Browsing by Subject "Quantitative Trait, Heritable"
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Item Open Access Behavior genetics and postgenomics.(Behav Brain Sci, 2012-10) Charney, EvanThe science of genetics is undergoing a paradigm shift. Recent discoveries, including the activity of retrotransposons, the extent of copy number variations, somatic and chromosomal mosaicism, and the nature of the epigenome as a regulator of DNA expressivity, are challenging a series of dogmas concerning the nature of the genome and the relationship between genotype and phenotype. According to three widely held dogmas, DNA is the unchanging template of heredity, is identical in all the cells and tissues of the body, and is the sole agent of inheritance. Rather than being an unchanging template, DNA appears subject to a good deal of environmentally induced change. Instead of identical DNA in all the cells of the body, somatic mosaicism appears to be the normal human condition. And DNA can no longer be considered the sole agent of inheritance. We now know that the epigenome, which regulates gene expressivity, can be inherited via the germline. These developments are particularly significant for behavior genetics for at least three reasons: First, epigenetic regulation, DNA variability, and somatic mosaicism appear to be particularly prevalent in the human brain and probably are involved in much of human behavior; second, they have important implications for the validity of heritability and gene association studies, the methodologies that largely define the discipline of behavior genetics; and third, they appear to play a critical role in development during the perinatal period and, in particular, in enabling phenotypic plasticity in offspring. I examine one of the central claims to emerge from the use of heritability studies in the behavioral sciences, the principle of minimal shared maternal effects, in light of the growing awareness that the maternal perinatal environment is a critical venue for the exercise of adaptive phenotypic plasticity. This consideration has important implications for both developmental and evolutionary biology.Item Open Access Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies.(PLoS One, 2015) Kulminski, Alexander M; Culminskaya, Irina; Arbeev, Konstantin G; Arbeeva, Liubov; Ukraintseva, Svetlana V; Stallard, Eric; Wu, Deqing; Yashin, Anatoliy IInsights into genetic origin of diseases and related traits could substantially impact strategies for improving human health. The results of genome-wide association studies (GWAS) are often positioned as discoveries of unconditional risk alleles of complex health traits. We re-analyzed the associations of single nucleotide polymorphisms (SNPs) associated with total cholesterol (TC) in a large-scale GWAS meta-analysis. We focused on three generations of genotyped participants of the Framingham Heart Study (FHS). We show that the effects of all ten directly-genotyped SNPs were clustered in different FHS generations and/or birth cohorts in a sex-specific or sex-unspecific manner. The sample size and procedure-therapeutic issues play, at most, a minor role in this clustering. An important result was clustering of significant associations with the strongest effects in the youngest, or 3rd Generation, cohort. These results imply that an assumption of unconditional connections of these SNPs with TC is generally implausible and that a demographic perspective can substantially improve GWAS efficiency. The analyses of genetic effects in age-matched samples suggest a role of environmental and age-related mechanisms in the associations of different SNPs with TC. Analysis of the literature supports systemic roles for genes for these SNPs beyond those related to lipid metabolism. Our analyses reveal strong antagonistic effects of rs2479409 (the PCSK9 gene) that cautions strategies aimed at targeting this gene in the next generation of lipid drugs. Our results suggest that standard GWAS strategies need to be advanced in order to appropriately address the problem of genetic susceptibility to complex traits that is imperative for translation to health care.Item Open Access Correlations between physical and chemical defences in plants: tradeoffs, syndromes, or just many different ways to skin a herbivorous cat?(The New phytologist, 2013-04) Moles, Angela T; Peco, Begoña; Wallis, Ian R; Foley, William J; Poore, Alistair GB; Seabloom, Eric W; Vesk, Peter A; Bisigato, Alejandro J; Cella-Pizarro, Lucrecia; Clark, Connie J; Cohen, Philippe S; Cornwell, William K; Edwards, Will; Ejrnaes, Rasmus; Gonzales-Ojeda, Therany; Graae, Bente J; Hay, Gregory; Lumbwe, Fainess C; Magaña-Rodríguez, Benjamín; Moore, Ben D; Peri, Pablo L; Poulsen, John R; Stegen, James C; Veldtman, Ruan; von Zeipel, Hugo; Andrew, Nigel R; Boulter, Sarah L; Borer, Elizabeth T; Cornelissen, Johannes HC; Farji-Brener, Alejandro G; DeGabriel, Jane L; Jurado, Enrique; Kyhn, Line A; Low, Bill; Mulder, Christa PH; Reardon-Smith, Kathryn; Rodríguez-Velázquez, Jorge; De Fortier, An; Zheng, Zheng; Blendinger, Pedro G; Enquist, Brian J; Facelli, Jose M; Knight, Tiffany; Majer, Jonathan D; Martínez-Ramos, Miguel; McQuillan, Peter; Hui, Francis KCMost plant species have a range of traits that deter herbivores. However, understanding of how different defences are related to one another is surprisingly weak. Many authors argue that defence traits trade off against one another, while others argue that they form coordinated defence syndromes. We collected a dataset of unprecedented taxonomic and geographic scope (261 species spanning 80 families, from 75 sites across the globe) to investigate relationships among four chemical and six physical defences. Five of the 45 pairwise correlations between defence traits were significant and three of these were tradeoffs. The relationship between species' overall chemical and physical defence levels was marginally nonsignificant (P = 0.08), and remained nonsignificant after accounting for phylogeny, growth form and abundance. Neither categorical principal component analysis (PCA) nor hierarchical cluster analysis supported the idea that species displayed defence syndromes. Our results do not support arguments for tradeoffs or for coordinated defence syndromes. Rather, plants display a range of combinations of defence traits. We suggest this lack of consistent defence syndromes may be adaptive, resulting from selective pressure to deploy a different combination of defences to coexisting species.Item Open Access Heritability estimates of endophenotypes of long and health life: the Long Life Family Study.(J Gerontol A Biol Sci Med Sci, 2010-12) Matteini, Amy M; Fallin, M Daniele; Kammerer, Candace M; Schupf, Nicole; Yashin, Anatoli I; Christensen, Kaare; Arbeev, Konstantin G; Barr, Graham; Mayeux, Richard; Newman, Anne B; Walston, Jeremy DBACKGROUND: Identification of gene variants that contribute to exceptional survival may provide critical biologic information that informs optimal health across the life span. METHODS: As part of phenotype development efforts for the Long Life Family Study, endophenotypes that represent exceptional survival were identified and heritability estimates were calculated. Principal components (PCs) analysis was carried out using 28 physiologic measurements from five trait domains (cardiovascular, cognition, physical function, pulmonary, and metabolic). RESULTS: The five most dominant PCs accounted for 50% of underlying trait variance. The first PC (PC1), which consisted primarily of poor pulmonary and physical function, represented 14.3% of the total variance and had an estimated heritability of 39%. PC2 consisted of measures of good metabolic and cardiovascular function with an estimated heritability of 27%. PC3 was made up of cognitive measures (h(2) = 36%). PC4 and PC5 contained measures of blood pressure and cholesterol, respectively (h(2) = 25% and 16%). CONCLUSIONS: These PCs analysis-derived endophenotypes may be used in genetic association studies to help identify underlying genetic mechanisms that drive exceptional survival in this and other populations.Item Open Access Tissue-specific genetic control of splicing: implications for the study of complex traits.(PLoS Biol, 2008-12-23) Heinzen, Erin L; Ge, Dongliang; Cronin, Kenneth D; Maia, Jessica M; Shianna, Kevin V; Gabriel, Willow N; Welsh-Bohmer, Kathleen A; Hulette, Christine M; Denny, Thomas N; Goldstein, David BNumerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.Item Open Access Transgenerational Effects of Early Life Starvation on Growth, Reproduction, and Stress Resistance in Caenorhabditis elegans.(Genetics, 2015-09) Jobson, Meghan A; Jordan, James M; Sandrof, Moses A; Hibshman, Jonathan D; Lennox, Ashley L; Baugh, L RyanStarvation during early development can have lasting effects that influence organismal fitness and disease risk. We characterized the long-term phenotypic consequences of starvation during early larval development in Caenorhabditis elegans to determine potential fitness effects and develop it as a model for mechanistic studies. We varied the amount of time that larvae were developmentally arrested by starvation after hatching ("L1 arrest"). Worms recovering from extended starvation grew slowly, taking longer to become reproductive, and were smaller as adults. Fecundity was also reduced, with the smallest individuals most severely affected. Feeding behavior was impaired, possibly contributing to deficits in growth and reproduction. Previously starved larvae were more sensitive to subsequent starvation, suggesting decreased fitness even in poor conditions. We discovered that smaller larvae are more resistant to heat, but this correlation does not require passage through L1 arrest. The progeny of starved animals were also adversely affected: Embryo quality was diminished, incidence of males was increased, progeny were smaller, and their brood size was reduced. However, the progeny and grandprogeny of starved larvae were more resistant to starvation. In addition, the progeny, grandprogeny, and great-grandprogeny were more resistant to heat, suggesting epigenetic inheritance of acquired resistance to starvation and heat. Notably, such resistance was inherited exclusively from individuals most severely affected by starvation in the first generation, suggesting an evolutionary bet-hedging strategy. In summary, our results demonstrate that starvation affects a variety of life-history traits in the exposed animals and their descendants, some presumably reflecting fitness costs but others potentially adaptive.