Association studies in outbred mice in a new era of full-genome sequencing

Thousands of loci that contribute to quantitative traits in outbred crosses of mice have been reported over the last two decades. In this review we discuss how outbred mouse populations can be used to map and identify the genes and sequence variants that give rise to quantitative variation. We discuss heterogeneous stocks, the diversity outbred, and commercially available outbred populations of mice. All of these populations are descended from a small number of progenitor strains. The availability of the complete sequence of laboratory strains means that in many cases it will be possible to reconstruct the genomes of the outbred animals so that in a genetic association study we can detect the effect of all variants, a situation that has so far eluded studies in completely outbred populations. These resources constitute a major advance and make it possible to progress from a quantitative trait locus to a gene at an unprecedented spee

Genomes and phenomes of a population of outbred rats and its progenitors

Finding genetic variants that contribute to phenotypic variation is one of the main challenges of modern genetics. We used an outbred population of rats (Heterogeneous Stock, HS) in a combined sequence-based and genetic mapping analysis to identify sequence variants and genes contributing to complex traits of biomedical relevance. Here we describe the sequences of the eight inbred progenitors of the HS and the variants that segregate between them. We report the genotyping of 1,407 HS rats, and the collection from 2,006 rats of 195 phenotypic measures that are relevant to models of anxiety, type 2 diabetes, hypertension and osteoporosis. We make available haplotype dosages for the 1,407 genotyped rats, since genetic mapping in the HS is best carried out by reconstructing each HS chromosome as a mosaic of the progenitor genomes. Finally, we have deposited an R object that makes it easy to incorporate our sequence data into any genetic study of HS rats. Our genetic data are available for both Rnor3.4 and Rnor5.0 rat assemblies

Assumptions, Resources, and Inputs to Case Management: Implications for California’s Regional Center System

This project adds to knowledge of case management assumptions, resources, and inputs for California’s Regional Center system by surveying members of the Service Access and Equity working group, formed by the Department of Developmental Services (DDS). It recommends development of a logic model to evaluate case management activities because their intended societal impacts are difficult to directly measure. Additionally, it adds to the debate on health equity and racial disparities in Medicaid long-term services and supports (LTSS). In 1969, passage of the Lanterman Developmental Disabilities Services Act (The Lanterman Act) led to the first and still only entitlement to community-based services that is granted to people with developmental and intellectual disabilities (I/DD) by a state. Twenty-one private, nonprofit Regional Centers have exclusive rights to provide case management and to purchase community- based services for eligible consumers within their catchment area. By contracting with DDS, Regional Centers receive reimbursement for case management operations, pass-through rates to purchase community-based services, and administer various grants, projects, and funds. This project contributes to understanding whether and how knowledge gaps in Regional Center case management affect expenditures of home- and community-based services (HCBS). In addition, Vogel et al. (2019) lay out systemic LTSS and demographic challenges in California: a higher percentage of people require services and have autism; a growing unpaid caregiver and adult consumer population aging-in-place at home; a struggle with rising labor costs to recruit and retain qualified personnel, high cost of housing for community living, and non-compliance with Medicaid HCBS regulation that may restrict federal funding. Surveying working group members’ knowledge of case management in home- and community-based services improves understanding of the disparities in service access for racial and non-English speaking consumers

G = E:What GWAS Can Tell Us about the Environment

As our understanding of genetics has improved, genome-wide association studies (GWAS) have identified numerous variants associated with lifestyle behaviours and health outcomes. However, what is sometimes overlooked is the possibility that genetic variants identified in GWAS of disease might reflect the effect of modifiable risk factors as well as direct genetic effects. We discuss this possibility with illustrative examples from tobacco and alcohol research, in which genetic variants that predict behavioural phenotypes have been seen in GWAS of diseases known to be causally related to these behaviours. This consideration has implications for the interpretation of GWAS findings

A high-resolution single nucleotide polymorphism genetic map of the mouse genome

High-resolution genetic maps are required for mapping complex traits and for the study of recombination. We report the highest density genetic map yet created for any organism, except humans. Using more than 10,000 single nucleotide polymorphisms evenly spaced across the mouse genome, we have constructed genetic maps for both outbred and inbred mice, and separately for males and females. Recombination rates are highly correlated in outbred and inbred mice, but show relatively low correlation between males and females. Differences between male and female recombination maps and the sequence features associated with recombination are strikingly similar to those observed in humans. Genetic maps are available from http://gscan.well.ox.ac.uk/#genetic_map and as supporting information to this publication

The Poetry In-Between: Presence and Absence in Whitman, Rimbaud, and Hopkins.

The Poetry In-Between: Presence and Absence in Whitman, Rimbaud, and Hopkins analyzes three major nineteenth-century poets and their development of a poetics which has as its chief focus of concern the issue of presencing an eternal and universal Other by which to assess self identity. After the Kantian critique and the seeming reduction of human knowledge to phenomenal perceptions, early nineteenth-century poets and theorists feared the entrapment and isolation of the self in subjective awareness. The romantics, such as Friedrich Schlegel, sought ways to overcome such alienating subjectivity and ultimately conceived of the poet as a privileged spokesman and arbiter for a harmonious and divine origin of life; it is through the poet\u27s imagination, argue Schlegel and his followers, that the noumenal or total, eternal Other is presenced. Through such presencing, which essentially involves the collapsing of boundaries between the phenomenal body and the transcendent soul, the individual self gains identity as part of an integrated, universal, and eternal cosmos. However, each poet faced crises of separation which challenged their presencing of this Other ; in general, the death of the body in war or sickness threatened to cut the poet off from his vision and participation in an eternal, harmonious Other. Ultimately, towards the end of their poetic careers, Whitman, Rimbaud, and Hopkins negotiated a poetic stance which views the self as in-between a full presence and a complete absence of cosmic totality; the desire of the self for the Other banishes its complete absence, but the self must also recognize the transiency of humanity and our inability to grasp individually the complete presence of an eternity

So You Want Your Child to Be a Genius?

Geneticist Jonathan Flint reviews David Plotz's book The Genius Factory: The Curious History of the Nobel Prize Sperm Bank

Strategic restraint : modelling the role of moral weight in modern conflicts

Strategic Restraint: Modelling the Role of Moral Weight in Modern Conflicts is a PhD thesis that seeks to make the argument that restraint has a strategic purpose. It begins with a discussion of an understanding of ethics as the negotiation of hierarchies of ‘goods’ and develops an idea of Primary and Contingent goods, how those goods are decided and the role of morality, ethics and the law in human affairs. Following that is a consideration of strategy, and the nature of war. These discussions begin to form the basis of the following chapters. It develops a model for understanding the nature of war, and using this model makes suggestions about the controlled application of force and the effects of overapplication of force. The construction of the model is supported by examination of military history, concentrating on conflicts in the latter part of the of the 20th century to more recent conflicts.In considering the difficulties the model indicates in this overapplication, the work argues that there is need for the ‘artificial’ application of perceived mass, and suggests that it is here that the utility of ethical behaviour in warfare can be found for strategy. In using restraint, guided by higher ethical choices which necessarily reduce efficacy, it is argued that there is strategic advantage to be found. This is supported by analyses from modern Counter Insurgency campaigns, where such activity has been undertaken by commanders independently, while attempting to provide a theoretical explanation for the seeming success of these decisions. The work also considers outcomes from applying such strategic choices, from operational and policy concerns to the consequences in interstate relations before, during and after armed conflict

A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice.

In mammals the regulation of genomic instability plays a key role in tumor suppression and also controls genome plasticity, which is important for recombination during the processes of immunity and meiosis. Most studies to identify regulators of genomic instability have been performed in cells in culture or in systems that report on gross rearrangements of the genome, yet subtle differences in the level of genomic instability can contribute to whole organism phenotypes such as tumor predisposition. Here we performed a genome-wide association study in a population of 1379 outbred Crl:CFW(SW)-US_P08 mice to dissect the genetic landscape of micronucleus formation, a biomarker of chromosomal breaks, whole chromosome loss, and extranuclear DNA. Variation in micronucleus levels is a complex trait with a genome-wide heritability of 53.1%. We identify seven loci influencing micronucleus formation (false discovery rate <5%), and define candidate genes at each locus. Intriguingly at several loci we find evidence for sexual dimorphism in micronucleus formation, with a locus on chromosome 11 being specific to males.This work was supported by Cancer Research UK and the Wellcome Trust.This is the final version of the article. It first appeared from the Genetics Society of America via http://dx.doi.org/10.1534/g3.116.03076

Mutation of the Diamond-Blackfan Anemia Gene Rps7 in Mouse Results in Morphological and Neuroanatomical Phenotypes

The ribosome is an evolutionarily conserved organelle essential for cellular function. Ribosome construction requires assembly of approximately 80 different ribosomal proteins (RPs) and four different species of rRNA. As RPs co-assemble into one multi-subunit complex, mutation of the genes that encode RPs might be expected to give rise to phenocopies, in which the same phenotype is associated with loss-of-function of each individual gene. However, a more complex picture is emerging in which, in addition to a group of shared phenotypes, diverse RP gene-specific phenotypes are observed. Here we report the first two mouse mutations (Rps7(Mtu) and Rps7(Zma)) of ribosomal protein S7 (Rps7), a gene that has been implicated in Diamond-Blackfan anemia. Rps7 disruption results in decreased body size, abnormal skeletal morphology, mid-ventral white spotting, and eye malformations. These phenotypes are reported in other murine RP mutants and, as demonstrated for some other RP mutations, are ameliorated by Trp53 deficiency. Interestingly, Rps7 mutants have additional overt malformations of the developing central nervous system and deficits in working memory, phenotypes that are not reported in murine or human RP gene mutants. Conversely, Rps7 mouse mutants show no anemia or hyperpigmentation, phenotypes associated with mutation of human RPS7 and other murine RPs, respectively. We provide two novel RP mouse models and expand the repertoire of potential phenotypes that should be examined in RP mutants to further explore the concept of RP gene-specific phenotypes.This research was supported in part by the Intramural Research Program of NHGRI, NIH, and the Wellcome Trust and by NHMRC Australia grant 366746. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript