The Role of Leptin in the Development of Energy Homeostatic Systems and the Maintenance of Body Weight

LEP is a pleiotropic gene and the actions of leptin extend well beyond simply acting as the signal of the size of adipose tissue stores originally proposed. This is a discussion of the multi-system interactions of leptin with the development of the neural systems regulating energy stores, and the subsequent maintenance of energy stores throughout the lifespan. The prenatal, perinatal, and later postnatal effects of leptin on systems regulating body energy stores and on the energy stores themselves are heavily influenced by the nutritional environment which leptin exposure occurs. This review discusses the prenatal and perinatal roles of leptin in establishing the neuronal circuitry and other systems relevant to the adiposity set-point (or “threshold”) and the role of leptin in maintaining weight homeostasis in adulthood. Therapeutic manipulation of the intrauterine environment, use of leptin sensitizing agents, and identification of specific cohorts who may be more responsive to leptin or other means of activating the leptin signaling pathway are ripe areas for future research.

The natural adaptation and human selection history of African sheep genomes

African sheep manifest diverse but distinct physio-anatomical traits which are the outcomes of natural- and human-driven selection. Here, we generated 34.8 million variants from 150 indigenous African sheep genomes sequenced at an average depth of ∼54x for 130 samples (Ethiopia, Libya) and ∼10x for 20 samples (Sudan), representing sheep from diverse environments, tail morphology and post-Neolithic introductions to Africa. Phylogenetic and model-based admixture analysis provided evidence of four genetic groups that correspond to altitudinal geographic origins and tail morphotypes. Comparative genomic analysis identified targets of selection spanning conserved haplotype structures overlapping genes and gene families relating to hypoxia responses, caudal vertebrae and tail skeleton length, ear morphology, and tail fat-depot structure. Our findings provide novel insights underpinning variation and response to human selection and environmental adaptation, and possible pleiotropic gene interactions in indigenous African sheep genomes, which guaranteed the successful establishment of the species on the continent.

Societies to genes: can we get there from here?

Understanding the organization and evolution of social complexity is a major task because it requires building an understanding of mechanisms operating at different levels of biological organization from genes to social interactions. I discuss here, a unique forward genetic approach spanning more than 30 years beginning with human-assisted colony-level selection for a single social trait, the amount of pollen honey bees (Apis mellifera L.) store. The goal was to understand a complex social trait from the social phenotype to genes responsible for observed trait variation. The approach combined the results of colony-level selection with detailed studies of individual behavior and physiology resulting in a mapped, integrated phenotypic architecture composed of correlative relationships between traits spanning anatomy, physiology, sensory response systems, and individual behavior that affect individual foraging decisions. Colony-level selection reverse engineered the architecture of an integrated phenotype of individuals resulting in changes in the social trait. Quantitative trait locus (QTL) studies combined with an exceptionally high recombination rate (60 kb/cM), and a phenotypic map, provided a genotype–phenotype map of high complexity demonstrating broad QTL pleiotropy, epistasis, and epistatic pleiotropy suggesting that gene pleiotropy or tight linkage of genes within QTL integrated the phenotype. Gene expression and knockdown of identified positional candidates revealed genes affecting foraging behavior and confirmed one pleiotropic gene, a tyramine receptor, as a target for colony-level selection that was under selection in two different tissues in two different life stages. The approach presented here has resulted in a comprehensive understanding of the structure and evolution of honey bee social organization.

Genome-wide pleiotropy analysis of coronary artery disease and pneumonia identifies shared immune pathways

Coronary artery disease (CAD) remains the leading cause of death despite scientific advances. Elucidating shared CAD/pneumonia pathways may reveal novel insights regarding CAD pathways. We performed genome-wide pleiotropy analyses of CAD and pneumonia, examined the causal effects of the expression of genes near independently replicated SNPs and interacting genes with CAD and pneumonia, and tested interactions between disruptive coding mutations of each pleiotropic gene and smoking status on CAD and pneumonia risks. Identified pleiotropic SNPs were annotated to ADAMTS7 and IL6R. Increased ADAMTS7 expression across tissues consistently showed decreased risk for CAD and increased risk for pneumonia; increased IL6R expression showed increased risk for CAD and decreased risk for pneumonia. We similarly observed opposing CAD/pneumonia effects for NLRP3. Reduced ADAMTS7 expression conferred a reduced CAD risk without increased pneumonia risk only among never-smokers. Genetic immune-inflammatory axes of CAD linked to respiratory infections implicate ADAMTS7 and IL6R, and related genes.

Comparison of the fertility of tumor suppressor gene-deficient C57BL/6 mouse strains reveals stable reproductive aging and novel pleiotropic gene

Tumor suppressor genes are involved in maintaining genome integrity during reproduction (e.g., meiosis). Thus, deleterious alleles in tumor suppressor-deficient mice would exhibit higher mortality during the perinatal period. A recent aging model proposes that perinatal mortality and age-related deleterious changes might define lifespan. This study aimed to quantitatively understand the relationship between reproduction and lifespan using three established tumor suppressor gene (p53, APC, and RECQL4)-deficient mouse strains with the same C57BL/6 background. Transgenic mice delivered slightly reduced numbers of 1st pups than wild-type mice [ratio: 0.81–0.93 (p = 0.1–0.61)] during a similar delivery period, which suggest that the tumor suppressor gene-deficient mice undergo relatively stable reproduction. However, the transgenic 1st pups died within a few days after birth, resulting in a further reduction in litter size at 3 weeks after delivery compared with that of wild-type mice [ratio: 0.35–0.68 (p = 0.034–0.24)] without sex differences, although the lifespan was variable. Unexpectedly, the significance of reproductive reduction in transgenic mice was decreased at the 2nd or later delivery. Because mice are easily affected by environmental factors, our data underscore the importance of defining reproductive ability through experiments on aging-related reproduction that can reveal a trade-off between fecundity and aging and identify RECQL4 as a novel pleiotropic gene.

Comparison of the fertility of tumor suppressor gene-deficient C57BL/6 mouse strains reveals stable reproductive aging and novel pleiotropic gene

Tumor suppressor genes are involved in maintaining genome integrity during reproduction (e.g., meiosis). Thus, deleterious alleles in tumor suppressor-deficient mice would exhibit higher mortality during the perinatal period. A recent aging model proposes that perinatal mortality and age-related deleterious changes might define lifespan. This study aimed to quantitatively understand the relationship between reproduction and lifespan using three established tumor suppressor gene (p53, APC, and RECQL4)-deficient mouse strains with the same C57BL/6 background. Transgenic mice delivered slightly reduced numbers of 1st pups than wild-type mice [ratio: 0.81-0.93 (p=0.1-0.61)] during a similar delivery period, which suggest that the tumor suppressor gene-deficient mice undergo relatively stable reproduction. However, the transgenic 1st pups died within a few days after birth, resulting in a further reduction in litter size at 3 weeks after delivery compared with that of wild-type mice [ratio: 0.35-0.68 (p=0.034-0.24)] without sex differences, although the lifespan was variable. Unexpectedly, the significance of reproductive reduction in transgenic mice was decreased at the 2nd or later delivery. Because mice are easily affected by environmental factors, our data underscore the importance of defining reproductive ability through experiments on aging-related reproduction that can reveal a trade-off between fecundity and aging and identify RECQL4 as a novel pleiotropic gene.

The effect of developmental pleiotropy on the evolution of immune genes in Drosophila melanogaster

The pressure to survive relentless pathogen exposure explains the frequent observation that immune genes are among the fastest-evolving ones in the genomes of many taxa, but an intriguing proportion of immune genes also appear to be under purifying selection. Though variance in evolutionary signatures of immune genes is often attributed to differences in gene-specific interactions with microbes, this explanation neglects the possibility that immune genes pleiotropically participate in other biological processes that could constrain adaptive selection. In this study, we analyzed available transcriptomic and manual annotation data from Drosophila melanogaster to uncover substantial pleiotropic overlap in the developmental and immunological functions of genes involved in immune signaling. As developmental pleiotropy could constrain both the deployment and evolution of a gene product for immunological purposes, we predicted that pleiotropic immune genes would show stronger signatures of purifying selection than non-pleiotropic immune genes. We further predicted that, within the pleiotropic gene class, genes expressed early in development or more broadly across developmental stages would be under stronger purifying selection than genes with stage-specific functions. Using population genomics data from D. melanogaster and related species, we show that pleiotropic immune genes do undergo slightly slower evolutionary rates than those having no known developmental functions, and that signatures of purifying selection are significantly stronger for broadly-expressed pleiotropic immune genes. This study underscores the need to investigate immune system evolution in the broader context of host life history and development, and raises new questions about the evolution and maintenance of pleiotropic genetic architecture.

Virus infection of the CNS disrupts the immune-neural-synaptic axis via induction of pleiotropic gene regulation of host responses

Treatment for many viral infections of the central nervous system (CNS) remains only supportive. Here we address a remaining gap in our knowledge regarding how the CNS and immune systems interact during viral infection. By examining the regulation of the immune and nervous system processes in a nonhuman primate model of West Nile virus neurological disease, we show that virus infection disrupts the homeostasis of the immune-neural-synaptic axis via induction of pleiotropic genes with distinct functions in each component of the axis. This pleiotropic gene regulation suggests an unintended off-target negative impact of virus-induced host immune responses on the neurotransmission, which may be a common feature of various viral infections of the CNS.