Michael O'Neill

Associate Professor

Molecular and Cell Biology / Genetics and Genomics

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Education: PhD- University of Texas at Austin: Post-doctoral study- University of Melbourne, Princeton University

Research Interests: Sex biases are found for numerous neurodevelopmental and neuropsychiatric diseases, most often skewing to higher prevalence among males than females. Among the most dramatic sex biases is the 4:1 male to female bias in the occurrence of Autism Spectrum Disorder (ASD). The male bias has generally been attributed a female protective effect (FPE) that remains poorly defined. Over the last two decades numerous studies have been published focusing on genetic or physiological factors underlying the FPE, but often with contradictory results. The X Chromosome Imprinting hypothesis posits that the FPE results from the difference in sex chromosome complement between males and females. This hypothesis emerged from a study of X chromosome parent-of-origin effects on social cognition in girls with Turner Syndrome (TS). David Skuse and coworkers reported that, among TS females, individuals with a maternally-derived X chromosome (45,X^M) performed worse in social tasks than 45,X^P (paternally-derived X chromosome) and 46,XX females. Skuse et al. hypothesized that this difference was attributable to imprinted genes on the X chromosome. The expression of imprinted genes is determined by parent-of-origin epigenetic factors. Heritable effects that do not alter DNA sequence but are, nevertheless, transmitted across generations are termed Transgenerational Epigenetic effects. Certain environmental insults effected through physiological, or even behavioral, inputs to individuals have been documented to alter patterns of neurodevelopmental gene expression in first and second generation offspring in humans, rodents, fruit flies and the nematode worm, C. elegans. The molecular mechanisms by which regulatory information affecting these genes is transmitted from generation to generation are poorly understood but are thought to involve epigenetic factors in the germline (eggs/sperm). Using mouse models for Turner Syndrome, our laboratory discovered a family of X-linked imprinted genes involved in germline and central nervous system development. Using an RNAi knockdown (KD) model targeting one of these genes, Xlr3, we recently discovered that this gene plays an essential role in a spermatocyte specific epigenetic phenomenon known as Meiotic Sex Chromosome Inactivation (MSCI), wherein the X and Y chromosome are transcriptionally repressed through meiosis. KD males are fertile, but sperm production is compromised. Daughters of KD males exhibit disrupted imprinted expression of Xlr3 and other X-linked imprinted genes. Moreover, the grandsons of KD males (F2 generation) exhibit deficits in spatial learning and dominance as revealed in a battery of preliminary behavioral tests. To our knowledge, this is the first evidence of a transgenerational effect involving MSCI. We hypothesize that Xlr3, through its role in MSCI, is a mediator of epigenetic signaling passed from generation to generation.

Selected Publications:

Sobel Naveh, N., Foley, R.J., Denegre, K.R., Evans, T.C., Czechanski, A., Reinholdt, L.G., and O’Neill, M.J. (2021) Deficiency of SYCP3-related XLR3 disrupts the initiation of meiotic sex chromosome inactivation in mouse spermatogenesis. bioRxiv 2021.03.30.437712; doi: https://doi.org/10.1101/2021.03.30.437712

O’Neill MJ, O’Neill RJ. Sex chromosome repeats tip the balance towards speciation. Mol Ecol. 2018 Oct;27(19):3783-3798. doi: 10.1111/mec.14577. Epub 2018 May 8. Review. PubMed PMID: 29624756.

Jue NK, Foley RJ, Reznick DN, O’Neill RJ, O’Neill MJ. Tissue-Specific Transcriptome for Poeciliopsis prolifica Reveals Evidence for Genetic Adaptation Related to the Evolution of a Placental Fish. G3 (Bethesda). 2018 Jul 2;8(7):2181-2192. doi: 10.1534/g3.118.200270. PubMed PMID: 29720394; PubMed Central PMCID: PMC6027864.

O’Neill RJ, O’Neill MJ. Replication timing kept in LINE. J Cell Biol. 2018 Feb 5;217(2):441-443. doi: 10.1083/jcb.201712173. Epub 2018 Jan 18. PubMed PMID: 29348148; PubMed Central PMCID: PMC5800820.

Jue NK, Batta-Lona PG, Trusiak S, Obergfell C, Bucklin A, O’Neill MJ, O’Neill RJ. Rapid Evolutionary Rates and Unique Genomic Signatures Discovered in the First Reference Genome for the Southern Ocean Salp, Salpa thompsoni (Urochordata, Thaliacea). Genome Biol Evol. 2016 Oct 30;8(10):3171-3186. doi: 10.1093/gbe/evw215. PubMed PMID: 27624472; PubMed Central PMCID: PMC5174732.

Longo MS, Brown JD, Zhang C, O’Neill MJ, O’Neill RJ. Identification of a recently active mammalian SINE derived from ribosomal RNA. Genome Biol Evol. 2015 Jan 29;7(3):775-88. doi: 10.1093/gbe/evv015. PubMed PMID: 25637222; PubMed Central PMCID: PMC4994717.

O’Neill MJ, O’Neill RJ. Genomics: Something to swing about. Nature. 2014 Sep 11;513(7517):174-5. doi: 10.1038/513174a. PubMed PMID: 25209792.

Jue NK, Murphy MB, Kasowitz SD, Qureshi SM, Obergfell CJ, Elsisi S, Foley RJ, O’Neill RJ, O’Neill MJ. Determination of dosage compensation of the mammalian X chromosome by RNA-seq is dependent on analytical approach. BMC Genomics. 2013 Mar 6;14:150. doi: 10.1186/1471-2164-14-150. PubMed PMID: 23497106; PubMed Central PMCID: PMC3769146.

Carone DM, Zhang C, Hall LE, Obergfell C, Carone BR, O’Neill MJ, O’Neill RJ. Hypermorphic expression of centromeric retroelement-encoded small RNAs impairs CENP-A loading. Chromosome Res. 2013 Mar;21(1):49-62. doi: 10.1007/s10577-013-9337-0. Epub 2013 Feb 8. PubMed PMID: 23392618.

Lindsay J, Carone DM, Brown J, Hall L, Qureshi S, Mitchell SE, Jannetty N, Hannon G, Renfree M, Pask A, O’Neill M, O’Neill R. Unique small RNA signatures uncovered in the tammar wallaby genome. BMC Genomics. 2012 Oct 17;13:559. doi: 10.1186/1471-2164-13-559. PubMed PMID: 23075437; PubMed Central PMCID: PMC3576234.

Ferreri GC, Brown JD, Obergfell C, Jue N, Finn CE, O’Neill MJ, O’Neill RJ. Recent amplification of the kangaroo endogenous retrovirus, KERV, limited to the centromere. J Virol. 2011 May;85(10):4761-71. doi: 10.1128/JVI.01604-10. Epub 2011 Mar 9. PubMed PMID: 21389136; PubMed Central PMCID: PMC3126163.

Longo MS, O’Neill MJ, O’Neill RJ. Abundant human DNA contamination identified in non-primate genome databases. PLoS One. 2011 Feb 16;6(2):e16410. doi: 10.1371/journal.pone.0016410. PubMed PMID: 21358816; PubMed Central PMCID: PMC3040168.

Okpeku M, Peters SO, Ozoje MO, Adebambo OA, Agaviezor BO, O’Neill MJ, Imumorin IG. Preliminary analysis of microsatellite-based genetic diversity of goats in southern Nigeria. Animal Genetic Resources. 2011; 49:33-41. doi: 10.1017/S207863361100035X.

Mlynarski EE, Obergfell CJ, O’Neill MJ, O’Neill RJ. Divergent patterns of breakpoint reuse in Muroid rodents. Mamm Genome. 2010 Feb;21(1-2):77-87. doi: 10.1007/s00335-009-9242-1. Epub 2009 Dec 22. PubMed PMID: 20033182.

Longo MS, Carone DM, Green ED, O’Neill MJ, O’Neill RJ. Distinct retroelement classes define evolutionary breakpoints demarcating sites of evolutionary novelty. BMC Genomics. 2009 Jul 24;10:334. doi: 10.1186/1471-2164-10-334. PubMed PMID: 19630942; PubMed Central PMCID: PMC2736999.

Carone DM, Longo MS, Ferreri GC, Hall L, Harris M, Shook N, Bulazel KV, Carone BR, Obergfell C, O’Neill MJ, O’Neill RJ. A new class of retroviral and satellite encoded small RNAs emanates from mammalian centromeres. Chromosoma. 2009 Feb;118(1):113-25. doi: 10.1007/s00412-008-0181-5. Epub 2008 Oct 7. PubMed PMID: 18839199.

Mlynarski EE, Obergfell CJ, Rens W, O’Brien PC, Ramsdell CM, Dewey MJ, O’Neill MJ, O’Neill RJ. Peromyscus maniculatus–Mus musculus chromosome homology map derived from reciprocal cross species chromosome painting. Cytogenet Genome Res. 2008;121(3-4):288-92. doi: 10.1159/000138900. Epub 2008 Aug 29. PubMed PMID: 18758174.

Bartolomei MS, Vigneau S, O’Neill MJ. H19 in the pouch. Nat Genet. 2008 Aug;40(8):932-3. doi: 10.1038/ng0808-932. PubMed PMID: 18665128.

Lawton BR, Carone BR, Obergfell CJ, Ferreri GC, Gondolphi CM, Vandeberg JL, Imumorin I, O’Neill RJ, O’Neill MJ. Genomic imprinting of IGF2 in marsupials is methylation dependent. BMC Genomics. 2008 May 2;9:205. doi: 10.1186/1471-2164-9-205. PubMed PMID: 18454865; PubMed Central PMCID: PMC2386826.

Li C, Bin Y, Curchoe C, Yang L, Feng D, Jiang Q, O’Neill M, Tian XC, Zhang S. Genetic imprinting of H19 and IGF2 in domestic pigs (Sus scrofa). Anim Biotechnol. 2008;19(1):22-7. doi: 10.1080/10495390701758563. PubMed PMID: 18228173.

O’Neill MJ, Lawton BR, Mateos M, Carone DM, Ferreri GC, Hrbek T, Meredith RW, Reznick DN, O’Neill RJ. Ancient and continuing Darwinian

ion on insulin-like growth factor II in placental fishes. Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12404-9. doi: 10.1073/pnas.0705048104. Epub 2007 Jul 16. PubMed PMID: 17636118; PubMed Central PMCID: PMC1941482.

Lawton BR, Obergfell C, O’Neill RJ, O’Neill MJ. Physical mapping of the IGF2 locus in the South American opossum Monodelphis domestica. Cytogenet Genome Res. 2007;116(1-2):130-1. doi: 10.1159/000097431. PubMed PMID: 17268191.

Raefski AS, Carone BR, Kaur A, Krueger W, O’Neill MJ. Wnt pathway anomalies in developing amygdalae of Turner syndrome-like mice. J Mol Neurosci. 2007;32(2):111-9. doi: 10.1007/s12031-007-0022-7. PubMed PMID: 17873295.

Duselis AR, Obergfell C, Mack JA, O’Neill MJ, Nguyen QK, O’Neill RJ, Vrana PB. Changes in cell cycle and extracellular matrix gene expression during placental development in deer mouse (Peromyscus) hybrids. Reprod Fertil Dev. 2007;19(5):695-708. doi: 10.1071/rd07015. PubMed PMID: 17601418.

Duselis AR, Wiley CD, O’Neill MJ, Vrana PB. Genetic evidence for a maternal effect locus controlling genomic imprinting and growth. Genesis. 2005 Dec;43(4):155-65. doi: 10.1002/gene.20166. PubMed PMID: 16283622.

Curchoe C, Zhang S, Bin Y, Zhang X, Yang L, Feng D, O’Neill M, Tian XC. Promoter-specific expression of the imprinted IGF2 gene in cattle (Bos taurus). Biol Reprod. 2005 Dec;73(6):1275-81. doi: 10.1095/biolreprod.105.044727. Epub 2005 Aug 24. PubMed PMID: 16120826.

Yang L, Chavatte-Palmer P, Kubota C, O’neill M, Hoagland T, Renard JP, Taneja M, Yang X, Tian XC. Expression of imprinted genes is aberrant in deceased newborn cloned calves and relatively normal in surviving adult clones. Mol Reprod Dev. 2005 Aug;71(4):431-8. doi: 10.1002/mrd.20311. PubMed PMID: 15895469.

Raefski AS, O’Neill MJ. Identification of a cluster of X-linked imprinted genes in mice. Nat Genet. 2005 Jun;37(6):620-4. doi: 10.1038/ng1567. Epub 2005 May 22. PubMed PMID: 15908953.

O’Neill MJ. The influence of non-coding RNAs on allele-specific gene expression in mammals. Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R113-20. doi: 10.1093/hmg/ddi108. Review. PubMed PMID: 15809263.

Lawton BR, Sevigny L, Obergfell C, Reznick D, O’Neill RJ, O’Neill MJ. Allelic expression of IGF2 in live-bearing, matrotrophic fishes. Dev Genes Evol. 2005 Apr;215(4):207-12. doi: 10.1007/s00427-004-0463-8. Epub 2005 Jan 15. PubMed PMID: 15654625.

Zhang S, Kubota C, Yang L, Zhang Y, Page R, O’Neill M, Yang X, Tian XC. Genomic imprinting of H19 in naturally reproduced and cloned cattle. Biol Reprod. 2004 Nov;71(5):1540-4. doi: 10.1095/biolreprod.104.031807. Epub 2004 Jul 7. PubMed PMID: 15240429.

Andrews JE, O’Neill MJ, Binder M, Shioda T, Sinclair AH. Isolation and expression of a novel member of the CITED family. Mech Dev. 2000 Jul;95(1-2):305-8. doi: 10.1016/s0925-4773(00)00362-2. PubMed PMID: 10906483.

O’Neill M, Binder M, Smith C, Andrews J, Reed K, Smith M, Millar C, Lambert D, Sinclair A. ASW: a gene with conserved avian W-linkage and female specific expression in chick embryonic gonad. Dev Genes Evol. 2000 May;210(5):243-9. doi: 10.1007/s004270050310. PubMed PMID: 11180828.

Vrana PB, Fossella JA, Matteson P, del Rio T, O’Neill MJ, Tilghman SM. Genetic and epigenetic incompatibilities underlie hybrid dysgenesis in Peromyscus. Nat Genet. 2000 May;25(1):120-4. doi: 10.1038/75518. PubMed PMID: 10802670.

O’Neill MJ, Ingram RS, Vrana PB, Tilghman SM. Allelic expression of IGF2 in marsupials and birds. Dev Genes Evol. 2000 Jan;210(1):18-20. doi: 10.1007/pl00008182. PubMed PMID: 10603082.

O’Neill MJ, O’Neill RJ. Whatever happened to SRY?. Cell Mol Life Sci. 1999 Dec;56(11-12):883-93. doi: 10.1007/s000180050481. Review. PubMed PMID: 11212323.

O’Neill M, Brewer W, Thornley C, Copolov D, Warne G, Sinclair A, Forrest S, Williamson R. Kallmann syndrome gene (KAL-X) is not mutated in schizophrenia. Am J Med Genet. 1999 Feb 5;88(1):34-7. doi: 10.1002/(sici)1096-8628(19990205)88:1<34::aid-ajmg6>3.0.co;2-6. PubMed PMID: 10050964.

O’Neill RJ, O’Neill MJ, Graves JA. Undermethylation associated with retroelement activation and chromosome remodelling in an interspecific mammalian hybrid. Nature. 1998 May 7;393(6680):68-72. doi: 10.1038/29985. PubMed PMID: 9590690.

O’Neill MJ, Tridjaja B, Smith MJ, Bell KM, Warne GL, Sinclair AH. Familial Kallmann syndrome: a novel splice acceptor mutation in the KAL gene. Hum Mutat. 1998;11(4):340-2. PubMed PMID: 9554756.

O’Neill MJ, Sinclair AH. Isolation of rare transcripts by representational difference analysis. Nucleic Acids Res. 1997 Jul 1;25(13):2681-2. doi: 10.1093/nar/25.13.2681. PubMed PMID: 9185582; PubMed Central PMCID: PMC146778.

O’Neill MJ, Artzt K. Identification of a germ-cell-specific transcriptional repressor in the promoter of Tctex-1. Development. 1995 Feb;121(2):561-8. doi: 10.1242/dev.121.2.561. PubMed PMID: 7768192.

O’Neill MJ, Binder MD, Sinclair AH. Sex Specific Transcripts from Chick Genital Ridge Identified by Differential Display RT-PCR. Journal of Cellular Biochemistry. 1995; 19B:51.

Lader E, Ha HS, O’Neill M, Artzt K, Bennett D. tctex-1: a candidate gene family for a mouse t complex sterility locus. Cell. 1989 Sep 8;58(5):969-79. doi: 10.1016/0092-8674(89)90948-3. PubMed PMID: 2570638.