Biology subjects

Fletcher, J.

Publications and source records attributed to Fletcher, J..

27 records · Page 2Linked to original sources

bioRxiv2020

Remodeling of pre-existing myelinated axons and oligodendrocytes is stimulated by environmental enrichment in the young adult brain

Oligodendrocyte production and central nervous system (CNS) myelination is a protracted process, extending into adulthood. While stimulation of neuronal circuits has been shown to enhance oligodendrocyte production and myelination during development, the extent to which physiological stimuli induces activity-dependent plasticity within oligodendrocytes and myelin is unclear, particularly in the adult CNS. Here, we find that using environmental enrichment (EE) to physiologically stimulate neuronal activity for 6-weeks during young adulthood in C57Bl/6 mice results in an enlargement of callosal axon diameters, with a corresponding increase in thickness of pre-existing myelin sheaths. Additionally, EE uniformly promotes the direct differentiation of pre-existing oligodendroglia in both corpus callosum and somatosensory cortex, while differentially impeding OPC homeostasis in these regions. Furthermore, results of this study indicate that physiologically relevant stimulation in young adulthood exerts little influence upon the de novo generation of new myelin sheaths on previously unmyelinated segments and does not enhance OPC proliferation. Rather in this context, activity-dependent plasticity involves the coincident structural remodeling of axons and pre-existing myelin sheaths and increases the direct differentiation of pre-existing oligodendroglia, implying constraints on maximal de novo production in the adult CNS. Together, our findings of myelinated axon remodeling and increased pre-existing oligodendroglial differentiation constitute a previously undescribed form of adaptive myelination that likely contributes to neuronal circuit maturation and the maintenance of optimum cognitive function in the young adult CNS. Main pointsO_LIEnvironmental enrichment induces the plasticity of myelinated axons, resulting in axon caliber enlargement and increased thickness of pre-existing myelin sheaths C_LIO_LIEnvironmental enrichment increases the direct differentiation of pre-existing oligodendroglia C_LIO_LIEnvironmental enrichment alters OPC homeostasis C_LI

neuroscience↗

bioRxiv2019

Decoupling Genetics from Attainments: The Role of Social Environments

This paper examines the extent to which growing up in a socially mobile environment might decouple genetic endowments related to educational attainment with actual attainments. Many models of intergenerational transmission of advantage contain both a transmission channel through endowments (i.e. genetics) from parents to children as well as from parental investments and \"luck\". Indeed, many scholars consider the intergenerational links due to the transmission of genetically based advantage to place a lower bound on plausible levels of social mobility--genetics may be able to \"lock in\" advantage across generations. This paper explores this idea by using new genetic measurements in the Health and Retirement Study to examine potential interactions between social environments and genetics related to attainments. The results suggest evidence of gene environment interactions: children born in high mobility states have lower genetic penetrance--the interaction between state-level mobility and the polygenic score for education is negative. These results suggest a need to incorporate gene-environment interactions in models of attainment and mobility and to pursue the mechanisms behind the interactions.

genetics↗

bioRxiv2019

Fine-tuning Polygenic Risk Scores with GWAS Summary Statistics

Polygenic risk scores (PRSs) have wide applications in human genetics research. Notably, most PRS models include tuning parameters which improve predictive performance when properly selected. However, existing model-tuning methods require individual-level genetic data as the training dataset or as a validation dataset independent from both training and testing samples. These data rarely exist in practice, creating a significant gap between PRS methodology and applications. Here, we introduce PUMAS (Parameter-tuning Using Marginal Association Statistics), a novel method to fine-tune PRS models using summary statistics from genome-wide association studies (GWASs). Through extensive simulations, external validations, and analysis of 65 traits, we demonstrate that PUMAS can perform a variety of model-tuning procedures (e.g. cross-validation) using GWAS summary statistics and can effectively benchmark and optimize PRS models under diverse genetic architecture. On average, PUMAS improves the predictive R2 by 205.6% and 62.5% compared to PRSs with arbitrary p-value cutoffs of 0.01 and 1, respectively. Applied to 211 neuroimaging traits and Alzheimers disease, we show that fine-tuned PRSs will significantly improve statistical power in downstream association analysis. We believe our method resolves a fundamental problem without a current solution and will greatly benefit genetic prediction applications.

genetics↗

bioRxiv2019

Separating Measured Genetic and Environmental Effects: Evidence Linking Parental Genotype and Adopted Child Outcomes

There has been widespread adoption of genome wide summary scores (polygenic scores) as tools for studying the importance of genetics and associated lifecourse mechanisms across a range of demographic and socioeconomic outcomes. However, an often unacknowledged issue with these studies is that parental genetics impact both child environments and child genetics, leaving the effects of polygenic scores difficult to interpret. This paper uses multi-generational data containing polygenic scores for parents (n=7,193) and educational outcomes for adopted (n=855) and biological (n=20,939) children, many raised in the same families, which allows us to separate the influence of parental polygenic scores on children outcomes between environmental (adopted children) and environmental and genetic (biological children) effects. Our results complement recent work on "genetic nurture" by showing associations of parental polygenic scores with adopted childrens schooling, providing additional evidence that polygenic scores combine genetic and environmental influences and that research designs are needed to separate these estimated impacts.

genomics↗

bioRxiv2019

Decoding the development of the blood and immune systems during human fetal liver haematopoiesis

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells/multipotent progenitors (HSC/MPPs), yet remains poorly defined in humans. Using single cell transcriptome profiling of ~133,000 fetal liver and ~65,000 fetal skin and kidney cells, we identify the repertoire of blood and immune cells in first and early second trimesters of development. From this data, we infer differentiation trajectories from HSC/MPPs, and evaluate the impact of tissue microenvironment on blood and immune cell development. We predict coupling of mast cell differentiation with erythro-megakaryopoiesis and identify physiological erythropoiesis in fetal skin. We demonstrate a shift in fetal liver haematopoietic composition during gestation away from being erythroid-predominant, accompanied by a parallel change in HSC/MPP differentiation potential, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a valuable reference for understanding and harnessing the therapeutic potential of HSC/MPPs.

developmental biology↗

bioRxiv2019

TrkB Agonist LM22A-4 Increases Oligodendroglial Populations During Myelin Repair in the Brain

The neurotrophin, brain-derived neurotrophic factor (BDNF) promotes central nervous system (CNS) myelination during development and after injury. This is achieved via activation of oligodendrocyte-expressed tropomyosin-related kinase (Trk) B receptors. However, while administration of BDNF has shown beneficial effects, BDNF itself has a poor pharmacokinetic profile. Here, we compare two TrkB-targeted BDNF-mimetics, the structural-mimetic, tricyclic dimeric peptide-6 (TDP6) and the non-peptide small molecule TrkB agonist LM22A-4 in the cuprizone model of central demyelination in female mice. Both mimetics promoted remyelination, increasing myelin sheath thickness and oligodendrocyte densities after one-week recovery. Importantly, LM22A-4 exerts these effects in an oligodendroglial TrkB-dependent manner. However, analysis of TrkB signaling by LM22A-4 suggests rather than direct activation of TrkB, LM22A-4 exerts its effects via indirect transactivation of Trk receptors. Overall, these studies support the therapeutic strategy to selectively targeting TrkB activation to promote remyelination in the brain.

neuroscience↗

bioRxiv2018

Genome-wide association study reveals sex-specific genetic architecture of facial attractiveness

Facial attractiveness is a complex human trait of great interest in both academia and industry. Literature on sociological and phenotypic factors associated with facial attractiveness is rich, but its genetic basis is poorly understood. In this paper, we conducted a genome-wide association study to discover genetic variants associated with facial attractiveness using 3,928 samples in the Wisconsin Longitudinal Study. We identified two genome-wide significant loci and highlighted a handful of candidate genes, many of which are specifically expressed in human tissues involved in reproduction and hormone synthesis. Additionally, facial attractiveness showed strong and negative genetic correlations with BMI in females and with blood lipids in males. Our analysis also suggested sex-specific selection pressure on variants associated with lower male attractiveness. These results revealed sex-specific genetic architecture of facial attractiveness and provided fundamental new insights into its genetic basis.

genetics↗

bioRxiv2018

Spousal Concordance in Telomere Length: New Evidence from Older Adults in the US

Telomere length (TL) has been associated with a range of aging outcomes as well as mortality. Recent research has shown both high heritability ([~]70 %) of TL as well as moderate spousal similarity (r[~].3) using European datasets. This paper explores the level of spousal concordance in telomere length in the Health and Retirement Study, a national sample of adults in the US. The results both show that the spousal similarity in TL is lower in the US and also varies by the length of time spouses have been married as well as the educational attainments of husbands. These findings suggest the possibility of both assortative mating patterns related to telomere length as well as likelihood of shared environmental factors that cause similarity in TL in people who are socially connected.

epidemiology↗

bioRxiv2017

Analysis of genetic similarity among friends and schoolmates in the National Longitudinal Study of Adolescent to Adult Health (Add Health)

Humans tend to form social relationships with others who resemble them. Whether this sorting of like with like arises from historical patterns of migration, meso-level social structures in modern society, or individual-level selection of similar peers remains unsettled. Recent research has evaluated the possibility that unobserved genotypes may play an important role in the creation of homophilous relationships. We extend this work by using data from 9,500 adolescents from the National Longitudinal Study of Adolescent to Adult Health (Add Health) to examine genetic similarities among pairs of friends. While there is some evidence that friends have correlated genotypes, both at the whole-genome level as well as at trait-associated loci (via polygenic scores), further analysis suggests that meso-level forces, such as school assignment, are a principal source of genetic similarity between friends. We also observe apparent social-genetic effects in which polygenic scores of an individuals friends and schoolmates predict the individuals own educational attainment. In contrast, an individuals height is unassociated with the height genetics of peers.\n\nSignificanceOur study reported significant findings of a \"social genome\" that can be quantified and studied to understand human health and behavior. In a national sample of more than 9,000 American adolescents, we found evidence of social forces that act to make friends and schoolmates more genetically similar to one another as compared to random pairs of unrelated individuals. This subtle genetic similarity was observed across the entire genome and at sets of genomic locations linked with specific traits--educational attainment and body-mass index--a phenomenon we term \"social-genetic correlation.\" We also find evidence of a \"social-genetic effect\" such that the genetics of a persons friends and schoolmates influenced their own education, even after accounting for the persons own genetics.

genetics↗