Laura Reinholdt
Education
- University of Connecticut, Department of Molecular and Cellular Biology, 2001, Ph.D. in Genetics
- Post-Doctoral Fellowship in Drs. John Schimenti and Mary Ann Handel’s laboratories
Brief Biography
Broadly, Dr. Reinholdt’s research interests are in the development and application of genetic approaches for understanding the etiology of genome variation and for understanding the role of genome variation in health and disease.
Dr. Reinholdt’s interests in the role of genetic variation in disease led her to focus her research efforts on an exceptional resource of laboratory mouse strains with proven Mendelian disorders with unknown genetic etiology, strains stewarded by the Mouse Mutant Resource at The Jackson Laboratory for over 50 years. Taking advantage of this resource, her laboratory was one of the first to apply exome sequencing at scale for the discovery of naturally occurring genetic variants (mutations) that cause Mendelian disease in mice. Her laboratory is now focusing on the significant proportion of mutations that escape detection by exome sequencing to further understand the nature of these mutations and to improve computational approaches mutation discovery. Using reverse genetic approaches, Dr. Reinholdt’s laboratory is also working closely with the human genetics community to create new strains of mice carrying human Mendelian disease mutations.
Heritable genetic variation is the result of genome instability during germ cell development, instability that arises through mutation, chromosome rearrangement or chromosome mis-segregation during mitosis or meiosis. Germ cells employ a variety of mechanisms to counteract these destabilizing events and these mechanisms can ultimately result in developmental arrest and cell death. However, these mechanisms are still poorly understood and when they fail, aneuploidy and infertility result. Dr. Reinholdt’s post-doctoral work on the discovery of genes required for normal germ line development and fertility led to the discovery that the germ line is exquisitely sensitive to mutations in components of the mitotic spindle that have the potential to lead to aneuploidy. This sensitivity may also extend to embryonic and adult stem cells. Dr. Reinholdt’s laboratory have gone on to show that the sensitivity of the germ line genome instability differs across inbred strains of mice, offering a unique opportunity to use systems genetics approaches to discover the underlying pathways governing cell division and survival across a variety of cell types.
We are interested in the development and application of both forward and reverse genetic approaches for understanding the etiology of genome variation and it’s role in health and disease.
Selected Publications
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Emily Swanzey, Callan O’Connor, Laura G. Reinholdt. Mouse Genetic Reference Populations: Cellular Platforms for Integrative Systems Genetics. Trends in Genetics. 2021;37(3).
https://doi.org/10.1016/j.tig.2020.09.007 -
Leslie A. Sepaniac, Whitney Martin, Louise A. Dionne, Timothy M. Stearns, Laura G. Reinholdt, Jason Stumpff; Micronuclei in Kif18a mutant mice form stable micronuclear envelopes and do not promote tumorigenesis. J Cell Biol 1 November 2021; 220 (11): e202101165. doi: https://doi.org/10.1083/jcb.202101165
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Saul MC, Philip VM, Reinholdt LG, Chesler EJ. High-Diversity Mouse Populations for Complex Traits. Trends Genet. 2019 Jul;35(7):501-514. doi: 10.1016/j.tig.2019.04.003. Epub 2019 May 24. Review. PubMed PMID: 31133439; PubMed Central PMCID: PMC6571031.
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Sarsani VK, Raghupathy N, Fiddes IT, Armstrong J, Thibaud-Nissen F, Zinder O, Bolisetty M, Howe K, Hinerfeld D, Ruan X, Rowe L, Barter M, Ananda G, Paten B, Weinstock GM, Churchill GA, Wiles MV, Schneider VA, Srivastava A, Reinholdt LG. The Genome of C57BL/6J “Eve”, the Mother of the Laboratory Mouse Genome Reference Strain. G3 (Bethesda). 2019 Jun 5;9(6):1795-1805. doi: 10.1534/g3.119.400071. PubMed PMID: 30996023; PubMed Central PMCID: PMC6553538.
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Goodwin LO, Splinter E, Davis TL, Urban R, He H, Braun RE, Chesler EJ, Kumar V, van Min M, Ndukum J, Philip VM, Reinholdt LG, Svenson K, White JK, Sasner M, Lutz C, Murray SA. Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis. Genome Res. 2019 Mar;29(3):494-505. doi: 10.1101/gr.233866.117. Epub 2019 Jan 18. PubMed PMID: 30659012; PubMed Central PMCID: PMC6396414.
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Slone J, Peng Y, Chamberlin A, Harris B, Kaylor J, McDonald MT, Lemmon M, El-Dairi MA, Tchapyjnikov D, Gonzalez-Krellwitz LA, Sellars EA, McConkie-Rosell A, Reinholdt LG, Huang T. Biallelic mutations in FDXR cause neurodegeneration associated with inflammation. J Hum Genet. 2018 Dec;63(12):1211-1222. doi: 10.1038/s10038-018-0515-y. Epub 2018 Sep 25. PubMed PMID: 30250212; PubMed Central PMCID: PMC6451867.
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Lilue J, Doran AG, Fiddes IT, Abrudan M, Armstrong J, Bennett R, Chow W, Collins J, Collins S, Czechanski A, Danecek P, Diekhans M, Dolle DD, Dunn M, Durbin R, Earl D, Ferguson-Smith A, Flicek P, Flint J, Frankish A, Fu B, Gerstein M, Gilbert J, Goodstadt L, Harrow J, Howe K, Ibarra-Soria X, Kolmogorov M, Lelliott CJ, Logan DW, Loveland J, Mathews CE, Mott R, Muir P, Nachtweide S, Navarro FCP, Odom DT, Park N, Pelan S, Pham SK, Quail M, Reinholdt L, Romoth L, Shirley L, Sisu C, Sjoberg-Herrera M, Stanke M, Steward C, Thomas M, Threadgold G, Thybert D, Torrance J, Wong K, Wood J, Yalcin B, Yang F, Adams DJ, Paten B, Keane TM. Sixteen diverse laboratory mouse reference genomes define strain-specific haplotypes and novel functional loci. Nat Genet. 2018 Nov;50(11):1574-1583. doi: 10.1038/s41588-018-0223-8. Epub 2018 Oct 1. PubMed PMID: 30275530; PubMed Central PMCID: PMC6205630.
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Wollenberg AL, O’Shea TM, Kim JH, Czechanski A, Reinholdt LG, Sofroniew MV, Deming TJ. Injectable polypeptide hydrogels via methionine modification for neural stem cell delivery. Biomaterials. 2018 Sep;178:527-545. doi: 10.1016/j.biomaterials.2018.03.057. Epub 2018 Apr 5. PubMed PMID: 29657091; PubMed Central PMCID: PMC6054810.
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Peng Y, Shinde DN, Valencia CA, Mo JS, Rosenfeld J, Truitt Cho M, Chamberlin A, Li Z, Liu J, Gui B, Brockhage R, Basinger A, Alvarez-Leon B, Heydemann P, Magoulas PL, Lewis AM, Scaglia F, Gril S, Chong SC, Bower M, Monaghan KG, Willaert R, Plona MR, Dineen R, Milan F, Hoganson G, Powis Z, Helbig KL, Keller-Ramey J, Harris B, Anderson LC, Green T, Sukoff Rizzo SJ, Kaylor J, Chen J, Guan MX, Sellars E, Sparagana SP, Gibson JB, Reinholdt LG, Tang S, Huang T. Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy. Hum Mol Genet. 2017 Dec 15;26(24):4937-4950. doi: 10.1093/hmg/ddx377. PubMed PMID: 29040572; PubMed Central PMCID: PMC5886230.
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Peterson KA, Beane GL, Goodwin LO, Kutny PM, Reinholdt LG, Murray SA. CRISPRtools: a flexible computational platform for performing CRISPR/Cas9 experiments in the mouse. Mamm Genome. 2017 Aug;28(7-8):283-290. doi: 10.1007/s00335-017-9681-z. Epub 2017 Mar 9. PubMed PMID: 28280930; PubMed Central PMCID: PMC5591755.
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Peachey NS, Hasan N, FitzMaurice B, Burrill S, Pangeni G, Karst SY, Reinholdt L, Berry ML, Strobel M, Gregg RG, McCall MA, Chang B. A missense mutation in Grm6 reduces but does not eliminate mGluR6 expression or rod depolarizing bipolar cell function. J Neurophysiol. 2017 Aug 1;118(2):845-854. doi: 10.1152/jn.00888.2016. Epub 2017 May 10. PubMed PMID: 28490646; PubMed Central PMCID: PMC5539458.
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Palmer K, Fairfield H, Borgeia S, Curtain M, Hassan MG, Dionne L, Yong Karst S, Coombs H, Bronson RT, Reinholdt LG, Bergstrom DE, Donahue LR, Cox TC, Murray SA. Discovery and characterization of spontaneous mouse models of craniofacial dysmorphology. Dev Biol. 2016 Jul 15;415(2):216-227. doi: 10.1016/j.ydbio.2015.07.023. Epub 2015 Jul 31. PubMed PMID: 26234751; PubMed Central PMCID: PMC4733616.
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Tomberg K, Khoriaty R, Westrick RJ, Fairfield HE, Reinholdt LG, Brodsky GL, Davizon-Castillo P, Ginsburg D, Di Paola J. Spontaneous 8bp Deletion in Nbeal2 Recapitulates the Gray Platelet Syndrome in Mice. PLoS One. 2016;11(3):e0150852. doi: 10.1371/journal.pone.0150852. eCollection 2016. PubMed PMID: 26950939; PubMed Central PMCID: PMC4780761.
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Pratt CH, Dionne LA, Fairfield H, Dadras SS, Potter CS, Sundberg JP. Gnaq(M1J): An ENU-Induced Mutant Allele Affecting Pigmentation in the Mouse. J Invest Dermatol. 2016 Jan;136(1):334-336. doi: 10.1038/JID.2015.382. PubMed PMID: 26763459; PubMed Central PMCID: PMC4731045.
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Sun F, Fujiwara Y, Reinholdt LG, Hu J, Saxl RL, Baker CL, Petkov PM, Paigen K, Handel MA. Nuclear localization of PRDM9 and its role in meiotic chromatin modifications and homologous synapsis. Chromosoma. 2015 Sep;124(3):397-415. doi: 10.1007/s00412-015-0511-3. Epub 2015 Apr 18. PubMed PMID: 25894966; PubMed Central PMCID: PMC4550572.
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Fairfield H, Srivastava A, Ananda G, Liu R, Kircher M, Lakshminarayana A, Harris BS, Karst SY, Dionne LA, Kane CC, Curtain M, Berry ML, Ward-Bailey PF, Greenstein I, Byers C, Czechanski A, Sharp J, Palmer K, Gudis P, Martin W, Tadenev A, Bogdanik L, Pratt CH, Chang B, Schroeder DG, Cox GA, Cliften P, Milbrandt J, Murray S, Burgess R, Bergstrom DE, Donahue LR, Hamamy H, Masri A, Santoni FA, Makrythanasis P, Antonarakis SE, Shendure J, Reinholdt LG. Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders. Genome Res. 2015 Jul;25(7):948-57. doi: 10.1101/gr.186882.114. Epub 2015 Apr 27. PubMed PMID: 25917818; PubMed Central PMCID: PMC4484392.
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Czechanski A, Kim H, Byers C, Greenstein I, Stumpff J, Reinholdt LG. Kif18a is specifically required for mitotic progression during germ line development. Dev Biol. 2015 Jun 15;402(2):253-262. doi: 10.1016/j.ydbio.2015.03.011. Epub 2015 Mar 28. PubMed PMID: 25824710; PubMed Central PMCID: PMC4450139.
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Li Y, Klena NT, Gabriel GC, Liu X, Kim AJ, Lemke K, Chen Y, Chatterjee B, Devine W, Damerla RR, Chang C, Yagi H, San Agustin JT, Thahir M, Anderton S, Lawhead C, Vescovi A, Pratt H, Morgan J, Haynes L, Smith CL, Eppig JT, Reinholdt L, Francis R, Leatherbury L, Ganapathiraju MK, Tobita K, Pazour GJ, Lo CW. Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature. 2015 May 28;521(7553):520-4. doi: 10.1038/nature14269. Epub 2015 Mar 25. PubMed PMID: 25807483; PubMed Central PMCID: PMC4617540.
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Jackson HM, Onos KD, Pepper KW, Graham LC, Akeson EC, Byers C, Reinholdt LG, Frankel WN, Howell GR. DBA/2J genetic background exacerbates spontaneous lethal seizures but lessens amyloid deposition in a mouse model of Alzheimer’s disease. PLoS One. 2015;10(5):e0125897. doi: 10.1371/journal.pone.0125897. eCollection 2015. PubMed PMID: 25933409; PubMed Central PMCID: PMC4416920.
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Herbert Pratt C, Potter CS, Fairfield H, Reinholdt LG, Bergstrom DE, Harris BS, Greenstein I, Dadras SS, Liang BT, Schofield PN, Sundberg JP. Dsp rul: a spontaneous mouse mutation in desmoplakin as a model of Carvajal-Huerta syndrome. Exp Mol Pathol. 2015 Apr;98(2):164-72. doi: 10.1016/j.yexmp.2015.01.015. Epub 2015 Feb 7. PubMed PMID: 25659760; PubMed Central PMCID: PMC4388778.
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Srivastava A, Philip VM, Greenstein I, Rowe LB, Barter M, Lutz C, Reinholdt LG. Discovery of transgene insertion sites by high throughput sequencing of mate pair libraries. BMC Genomics. 2014 May 14;15:367. doi: 10.1186/1471-2164-15-367. PubMed PMID: 24884803; PubMed Central PMCID: PMC4035081.
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Czechanski A, Byers C, Greenstein I, Schrode N, Donahue LR, Hadjantonakis AK, Reinholdt LG. Derivation and characterization of mouse embryonic stem cells from permissive and nonpermissive strains. Nat Protoc. 2014 Mar;9(3):559-74. doi: 10.1038/nprot.2014.030. Epub 2014 Feb 6. PubMed PMID: 24504480; PubMed Central PMCID: PMC4112089.
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Liu X, Francis R, Kim AJ, Ramirez R, Chen G, Subramanian R, Anderton S, Kim Y, Wong L, Morgan J, Pratt HC, Reinholdt L, Devine W, Leatherbury L, Tobita K, Lo CW. Interrogating congenital heart defects with noninvasive fetal echocardiography in a mouse forward genetic screen. Circ Cardiovasc Imaging. 2014 Jan;7(1):31-42. doi: 10.1161/CIRCIMAGING.113.000451. Epub 2013 Dec 6. PubMed PMID: 24319090; PubMed Central PMCID: PMC3962690.
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Akiyama K, Noguchi J, Hirose M, Kajita S, Katayama K, Khalaj M, Tsuji T, Fairfield H, Byers C, Reinholdt L, Ogura A, Kunieda T. A mutation in the nuclear pore complex gene Tmem48 causes gametogenesis defects in skeletal fusions with sterility (sks) mice. J Biol Chem. 2013 Nov 1;288(44):31830-41. doi: 10.1074/jbc.M113.492306. Epub 2013 Sep 17. PubMed PMID: 24045954; PubMed Central PMCID: PMC3814776.
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Reinholdt LG, Howell GR, Czechanski AM, Macalinao DG, Macnicoll KH, Lin CS, Donahue LR, John SW. Generating embryonic stem cells from the inbred mouse strain DBA/2J, a model of glaucoma and other complex diseases. PLoS One. 2012;7(11):e50081. doi: 10.1371/journal.pone.0050081. Epub 2012 Nov 27. PubMed PMID: 23209647; PubMed Central PMCID: PMC3507949.