensitivity, motifs and boundaries. Genetics 180, 2277–2293 (2008).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 20.

    Conrad, D. F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010).

    CAS 
    PubMed 

    Google Scholar
     

  • 21.

    McCole, R. B., Fonseka, C. Y., Koren, A. & Wu, C.-T. Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells but not cancer cells. PLoS Genet. 10, e1004646 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 22.

    Byeon, G. W. et al. Functional and structural basis of extreme conservation in vertebrate 5′ untranslated regions. Nat. Genet. 53, 729–741 (2021).

    CAS 
    PubMed 

    Google Scholar
     

  • 23.

    Leclair, N. K. et al. Poison exon splicing regulates a coordinated network of sr protein expression during differentiation and tumorigenesis. Mol. Cell 80, 648–665.e9 (2020).

    CAS 
    PubMed 

    Google Scholar
     

  • 24.

    Thomas, J. D. et al. RNA isoform screens uncover the essentiality and tumor-suppressor activity of ultraconserved poison exons. Nat. Genet. 52, 84–94 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 25.

    Lareau, L. F., Inada, M., Green, R. E., Wengrod, J. C. & Brenner, S. E. Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature 446, 926–929 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • 26.

    Pennacchio, L. A. et al. In vivo enhancer analysis of human conserved non-coding sequences. Nature 444, 499–502 (2006). This paper describes the first systematic characterization of ultraconserved elements for enhancer function and definitively establishes that many regulate gene expression during embryonic development.

    CAS 
    PubMed 

    Google Scholar
     

  • 27.

    Visel, A. et al. Ultraconservation identifies a small subset of extremely constrained developmental enhancers. Nat. Genet. 40, 158–160 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 28.

    Gorkin, D. U. et al. An atlas of dynamic chromatin landscapes in mouse fetal development. Nature 583, 744–751 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 29.

    Kushawah, G. & Mishra, R. K. Ultraconserved sequences associated with HoxD cluster have strong repression activity. Genome Biol. Evol. 9, 2049–2054 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 30.

    Calin, G. A. et al. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell 12, 215–229 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • 31.

    Cajigas, I. et al. The Evf2 ultraconserved enhancer lncRNA functionally and spatially organizes megabase distant genes in the developing forebrain. Mol. Cell 71, 956–972.e9 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 32.

    McCole, R. B., Erceg, J., Saylor, W. & Wu, C.-T. Ultraconserved elements occupy specific arenas of three-dimensional mammalian genome organization. Cell Rep. 24, 479–488 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 33.

    Ahituv, N. et al. Deletion of ultraconserved elements yields viable mice. PLoS Biol. 5, e234 (2007). This work describes the first mouse knockout studies of ultraconserved enhancers, which stunningly find that mice missing individual ultraconserved elements are viable and have no obvious phenotypes.

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 34.

    Dickel, D. E. et al. Ultraconserved enhancers are required for normal development. Cell 172, 491–499.e15 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 35.

    Nolte, M. J. et al. Functional analysis of limb transcriptional enhancers in the mouse. Evol. Dev. 16, 207–223 (2014). This work was the first to identify a phenotype resulting from the deletion of an ultraconserved enhancer in mice. Together with Dickel et al. (2018), this study establishes that loss of ultraconserved enhancers in mice commonly results in developmental phenotypes that are likely to be selectively disadvantageous, partially explaining their extreme conservation.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 36.

    Gaynor, K. U. et al. Studies of mice deleted for Sox3 and uc482: relevance to X-linked hypoparathyroidism. Endocr. Connect. 9, 173–186 (2020).

    CAS 
    PubMed Central 

    Google Scholar
     

  • 37.

    Colasante, G. et al. ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c. Cereb. Cortex 25, 322–335 (2015).

    PubMed 

    Google Scholar
     

  • 38.

    Kitamura, K. et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat. Genet. 32, 359–369 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 39.

    Squire, L. R. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99, 195–231 (1992).

    CAS 
    PubMed 

    Google Scholar
     

  • 40.

    Schliebs, R. & Arendt, T. The cholinergic system in aging and neuronal degeneration. Behav. Brain Res. 221, 555–563 (2011).

    CAS 
    PubMed 

    Google Scholar
     

  • 41.

    Visel, A. et al. A high-resolution enhancer atlas of the developing telencephalon. Cell 152, 895–908 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 42.

    Jindal, G. A. & Farley, E. K. Enhancer grammar in development, evolution, and disease: dependencies and interplay. Dev. Cell 56, 575–587 (2021).

    CAS 
    PubMed 

    Google Scholar
     

  • 43.

    Patwardhan, R. P. et al. Massively parallel functional dissection of mammalian enhancers in vivo. Nat. Biotechnol. 30, 265–270 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 44.

    Melnikov, A. et al. Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay. Nat. Biotechnol. 30, 271–277 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 45.

    Kircher, M. et al. Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution. Nat. Commun. 10, 3583 (2019).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 46.

    Canver, M. C. et al. BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 527, 192–197 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 47.

    Stefflova, K. et al. Cooperativity and rapid evolution of cobound transcription factors in closely related mammals. Cell 154, 530–540 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 48.

    Heinz, S. et al. Effect of natural genetic variation on enhancer selection and function. Nature 503, 487–492 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 49.

    Viturawong, T., Meissner, F., Butter, F. & Mann, M. A DNA-centric protein interaction map of ultraconserved elements reveals contribution of transcription factor binding hubs to conservation. Cell Rep. 5, 531–545 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • 50.

    Lettice, L. A., Hill, A. E., Devenney, P. S. & Hill, R. E. Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly. Hum. Mol. Genet. 17, 978–985 (2008).

    CAS 
    PubMed 

    Google Scholar
     

  • 51.

    Lettice, L. A. et al. Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Dev. Cell 22, 459–467 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 52.

    Kvon, E. Z. et al. Comprehensive in vivo interrogation reveals phenotypic impact of human enhancer variants. Cell 180, 1262–1271.e15 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 53.

    Siepel, A. et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034–1050 (2005). This paper introduces phastCons, one of the most widely used methods to identify highly conserved sequences with multiple species alignments.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 54.

    Lampe, X. et al. An ultraconserved Hox–Pbx responsive element resides in the coding sequence of Hoxa2 and is active in rhombomere 4. Nucleic Acids Res. 36, 3214–3225 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 55.

    Snetkova, V. et al. Ultraconserved enhancer function does not require perfect sequence conservation. Nat. Genet. 53, 521–528 (2021). This study describes the most comprehensive examination of how sequence changes alter the activity of ultraconserved enhancers, finding that they are surprisingly robust to mutation. Collectively, the results suggest that there are likely to be multiple molecular drivers behind ultraconservation.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 56.

    Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470, 279–283 (2011).

    CAS 
    PubMed 

    Google Scholar
     

  • 57.

    ENCODE Project Consortium. et al. Expanded encyclopaedias of DNA elements in the human and mouse genomes. . Nat. 583, 699–710 (2020).


    Google Scholar
     

  • 58.

    Warnefors, M., Hartmann, B., Thomsen, S. & Alonso, C. R. Combinatorial gene regulatory functions underlie ultraconserved elements in Drosophila. Mol. Biol. Evol. 33, 2294–2306 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 59.

    Stephen, S., Pheasant, M., Makunin, I. V. & Mattick, J. S. Large-scale appearance of ultraconserved elements in tetrapod genomes and slowdown of the molecular clock. Mol. Biol. Evol. 25, 402–408 (2008).

    CAS 
    PubMed 

    Google Scholar
     

  • 60.

    Christley, S., Lobo, N. F. & Madey, G. Multiple organism algorithm for finding ultraconserved elements. BMC Bioinforma. 9, 15 (2008).


    Google Scholar
     

  • 61.

    Mayor, C. et al. VISTA: visualizing global DNA sequence alignments of arbitrary length. Bioinformatics 16, 1046–1047 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 62.

    Schwartz, S. et al. PipMaker — a web server for aligning two genomic DNA sequences. Genome Res. 10, 577–586 (2000).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 63.

    Nobrega, M. A. & Pennacchio, L. A. Comparative genomic analysis as a tool for biological discovery. J. Physiol. 554, 31–39 (2004).

    CAS 
    PubMed 

    Google Scholar
     

  • 64.

    Sandelin, A. et al. Arrays of ultraconserved non-coding regions span the loci of key developmental genes in vertebrate genomes. BMC Genomics 5, 99 (2004).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 65.

    Woolfe, A. et al. Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol. 3, e7 (2005).

    PubMed 

    Google Scholar
     

  • 66.

    Ovcharenko, I., Stubbs, L. & Loots, G. G. Interpreting mammalian evolution using Fugu genome comparisons. Genomics 84, 890–895 (2004).

    CAS 
    PubMed 

    Google Scholar
     

  • 67.

    Nobrega, M. A., Ovcharenko, I., Afzal, V. & Rubin, E. M. Scanning human gene deserts for long-range enhancers. Science 302, 413 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 68.

    Cooper, G. M. et al. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 15, 901–913 (2005).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 69.

    Prabhakar, S. et al. Close sequence comparisons are sufficient to identify human cis-regulatory elements. Genome Res. 16, 855–863 (2006).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 70.

    Lindblad-Toh, K. et al. A high-resolution map of human evolutionary constraint using 29 mammals. Nature 478, 476–482 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 71.

    Royo, J. L. et al. Transphyletic conservation of developmental regulatory state in animal evolution. Proc. Natl Acad. Sci. USA 108, 14186–14191 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 72.

    Clarke, S. L. et al. Human developmental enhancers conserved between deuterostomes and protostomes. PLoS Genet. 8, e1002852 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 73.

    Kikuta, H. et al. Genomic regulatory blocks encompass multiple neighboring genes and maintain conserved synteny in vertebrates. Genome Res. 17, 545–555 (2007).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 74.

    Touceda-Suárez, M. et al. Ancient genomic regulatory blocks are a source for regulatory gene deserts in vertebrates after whole-genome duplications. Mol. Biol. Evol. 37, 2857–2864 (2020).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 75.

    Harmston, N. et al. Topologically associating domains are ancient features that coincide with metazoan clusters of extreme noncoding conservation. Nat. Commun. 8, 441 (2017).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 76.

    Poulin, F. et al. In vivo characterization of a vertebrate ultraconserved enhancer. Genomics 85, 774–781 (2005).

    CAS 
    PubMed 

    Google Scholar
     

  • 77.

    Ragvin, A. et al. Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3. Proc. Natl Acad. Sci. USA 107, 775–780 (2010).

    CAS 
    PubMed 

    Google Scholar
     

  • 78.

    Bao, B.-Y. et al. Genetic variants in ultraconserved regions associate with prostate cancer recurrence and survival. Sci. Rep. 6, 22124 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 79.

    Terracciano, D. et al. The role of a new class of long noncoding RNAs transcribed from ultraconserved regions in cancer. Biochim. Biophys. Acta Rev. Cancer 1868, 449–455 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • 80.

    Fabris, L. & Calin, G. A. Understanding the genomic ultraconservations: T-UCRs and cancer. Int. Rev. Cell Mol. Biol. 333, 159–172 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • 81.

    Bhatia, S. et al. Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia. Am. J. Hum. Genet. 93, 1126–1134 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 82.

    Martínez, F. et al. Enrichment of ultraconserved elements among genomic imbalances causing mental delay and congenital anomalies. BMC Med. Genomics 3, 54 (2010).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 83.

    McCole, R. B. et al. Structural disruption of genomic regions containing ultraconserved elements is associated with neurodevelopmental phenotypes. Preprint at bioRxiv doi.org/10.1101/233197 (2017).

    Article 

    Google Scholar
     

  • 84.

    Short, P. J. et al. De novo mutations in regulatory elements in neurodevelopmental disorders. Nature 555, 611–616 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 85.

    Faircloth, B. C. et al. Ultraconserved elements anchor thousands of genetic markers spanning multiple evolutionary timescales. Syst. Biol. 61, 717–726 (2012).

    PubMed 

    Google Scholar
     

  • 86.

    Winker, K., Glenn, T. C. & Faircloth, B. C. Ultraconserved elements (UCEs) illuminate the population genomics of a recent, high-latitude avian speciation event. PeerJ 6, e5735 (2018).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 87.

    Blaimer, B. B., Lloyd, M. W., Guillory, W. X. & Brady, S. G. Sequence capture and phylogenetic utility of genomic ultraconserved elements obtained from pinned insect specimens. PLoS ONE 11, e0161531 (2016).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 88.

    Gilbert, P. S. et al. Genome-wide ultraconserved elements exhibit higher phylogenetic informativeness than traditional gene markers in percomorph fishes. Mol. Phylogenet. Evol. 92, 140–146 (2015).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 89.

    Barrett, R. D. H. et al. Linking a mutation to survival in wild mice. Science 363, 499–504 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • 90.

    Dukler, N., Mughal, M. R., Ramani, R., Huang, Y.-F. & Siepel, A. Extreme purifying selection against point mutations in the human genome. Preprint at bioRxiv doi.org/10.1101/2021.08.23.457339 (2021).

    Article 

    Google Scholar
     

  • 91.

    Richter, F. et al. Genomic analyses implicate noncoding de novo variants in congenital heart disease. Nat. Genet. 52, 769–777 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 92.

    Werling, D. M. et al. An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder. Nat. Genet. 50, 727–736 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 93.

    Boycott, K. M. et al. A diagnosis for all rare genetic diseases: the horizon and the next frontiers. Cell 177, 32–37 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • 94.

    Lappalainen, T., Scott, A. J., Brandt, M. & Hall, I. M. Genomic analysis in the age of human genome sequencing. Cell 177, 70–84 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 95.

    Tewhey, R. et al. Direct identification of hundreds of expression-modulating variants using a multiplexed reporter assay. Cell 165, 1519–1529 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 96.

    Visel, A., Minovitsky, S., Dubchak, I. & Pennacchio, L. A. VISTA Enhancer Browser — a database of tissue-specific human enhancers. Nucleic Acids Res. 35, D88–D92 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • 97.

    Taliun, D. et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature 590, 290–299 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 98.

    O’Leary, N. A. et al. Reference Sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res. 44, D733–D745 (2016).

    PubMed 

    Google Scholar
     

  • 99.

    Kothary, R. et al. Inducible expression of an hsp68–lacZ hybrid gene in transgenic mice. Development 105, 707–714 (1989).

    CAS 
    PubMed 

    Google Scholar
     

  • 100.

    Zakany, J., Tuggle, C. K., Patel, M. D. & Nguyen-Huu, M. C. Spatial regulation of homeobox gene fusions in the embryonic central nervous system of transgenic mice. Neuron 1, 679–691 (1988).

    CAS 
    PubMed 

    Google Scholar
     

  • 101.

    Rijkers, T., Peetz, A. & Rüther, U. Insertional mutagenesis in transgenic mice. Transgenic Res. 3, 203–215 (1994).

    CAS 
    PubMed 

    Google Scholar
     

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