Complete List of Published Work in MyBibliography: https://www.ncbi.nlm.nih.gov/myncbi/1b7cuDRjojdQ6/bibliography/public/
Top Five Papers
Nadeau JH, Taylor BA. Lengths of chromosomal segments conserved since divergence of man and mouse. Proc Natl Acad Sci USA 1985 Feb;81(3)814-8. PubMed PMID: 6583681; PubMed Central PMCID: PMC344928.
Youngren KK, Coveney D, Peng X, Bhattacharya C, Schmidt LS, Nickerson ML, Lamb BT, Deng JM, Behringer RR, Capel B, Rubin EM, Nadeau JH, Matin A. The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature. 2005 May 19;435(7040):360-4.
Singer JB, Hill AE, Burrage LC, Olszens KR, Song J, Justice M, O’Brien WE, Conti DV, Witte JS, Lander ES, Nadeau JH. Genetic dissection of complex traits with chromosome substitution strains of mice. Science. 2004 Apr 16;304(5669):445-8. PubMed PMID: 15031436.
Shao H, Burrage LC, Sinasac DS, Hill AE, Ernest SR, O’Brien W, Courtland HW, Jepsen KJ, Kirby A, Kulbokas EJ, Daly MJ, Broman KW, Lander ES, Nadeau JH. Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis. Proc Natl Acad Sci USA. 2008 Dec 16;105(50):19910-4. PubMed PMID: 19066216; PubMed Central PMCID: PMC2604967.
Crosby JL, Varnum DS, Nadeau JH. Two-hit model for sporadic congenital anomalies in mice with the disorganization mutation. Am J Hum Genet. 1993 May;52(5):866-74. PMID: 8488837.
Five Most Recent
Nadeau JH, Auwerx J. The virtuous cycle of human genetics and mouse models in drug discovery. Nat Rev Drug Discov. 2019 Apr;18(4):255-272. doi: 10.1038/s41573-018-0009-9. Review. PMID: 30679805.
Blanc V, Xie Y, Kennedy S, Riordan JD, Rubin DC, Madison BB, Mills JC, Nadeau JH, Davidson NO. Apobec1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver. RNA. 2019 Jan;25(1):70-81. doi: 10.1261/rna.068395.118. Epub 2018 Oct 11. PMID: 30309881.
Tschida BR, Temiz NA, Kuka TP, Lee LA, Riordan JD, Tierrablanca CA, Hullsiek R, Wagner S, Hudson WA, Linden MA, Amin K, Beckmann PJ, Heuer RA, Sarver AL, Yang JD, Roberts LR, Nadeau JH, Dupuy AJ, Keng VW, Largaespada DA. Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors. Cancer Res. 2017 Dec 1;77(23):6576-6588. doi: 10.1158/0008-5472.CAN-17-2281. Epub 2017 Oct 9. PMID: 28993411.
Nadeau JH. Do Gametes Woo? Evidence for Their Nonrandom Union at Fertilization. Genetics. 2017 Oct;207(2):369-387. doi: 10.1534/genetics.117.300109. Review. PMID: 28978771.
Riordan JD, Nadeau JH. From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health. Am J Hum Genet. 2017 Aug 3;101(2):177-191. doi: 10.1016/j.ajhg.2017.06.004. Review. PMID: 28777930
Five Research Areas with References
Comparative genomics (Key paper: J. Nadeau and B.A. Taylor, PNAS 81:814-818, 1984)
My most significant accomplishment involves the first hypothesis-based quantitative analysis of mammalian genome organization and evolution. This work showed that the patterns of linkage conservation and disruption across the genome were consistent with a random distribution of chromosome rearrangement breakpoints. The paper helped establish the field of comparative genomics, was recognized as one of the most important discoveries in mouse genetics in the last century (E. Pennisi, Science 2000), and has been described as ‘visionary’, ‘prophetic’, and ‘landmark’ (P. Pevzner, PNAS 2003; D. Sankoff, Bioinformatics 2004). This work is significant because of its originality and impact. We defined a clear hypothesis and solved a hard problem in an innovative manner, with results that stood a dramatic increase in data. Many high profile papers have since used this approach as part of their characterization of the first complete genome sequences (E.S. Lander, Nature 2001; J.C. Venter, Science 2001; R.H. Waterston, Nature 2002). The work also has practical applications by providing a validated theoretical and empirical framework for transferring information from map-rich to map-poor species. In at least one case, this dynamic information exchange led to discovery not only of a gene for hereditary non-syndromic deafness, but also its genetic modifier, based on comparison of map locations and mutated genes in humans and mouse models (J.M. Schultz, NEJM 2005). The Nadeau-Taylor paper influenced fields as diverse as disease genetics and evolutionary biology, and stimulated a generation of mathematical genetics researchers (D. Sankoff, J.H. Nadeau, Comparative Genomics, Kluwer Publs, 2001).
a. Nadeau JH, Taylor BA. Lengths of chromosomal segments conserved since divergence of man and mouse. Proc Natl Acad Sci USA 1985 Feb;81(3)814-8. PubMed PMID: 6583681; PubMed Central PMCID: PMC344928.
b. Sankoff D, Ferretti V, Nadeau JH. Conserved segment identification. J Comput Biol. 1997 Winter;4(4):559-65. PubMed PMID: 9385546.
c. Ehrlich J, Sankoff D, Nadeau JH. Synteny conservation and chromosome rearrangements during mammalian evolution. Genetics. 1997 Sep;147(1):289-96. PubMed PMID: 9286688; PubMed Central PMCID: PMC1208112.
d. Nadeau JH, Sankoff D. Comparable rates of gene loss and functional divergence after genome duplications early in vertebrate evolution. Genetics. 1997 Nov;147(3):1259-66. PubMed PMID: 9383068; PubMed Central PMCID: PMC1208249.
Testicular cancer (TGCTs)
Until recently the genetic basis for the unusually high heritability of TGCT susceptibility was elusive in both humans and model organisms. Our studies of spontaneous TGCTs led to discovery of susceptibility genes and pathways, some of which have been validated in humans. The Ter mutant in the Deadend1 (Dnd1) gene is the most potent cancer modifier gene in mammals (Youngren, 2005). Dnd1 is the first RNA-binding protein associated with risk for a heritable cancer. Given the sequence similarity between Dnd1 and several genes involved in RNA-editing, we tested whether the Apobec1 cytidine deaminase (Apobec1) and its RNA-binding subunit control susceptibility (A1cf) contribute to TGTCs. Interestingly these act in both a conventional and epigenetic manner (see below). We also showed that signaling through the Kit pathway controls susceptibility in a conventional and epigenetic manner (Heaney, 2008). Finally, we found that the rate-limiting translation initiation factor Eif2s2 is a potent suppressor of TGCTs. Finally, we discovered spontaneous metastasis in these strains and mutants (Zechel, 2011). Together these studies have provided deep and novel insights into TGCT genetics.
a. Youngren KK, Coveney D, Peng X, Bhattacharya C, Schmidt LS, Nickerson ML, Lamb BT, Deng JM, Behringer RR, Capel B, Rubin EM, Nadeau JH, Matin A. The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature. 2005 May 19;435(7040):360-4. PubMed PMID: 15902260; NIHMSID: NIHMS4380; PubMed Central PMCID: PMC1421521.
b. Heaney JD, Lam MY, Michelson MV, Nadeau JH. Loss of the transmembrane but not the soluble kit ligand isoform increases testicular germ cell tumor susceptibility in mice. Cancer Res. 2008 Jul 1;68(13):5193-7. PubMed PMID: 18593919; NIHMSID: NIHMS54606; PubMed Central PMCID: PMC2562736.
c. Heaney JD, Michelson MV, Youngren KK, Lam MY, Nadeau JH. Deletion of eIF2beta suppresses testicular cancer incidence and causes recessive lethality in agouti-yellow mice. Hum Mol Genet. 2009 Apr 15;18(8):1395-404. PubMed PMID: 19168544; PubMed Central PMCID: PMC2664146.
d. Zechel JL, MacLennan GT, Heaney JD, Nadeau JH. Spontaneous metastasis in mouse models of testicular germ-cell tumours. Int J Androl. 2011 Aug;34(4 Pt 2):e278-87. PubMed PMID: 21651572; NIHMSID: NIHMS344453; PubMed Central PMCID: PMC3979466.
Germ cells are the only lineage of cells that persist across generations; they are also the TGCT stem cell. Reprogramming in the germline must occur at each generation to erase most epigenetic marks, replacing than with sex- and individual-specific marks. Germ cells are therefore especially vulnerable to epigenetic modifications as well as transformation to TGCTs. We discovered that epigenetic inheritance contributes significantly to inherited risk for testicular cancer (TGCTs). Dnd1 acting in offspring controls vulnerability to inherited epigenetic changes (Lam, 2007). We also showed that Apobec1 and A1cf trigger epigenetically transmit protection against TGCTs through the maternal lineage, while increasing TGCT risk in a conventional manner through the paternal germline (Nelson, 2012; D. Carouge, in prep). In parallel, we showed that genetically distinct Y chromosomes induce epigenetic inheritance that significantly affects many traits among genetically identical female offspring (Nelson, 2010). The only difference among these females is the identity of the paternal Y chromosome, which they do not inherit. These and other studies were among the first evidence for epigenetic inheritance in mammals and were the foundation for an NIH Pioneer Award. With these model systems, we are currently seeking to understand the modes of inheritance and the underlying molecular basis for epigenetic inheritance.
a. Lam MY, Heaney JD, Youngren KK, Kawasoe JH, Nadeau JH. Trans-generational epistasis between Dnd1Ter and other modifier genes controls susceptibility to testicular germ cell tumors. Hum Mol Genet. 2007 Sep 15;16(18):2233-40. PubMed PMID: 17616517.
b. Yazbek SN, Spiezio SH, Nadeau JH, Buchner DA. Ancestral paternal genotype controls body weight and food intake for multiple generations. Hum Mol Genet. 2010 Nov 1;19(21):4134-44. PubMed PMID: 20696673; PubMed Central PMCID: PMC2951864.
c. Nelson VR, Heaney JD, Tesar PJ, Davidson NO, Nadeau JH. Transgenerational epigenetic effects of the Apobec1 cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability. Proc Natl Acad Sci USA. 2012 Oct 9;109(41):E2766-73. PubMed PMID: 22923694; PubMed Central PMCID: PMC3478648.
d. Carouge D, Blanc V, Knoblaugh SE, Hunter RJ, Davidson NO, Nadeau JH. Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias. Proc Natl Acad Sci USA. 2016 (113:E5425-33) PMID: 27582469.
Complex traits, gene discovery, genetic architecture, systems biology.
Early in the Genome Project, Eric Lander and I recognized that we would soon have the genetic markers, genotyping technologies, and analytical methods for genome-wide association studies of complex traits. We also recognized that because of sample size, study design, and signal-noise issues, most QTLs would elude discovery, a problem now known as ‘missing heritability’. We made the first complete panel of Chromosome Substitution Strains in mammals, thereby establishing a new way to study complex traits (Matin, 1999; Nadeau, 2000). With CSSs, each chromosome is tested independently of the others and the tests are made on an inbred and uniform genetic background. Our expectation to find more QTLs with small effects that escape detection in other study populations was verified (Singer, 2004). However, reanalysis of the CSS data revealed too many genetic variants whose phenotypic effects were stronger than expected. This led in turn to reconsideration of the nature of the evidence. Development of a new way to test for gene interactions led to the first adequately powered, genome-wide survey for epistasis (Shao, 2008). Epistasis was found to be more pervasive and stronger than anticipated. We also found evidence for bistable states, ceiling-floor effects, and related systems properties. A recent review showed that more QTLs have been discovered with CSSs than with all other resources combined, and nearly as many genes identified (Buchner, 2015). This unique genetic paradigm not only enables conventional genetic studies, but also creates unprecedented opportunities to study systems properties and their interplay with genetic variation.
a. Matin A, Collin GB, Asada Y, Varnum D, Nadeau JH. Susceptibility to testicular germ-cell tumours ina 129MOLF-Chr19 chromosome substitution strain. Nat Genet. 1999 Oct;23(2):237-40. PubMed PMID:10508525.
b. Nadeau JH, Singer JB, Matin A, Lander ES. Analysing complex genetic traits with chromosome substitution strains. Nat Genet. 2000 Mar;24(3):221-5. PubMed PMID: 10700173.
c. Singer JB, Hill AE, Burrage LC, Olszens KR, Song J, Justice M, O’Brien WE, Conti DV, Witte JS, Lander ES, Nadeau JH. Genetic dissection of complex traits with chromosome substitution strains of mice. Science. 2004 Apr 16;304(5669):445-8. PubMed PMID: 15031436.
d. Shao H, Burrage LC, Sinasac DS, Hill AE, Ernest SR, O’Brien W, Courtland HW, Jepsen KJ, Kirby A, Kulbokas EJ, Daly MJ, Broman KW, Lander ES, Nadeau JH. Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis. Proc Natl Acad Sci USA. 2008 Dec 16;105(50):19910-4. PubMed PMID: 19066216; PubMed Central PMCID: PMC2604967.
Genetic and dietary effects on fertilization.
During work on diet effects on mouse models of neural tube defects as well as on genetic effects of RNA-editing genes on TGCTs, we discovered strong evidence that both dietary and genetic factors control the identity of sperm and egg that join at fertilization (Nelson, 2012; Zechel, 2013; Nakouzi, 2014). In various publications, we and others attributed strong departures from Mendelian expectations to embryonic lethality (Gray, 2010). My student and I later realized that litter sizes were normal rather than significantly reduced as expected if embryonic lethality contributed to these non-Mendelian ratios. With normal litter sizes, genetically biased fertilization is a better explanation than embryonic lethality. Remarkably, the prediction for litter size is rarely tested and as a result studies are often misinterpreted. Reanalysis of the published literature revealed other examples of both diet (folate) effects as well as for Apobec1 and related RNA binding proteins that act during gametogenesis. We proposed that functional dependency between folate and polyamine metabolism is the underlying molecular and epigenetic mechanism, a hypothesis that we now seek to test. Polyamines are involved in the genetics and biology of haploid gametes as well as in transcription, translation and epigenetic controls in somatic and germ cells. Our discovery raises the possibility that folate supplementation in humans may reduce occurrence of NTDs by biasing fertilization away from combinations that lead to NTDs, rather than by correcting a developmental problem. The public health implications are obvious. Biased fertilization violates Mendel’s First Law and provides unique opportunities to study the genetics of fertilization.
a. Nelson VR, Heaney JD, Tesar PJ, Davidson NO, Nadeau JH. Transgenerational epigenetic effects of the Apobec1 cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability. Proc Natl Acad Sci USA. 2012 Oct 9;109(41):E2766-73. PubMed PMID: 22923694; PubMed Central PMCID: PMC3478648.
b. Nakouzi GA, Nadeau JH. Does dietary folic acid supplementation in mouse NTD models affect neural tube development or gamete preference at fertilization. BMC Genet. 2014 Aug 27 15:91. PubMed PMID 25154628; PubMed Central PMCID: PMC4151023.
c. Carouge D, Blanc V, Knoblaugh SE, Hunter RJ, Davidson NO, Nadeau JH. Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias. Proc Natl Acad Sci USA. 2016 Sep 13;113(37):E5425-33. PubMed PMID: 27582469; PubMed Central PMCID: PMC5027451.
d. Nadeau JH. Do gametes woo? Evidence for their nonrandom union at fertilization. Genetics 207:369-38. PubMed PMID:28978771; PubMed Central (in process).