Joseph H Nadeau

• Maine Medical Center Research Institute

Several genetic variants act as modifiers of testicular germ cell tumor (TGCT) susceptibility in the 129/Sv mouse model of human pediatric TGCTs. One such modifier, the Steel locus, encodes the transmembrane-bound and soluble ligand of the kit receptor. Some (Sl and SlJ) but not all (Sld) mutations of the Steel locus increase TGCT incidence in hete...

In mice, the Ter mutation causes primordial germ cell (PGC) loss in all genetic backgrounds. Ter is also a potent modifier of spontaneous testicular germ cell tumour (TGCT) susceptibility in the 129 family of inbred strains, and markedly increases TGCT incidence in 129-Ter/Ter males. In 129-Ter/Ter mice, some of the remaining PGCs transform into un...

Chromosome substitution strains (CSSs) have been proposed as a simple and powerful way to identify quantitative trait loci (QTLs) affecting developmental, physiological, and behavioral processes. Here, we report the construction of a complete CSS panel for a vertebrate species. The CSS panel consists of 22 mouse strains, each of which carries a sin...

An emerging theme of studies with spontaneous, engineered and induced mutant mice is that phenotypes often depend on genetic background, implying that genetic modifiers have a role in guiding the functional consequences of genetic variation. Understanding the molecular and cellular basis by which modifier genes exert their influence will provide in...

The genetic architecture of complex traits underlying physiology and disease in most organisms remains elusive. We still know little about the number of genes that underlie these traits, the magnitude of their effects, or the extent to which they interact. Chromosome substitution strains (CSSs) enable statistically powerful studies based on testing...

Studies in genetically ‘identical’ individuals indicate that as much as 50% of complex trait variation cannot be traced to genetics or to the environment. The mechanisms that generate this ‘unexplained’ phenotypic variation (UPV) remain largely unknown. Here, we identify neuronatin (NNAT) as a conserved factor that buffers against UPV. We find that...

Meiosis, recombination, and gametogenesis normally ensure that gametes combine randomly. But in exceptional cases, fertilization depends on the genetics of gametes from both females and males. A key question is whether their non-random union results from factors intrinsic to oocytes and sperm, or from their interactions with conditions in the repro...

The gene CHRNA5 is strongly associated with the level of nicotine consumption in humans and manipulation of the expression or function of Chrna5 similarly alters nicotine consumption in rodents. In both humans and rodents, reduced or complete loss of function of Chrna5 leads to increased nicotine consumption. However, the mechanism through which de...

Dopaminergic neurons (DA neurons) are controlled by multiple factors, many involved in neurological disease. Parkinson’s disease (PD) motor symptoms are caused by the demise of nigral DA neurons, leading to loss of striatal dopamine (DA). Here, we measured DA concentration in the dorsal striatum of 32 members of Collaborative Cross (CC) family and...

Dopaminergic neurons in the midbrain are of particular interest due to their role in diseases such as Parkinson’s disease and schizophrenia. Genetic variation between individuals can affect the integrity and function of dopaminergic neurons but the DNA variants and molecular cascades modulating dopaminergic neurons and other cells types of ventral...

The RNA-binding protein Apobec1 complementation factor (A1CF) regulates posttranscriptional ApoB mRNA editing, but the range of RNA targets and the long-term effect of altered A1CF expression on liver function are unknown. Here we studied hepatocyte-specific A1cf-transgenic (A1cf+/Tg), A1cf+/Tg Apobec1-/-, and A1cf-/- mice fed chow or high-fat/high...

The features of dopaminergic neurons (DAns) of nigrostriatal circuitry are orchestrated by a multitude of yet unknown factors, many of them genetic. Genetic variation between individuals at baseline can lead to differential susceptibility to and severity of diseases. As decline of DAns, a characteristic of Parkinson disease, heralds a significant d...

Background Dopaminergic neurons in the midbrain are of particular interest due to their role in diseases such as Parkinson’s disease and schizophrenia. Genetic variation between individuals can affect the integrity and function of dopaminergic neurons but the DNA variants and molecular cascades modulating dopaminergic neurons and other cells types...

DISCLOSURES: The authors have nothing to disclose. INTRODUCTION: Genes that alter bone strength and thus contribute to mechanical homeostasis have previously been identified by others when selectively perturbing the Wnt pathway. However, it remains unclear how genes and their interactions within the Wnt pathway contribute to the natural variation i...

Ongoing studies in many species seek to understand the origins, architecture and consequences of phenotypic variation under normal and dysfunctional conditions, with the aim of identifying targets for intervention that can prevent, stabilize or reverse disease. Some suggest that only humans are appropriate for studying these questions and argue tha...

Mammalian C to U RNA is mediated by APOBEC1, the catalytic deaminase, together with RNA binding cofactors (including A1CF and RBM47) whose relative physiological requirements are unresolved. Although A1CF complements APOBEC1 for in vitro RNA editing, A1cf-/- mice exhibited no change in apolipoproteinB (apoB) RNA editing, while Rbm47 mutant mice exh...

A high-fat diet induces obesity and is associated with heart disease characterized by cardiac hypertrophy, diastolic dysfunction, fibrosis, and mitochondrial dysfunction. However, the molecular mechanisms involved in the pathogenesis of cardiac disease are not known. Therefore, the objective of this study was to investigate the molecular changes in...

p>Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using Sleeping Beauty (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis, and compared...

A fundamental tenet of inheritance in sexually reproducing organisms such as humans and laboratory mice is that gametes combine randomly at fertilization, thereby ensuring a balanced and statistically predictable representation of inherited variants in each generation. This principle is encapsulated in Mendel’s First Law. But exceptions are known....

Phenotypes are rarely consistent across genetic backgrounds and environments, but instead vary in many ways depending on allelic variants, unlinked genes, epigenetic factors, and environmental exposures. In the extreme, individuals carrying the same causal DNA sequence variant but on different backgrounds can be classified as having distinct condit...

A fundamental tenet of inheritance in sexually reproducing organisms such as humans and laboratory mice is that genetic variants combine randomly at fertilization, thereby ensuring a balanced and statistically predictable representation of inherited variants in each generation. This principle is encapsulated in Mendel’s First Law. But exceptions ar...

Previously, we showed that cortical mineralization is coordinately adjusted to mechanically offset external bone size differences between A/J (narrow) and C57BL/6J (wide) mouse femora to achieve whole bone strength equivalence at adulthood. The identity of the genes and their interactions that are responsible for establishing this homeostatic state...

Cell Systems invited 16 experts to share their views on the field of systems genetics. In questions repeated in the headings, we asked them to define systems genetics, highlight its relevance to researchers outside the field, discuss what makes a strong systems genetics paper, and paint a picture of where the field is heading in the coming years. T...

Purpose of review: The task of cataloging human genetic variation and its relation to disease is rapidly approaching completion. The new challenge is to discover the function of disease-associated genes and to understand the pathways that lead to human disease. We propose that achieving this new level of understanding will increasingly rely on the...

Significance Usually diagnosed in young men, testicular germ cell tumors (TGCTs) originate from abnormalities in germ cells during fetal development. Testicular cancer is a complex disease combining multiple genetic variants and environmental factors. The discovery of unconventional inheritance for TGCT risk both in humans and mice highlighted the...

Obesity and related metabolic disturbances are closely associated with pathologies that represent a significant burden to global health. Epidemiological and molecular evidence links obesity and metabolic status with inflammation and increased risk of cancer. Here, using a mouse model of intestinal neoplasia and strains that are susceptible or resis...

The AU‐rich RNA binding protein ACF is thought to represent the RNA binding subunit of the apoB mRNA editosome. Known ACF targets include apoB and IL‐6; ACF binds and stabilizes IL‐6 mRNA playing a key role in liver growth. ACF exhibits nanomolar binding affinity to apoB RNA and recombinant ACF plus Apobec‐1 are both necessary and sufficient for C...

In 2016, a symposium was convened in Leroy C. Stevens’ honor, in association with a meeting of the International Stem Cell Initiative (ISCI). ISCI, funded internationally, is composed of a group of ~100 scientists from many countries, under the leadership of Peter Andrews, who have worked together to characterize a significant number of human pluri...

Organisms adapt developmental and physiological features to local and transient conditions in part by modulating transcription, translation, and protein functions, usually without changing DNA sequences. Remarkably, these epigenetic changes sometimes endure through meiosis and gametogenesis, thereby affecting phenotypic variation across generations...

Background/objectives: Both genetic and dietary factors contribute to the metabolic syndrome (MetS) in humans and animal models. Characterizing their individual roles as well as relationships among these factors is critical for understanding MetS pathogenesis and developing effective therapies. By studying phenotypic responsiveness to high-risk ve...

Not so fast. The Iqbal et. al. study and the associated Whitelaw commentary highlight the appropriately high standards of study design and interpretation needed to obtain good evidence for or against epigenetic inheritance. Please see related article: www.dx.doi.org/10.1186/s13059-015-0714-1

Quantitative trait loci (QTLs) are being used to study genetic networks, protein functions, and systems properties that underlie phenotypic variation and disease risk in humans, model organisms, agricultural species, and natural populations. The challenges are many, beginning with the seemingly simple tasks of mapping QTLs and identifying their und...

Significance Colorectal cancer results from genetic lesions in epithelial cells. However, the tumor microenvironment, which is formed by nonepithelial stromal cells, also plays an important role in this disease. The influence of the microenvironment on tumorigenesis is mediated by paracrine signals between tumor epithelial cells and neighboring str...

Serotonin acts as neurotransmitter in the brain and as a multifaceted signaling molecule coordinating many physiological processes in the periphery. In a recent issue of Nature Medicine, Crane et al. (2014) find that peripheral serotonin controls thermogenesis in adipose tissue by modulating β-adrenergic stimulation of UCP-1, thereby affecting gluc...

Background Neural tube defects (NTDs) are the second most common birth defect in humans. Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies. FA plays an established role in folate and homocysteine metabolism, but the means by which it suppresses occurrence of NTDs is...

Metabolic diseases such as obesity and atherosclerosis result from complex interactions between environmental factors and genetic variants. A panel of chromosome substitution strains (CSSs) was developed to characterize genetic and dietary factors contributing to metabolic diseases and other biological traits and biomedical conditions. Our goal her...

Background RNA editing encompasses a post-transcriptional process in which the genomically templated sequence is enzymatically altered and introduces a modified base into the edited transcript. Mammalian C-to-U RNA editing represents a distinct subtype of base modification, whose prototype is intestinal apolipoproteinB mRNA, mediated by the catalyt...

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world and its prevalence is rising. In the absence of disease progression, fatty liver poses minimal risk of detrimental health outcomes. However, advancement to non-alcoholic steatohepatitis (NASH) confers a markedly increased likelihood of developing severe liver pa...

Epidemiological and animal studies have shown that maternal diet can influence metabolism in adult offspring. However, the molecular mechanisms underlying these changes remain poorly understood. Here, we characterize the phenotypes induced by maternal obesity in a mouse model and examine gene expression and epigenetic changes induced by maternal di...

Cytomegalovirus (CMV) infection was previously reported in pregnancy complications. However, its seroprevalence and associated Toll-like receptor (TLR) expression in early-onset preeclampsia (EOPE) with hemolysis, elevated liver enzyme and low platelets syndrome (HELLPs) are unexplored. A case-control study was performed to examine maternal CMV ant...

Mouse early transposon insertions are responsible for ∼10% of spontaneous mutant phenotypes. We previously reported the phenotypes and genetic mapping of Polypodia, (Ppd), a spontaneous, X-linked dominant mutation with profound effects on body plan morphogenesis. Our new data shows that mutant mice are not born in expected Mendelian ratios secondar...

Diet-induced obesity (DIO) and metabolic syndrome (MetS) are important factors that contribute to the development and progression of cancer, especially colon cancer. DIO and MetS have reached epidemic proportions in the United States and are heavily influenced by diets high in saturated and omega-6 polyunsaturated fatty acids. Using the ApcMin/+ mo...

Background Certain mutations in the Deadend1 (Dnd1) gene are the most potent modifiers of testicular germ cell tumor (TGCT) susceptibility in mice and rats. In the 129 family of mice, the Dnd1Ter mutation significantly increases occurrence of TGCT-affected males. To test the hypothesis that he Dnd1Ter allele is a loss-of-function mutation; we chara...

Background: Because the histological and biochemical progression of liver disease is similar in alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH), we hypothesized that the genetic susceptibility to these liver diseases would be similar. To identify potential candidate genes that regulate the development of liver fibrosis, we...

Laboratory mice are valuable in biomedical research in part because of the extraordinary diversity of genetic resources that are available for studies of complex genetic traits and as models for human biology and disease. Chromosome substitution strains (CSSs) are important in this resource portfolio because of their demonstrated use for gene disco...

Environmental agents and genetic variants can induce heritable epigenetic changes that affect phenotypic variation and disease risk in many species. These transgenerational effects challenge conventional understanding about the modes and mechanisms of inheritance, but their molecular basis is poorly understood. The Deadend1 (Dnd1) gene enhances sus...

Disruption of cellular processes affected by multiple genes and accumulation of numerous insults throughout life dictate the progression of age-related disorders, but their complex etiology is poorly understood. Postmitotic neurons, such as photoreceptor cells in the retina and epithelial cells in the adjacent retinal pigmented epithelium, are espe...

Despite considerable effort, the identification of genes that regulate complex multigenic traits such as obesity has proven difficult with conventional methodologies. The use of a chromosome substitution strain-based mapping strategy based on deep congenic analysis overcame many of the difficulties associated with gene discovery and led to the find...

The HELLP syndrome is a serious complication in pregnancy characterized by haemolysis, elevated liver enzymes and low platelet count occurring in 10–20% of cases with severe preeclampsia and associated with metabolic disorders symptoms later in life. Emerging evidence indicated that cytomegalovirus (CMV) infection and TLR signaling activation are a...

The genetic architecture of complex traits strongly influences the consequences of inherited mutations, genetic engineering, environmental and genetic perturbations, and natural and artificial selection. But because most studies are under-powered, the picture of complex traits is often incomplete. Chromosome substitution strains (CSSs) are a unique...

Figure 1 Frequency distribution of phenotypic effect sizes for the three CSS panels, based on the Hi_Low method – the NormUnit method yielded similar results (not shown).

Testicular teratomas result from anomalies in germ cell development during embryogenesis. In the 129 family of inbred strains of mice, teratomas initiate around embryonic day (E) 13.5 during the same developmental period in which female germ cells initiate meiosis and male germ cells enter mitotic arrest. Here, we report that three germ cell develo...

The working group concluded that epigenetics research should incorporate multispecies comparisons to benefit from evolutionary insights and perspectives. Studies will require coordination of multidisciplinary teams combining expertise in clinical and basic research, as well as in computational and modeling methods. New insights and hypotheses will...

Obesity and high fat (HF) diet are associated with increased risk of colon cancer. However, assessing their independent contributions to intestinal carcinogenesis is difficult due to their close association in humans. We utilized Chromosome Substitution Strains (CSSs) in combination with the B6.ApcMin/+ mouse model of intestinal cancer to generate...

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensi...

Testicular germ-cell tumours (TGCTs) are the most common cancer in young men; the incidence is increasing worldwide and they have an unusually high rate of metastasis. Despite significant work on TGCTs and their metastases in humans, absence of a mouse model of spontaneous metastasis has greatly limited our understanding of the mechanisms by which...

Although central to many studies of phenotypic variation and disease susceptibility, characterizing the genetic architecture of complex traits has been unexpectedly difficult. For example, most of the susceptibility genes that contribute to highly heritable conditions such as obesity and type 2 diabetes (T2D) remain to be identified despite intensi...

This article is categorized under: Translational, Genomic, and Systems Medicine > Translational Medicine

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Hepatocellular Carcinoma (HCC) is the 5th most common cancer worldwide, with increased risk occurring in patients with hepatitis C and B, alcoholism, aflatoxin, and metabolic diseases. Animal models that target liver cells with chemical, physical or biological agents are usef...

This article is categorized under: Physiology > Mammalian Physiology in Health and Disease

Pluripotent stem cells provide a platform to interrogate control elements that function to generate all cell types of the body. Despite their utility for modeling development and disease, the relationship of mouse and human pluripotent stem cell states to one another remains largely undefined. We have shown that mouse embryonic stem (ES) cells and...

From studies with peas over 150 years ago, Gregor Mendel deduced the laws that govern the inheritance of traits in most organisms. The brilliance, but also the limitation, of Mendel's work was its focus on single-gene traits, such as flower color and plant height. However, phenotypic variation, including that which underlies health and disease in h...

A 6-year experimental study was used to examine the effects of resident, breeding males on recruitment and dispersal of juveniles on Muskeget Island, Massachusetts. Dispersal was studied by providing a vacant area into which mice could move. Residency and recruitment in males depended on weight but not breeding condition. Dispersing males were a ra...

Human germ cell tumors show a strong sensitivity to genetic background similar to Dnd1(Ter/Ter) mutant mice, where testicular teratomas arise only on the 129/SvJ genetic background. The introduction of the Bax mutation onto mixed background Dnd1(Ter/Ter) mutants, where teratomas do not typically develop, resulted in a high incidence of teratomas. H...

Crooked tail (Cd) mice bear a gain-of-function mutation in Lrp6, a co-receptor for canonical WNT signaling, and are a model of neural tube defects (NTDs), preventable with dietary folic acid (FA) supplementation. Whether the FA response reflects a direct influence of FA on LRP6 function was tested with prenatal supplementation in LRP6-deficient emb...

Since Mendel, studies of phenotypic variation and disease risk have emphasized associations between genotype and phenotype among affected individuals in families and populations. Although this paradigm has led to important insights into the molecular basis for many traits and diseases, most of the genetic variants that control the inheritance of th...

Current treatments have largely failed to slow the rapidly increasing world-wide prevalence of obesity and its co-morbidities. Despite a strong genetic contribution to obesity (40-70%), only a small percentage of heritability is explained with current knowledge of monogenic abnormalities, common sequence variants and conventional modes of inheritan...

Development of viral-induced chronic myocarditis is thought to involve both environmental and genetic factors. However, to date, no susceptibility genes have been identified. We sought to identify loci that confer susceptibility to viral-induced chronic myocarditis with the use of chromosome substitution strain mice that are composed of 1 chromosom...

Testicular germ cell tumors (TGCT) originate from germ cells. The 129-Ter and M19 (129.MOLF-Chr19 consomic) mouse strains have extremely high incidences of TGCTs. We found that the expression levels of Sf1-encoded splicing factor 1 (SF1) can modulate the incidence of TGCTs. We generated mice with inactivated Sf1. Sf1 null mice (Sf1-/-) died before...

Obesity is the result of excess energy intake relative to expenditure, however little is known about why some individuals are more prone to weight gain than others. Inbred strains of mice also vary in their susceptibility to obesity and therefore represent a valuable model to study the genetics and physiology of weight gain and its co-morbidities s...

Two overlapping quantitative trait loci (QTLs) for clot stability, Hmtb8 and Hmtb9, were identified on mouse chromosome 17 in an F2 intercross derived from C57BL/6J (B6) and B6-Chr17A/J (B6-Chr17) mouse strains. The intervals were in synteny with a QTL for thrombotic susceptibility on chromosome 18 in a human study, and there were 23 homologs betwe...

Recent evidence suggests that transgenerational genetic effects contribute to phenotypic variation in complex traits. To test for the general occurrence of these effects and to estimate their strength, we took advantage of chromosome substitution strains (CSSs) of mice where the Y chromosome of the host strain has been replaced with the Y chromosom...

To identify genes affecting bone strength, we studied how genetic variants regulate components of a phenotypic covariation network that was previously shown to accurately characterize the compensatory trait interactions involved in functional adaptation during growth. Quantitative trait loci (QTLs) regulating femoral robustness, morphologic compens...

This article is categorized under: Translational, Genomic, and Systems Medicine > Translational Medicine Analytical and Computational Methods > Computational Methods

Although recent genome-wide studies have provided valuable insights into the genetic basis of human disease, they have explained relatively little of the heritability of most complex traits, and the variants identified through these studies have small effect sizes. This has led to the important and hotly debated issue of where the 'missing heritabi...

Congenic strains continue to be a fundamental resource for dissecting the genetic basis of complex traits. Traditionally, genetic variants (QTLs) that account for phenotypic variation in a panel of congenic strains are sought first by comparing phenotypes for each strain to the host (reference) strain, and then by examining the results to identify...

For further resources related to this article, please visit the WIREs website.

Discovery of genes that confer resistance to diseases such as diet-induced obesity could have tremendous therapeutic impact. We previously demonstrated that the C57BL/6J-Chr(A/J)/NaJ panel of chromosome substitution strains (CSSs) is a unique model for studying resistance to diet-induced obesity. In the present study, three replicate CSS surveys sh...

For further resources related to this article, please visit the WIREs website.

For further resources related to this article, please visit the WIREs website.

Cancer susceptibility results from interactions between sensitivity and resistance alleles. We employed murine chromosome substitution strains to study how resistance alleles affected sensitive alleles during chemically-induced lung carcinogenesis. The C57BL/6J-Chr#(A/J) strains, constructed by selectively breeding sensitive A/J and resistant C57BL...

Despite strong heritability, little is known about the genetic control of susceptibility to testicular germ cell tumors (TGCT) in humans or mice. Although the mouse model of spontaneous TGCTs has been extensively studied, conventional linkage analysis has failed to locate the factors that control teratocarcinogenesis in the susceptible 129 family o...

This article is categorized under: Translational, Genomic, and Systems Medicine > Translational Medicine

Effects of applying different p-score thresholds on the accuracy and sensitivity of SNP calling from CAST/Ei sequence.

Single nucleotide differences between C57BL/6J and A/J that affect Ensembl coding exons, marked as either synonymous, non-synonymous or splice site changes. Also indicated are the sequencing depth and phred-like quality score.