Intermediate or brainless phenotypes for psychiatric research?

For highly heritable brain disorders, such as schizophrenia and autism, investigating genetic effects on the level of neural systems seems an obvious approach. Nevertheless, the usefulness of the intermediate phenotypes (‘endo’ phenotypes) continues to be debated energetically. We argue that, while not all intermediate phenotypes are created equal, the hypothesis-driven investigation of the translational cascades linking genetic variation to disturbed behavior is a viable and important strategy that should not be supplanted by an exclusive focus on brainless, clinical/categorical phenotypes investigated in very large numbers of participants.

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The expression of additive and nonadditive genetic variation under stress.

Genetics ◽

10.1093/genetics/140.3.1149 ◽

1995 ◽

Vol 140 (3) ◽

pp. 1149-1159

Author(s):

M W Blows ◽

M B Sokolowski

Keyword(s):

Genetic Variation ◽

Development Time ◽

Genetic Effects ◽

Hybrid Breakdown ◽

Bristle Number ◽

Gene Complexes ◽

General Expectation ◽

Faster Development ◽

Seven Generations ◽

Additive Genetic Effects

Abstract Experimental lines of Drosophila melanogaster derived from a natural population, which had been isolated in the laboratory for approximately 70 generations, were crossed to determine if the expression of additive, dominance and epistatic genetic variation in development time and viability was associated with the environment. No association was found between the level of additive genetic effects and environmental value for either trait, but nonadditive genetic effects increased at both extremes of the environmental range for development time. The expression of high levels of dominance and epistatic genetic variation at environmental extremes may be a general expectation for some traits. The disruption of the epistatic gene complexes in the parental lines resulted in hybrid breakdown toward faster development and there was some indication of hybrid breakdown toward higher viability. A combination of genetic drift and natural selection had therefore resulted in different epistatic gene complexes being selected after approximately 70 generations from a common genetic base. After crossing, the hybrid populations were observed for 10 generations. Epistasis contributed on average 12 hr in development time. Fluctuating asymmetry in sternopleural bristle number also evolved in the hybrid populations, decreasing by > 18% in the first seven generations after hybridization.

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Evaluating indirect genetic effects of siblings using singletons

10.31219/osf.io/j2rms ◽

2021 ◽

Author(s):

Laurence Howe ◽

David Evans ◽

Gibran Hemani ◽

George Davey Smith ◽

Neil Martin Davies

Keyword(s):

Genetic Variation ◽

Educational Attainment ◽

Family Environment ◽

Phenotypic Variation ◽

Molecular Genetic ◽

Genetic Effects ◽

Polygenic Risk Score ◽

Indirect Genetic Effects ◽

Molecular Genetic Evidence ◽

Older Siblings

Estimating effects of parental and sibling genotypes (indirect genetic effects) can provide insight into how the family environment influences phenotypic variation. There is growing molecular genetic evidence for effects of parental phenotypes on their offspring (e.g. parental educational attainment), but the extent to which siblings affect each other is currently unclear.Here we used data from samples of unrelated individuals, without (singletons) and with biological full-siblings (non-singletons), to investigate and estimate sibling effects. Indirect genetic effects of siblings increase (or decrease) the covariance between genetic variation and a phenotype. It follows that differences in genetic association estimates between singletons and non-singletons could indicate indirect genetic effects of siblings.We used UK Biobank data to estimate polygenic risk score (PRS) associations for height, BMI and educational attainment in singletons (N = 50,143) and non-singletons (N = 328,549). The educational attainment PRS association estimate was 12% larger (95% C.I. 3%, 21%) in the non-singleton sample than in the singleton sample, but the height and BMI PRS associations were consistent. Birth order data suggested that the difference in educational attainment PRS associations was driven by individuals with older siblings rather than firstborns. The relationship between number of siblings and educational attainment PRS associations was non-linear; PRS associations were 24% smaller in individuals with 6 or more siblings compared to the rest of the sample (95% C.I. 11%, 38%). We estimate that a 1 SD increase in sibling educational attainment PRS corresponds to a 0.025 year increase in the index individual’s years in schooling (95% C.I. 0.013, 0.036).Our results suggest that older siblings influence the educational attainment of younger siblings, adding to the growing evidence that effects of the environment on phenotypic variation partially reflect social effects of germline genetic variation in relatives.

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Control without Controllers: Toward a Distributed Neuroscience of Executive Control

Journal of Cognitive Neuroscience ◽

10.1162/jocn_a_01139 ◽

2017 ◽

Vol 29 (10) ◽

pp. 1684-1698 ◽

Cited By ~ 29

Author(s):

Benjamin R. Eisenreich ◽

Rei Akaishi ◽

Benjamin Y. Hayden

Keyword(s):

Control Systems ◽

Executive Control ◽

Neural Control ◽

Group Living ◽

Neural Systems ◽

Large Numbers ◽

Alternative Approach ◽

And Behavior ◽

Control Modules ◽

Organizing Principles

Executive control refers to the regulation of cognition and behavior by mental processes and is a hallmark of higher cognition. Most approaches to understanding its mechanisms begin with the assumption that our brains have anatomically segregated and functionally specialized control modules. The modular approach is intuitive: Control is conceptually distinct from basic mental processing, so an organization that reifies that distinction makes sense. An alternative approach sees executive control as self-organizing principles of a distributed organization. In distributed systems, control and controlled processes are colocalized within large numbers of dispersed computational agents. Control then is often an emergent consequence of simple rules governing the interaction between agents. Because these systems are unfamiliar and unintuitive, here we review several well-understood examples of distributed control systems, group living insects and social animals, and emphasize their parallels with neural systems. We then reexamine the cognitive neuroscience literature on executive control for evidence that its neural control systems may be distributed.

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Protocol for a longitudinal twin birth cohort study to unravel the complex interplay between early-life environmental and genetic risk factors in health and disease: the Chongqing Longitudinal Twin Study (LoTiS)

BMJ Open ◽

10.1136/bmjopen-2017-017889 ◽

2018 ◽

Vol 8 (2) ◽

pp. e017889 ◽

Cited By ~ 4

Author(s):

Chao Tong ◽

Li Wen ◽

Yinyin Xia ◽

Pamela Leong ◽

Lan Wang ◽

...

Keyword(s):

Genetic Variation ◽

Twin Study ◽

Twin Studies ◽

Birth Cohort Study ◽

Clinical Trial Registry ◽

Time Points ◽

Intermediate Phenotypes ◽

Genes And Environment ◽

Depth Analysis ◽

Longitudinal Twin Study

IntroductionNon-communicable diseases (NCD) now represent the major burden of adverse health in most countries. It is clear that much of the risk of such conditions begins very early in life, potentially in utero. Given their complex aetiology, an understanding of the origins of NCD requires an in-depth analysis of the interplay between genetic variation and environment, preferably over time. For decades, twin studies have played a key role in understanding such traits. Their strength lies in the ability to disentangle genetic and environmental factors that contribute to a phenotype. This is done by comparing genetically identical monozygotic (MZ) with dizygotic twins, who share on average 50% of genetic variation, or by comparing MZ twins within a pair. This study aims to determine the relative contributions of genes and environment to early-onset intermediate phenotypes related to later adult onset disease (such as growth and neurodevelopment) and to identify specific biomarkers and time points for emergence of phenotypes from infancy, largely independent of underlying genetic factors.Methods/designThe Chongqing Longitudinal Twin Study (LoTiS) will recruit 300 women pregnant with twins, enriched for MZ pregnancies, with follow-up to 3 years of age. Data collection will be undertaken at key time points in gestation (×3), at delivery and postnatally (×9). Maternal and infant biospecimens including blood, urine, hair, nails and buccal swabs along with measures such as fetal scans and body measurements will be collected. Additional information from questionnaires and medical records includes pregnancy, diet, sociodemographics, maternal stress, and infant growth and neurodevelopment.Ethics and disseminationThis study has been approved by the Ethics Committee of Chongqing Medical University (record no: 201530) and has been registered with the Chinese Clinical Trial Registry (registry no: ChiCTR-OOC-16008203). Results of the recruitment and all subsequent analyses will be submitted for publication in peer-reviewed journals.Trial registration numberChiCTR-OOC-16008203; Results.

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The nature of nurture in a wild mammal's fitness

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2014.2422 ◽

2015 ◽

Vol 282 (1806) ◽

pp. 20142422 ◽

Cited By ~ 20

Author(s):

S. Eryn McFarlane ◽

Jamieson C. Gorrell ◽

David W. Coltman ◽

Murray M. Humphries ◽

Stan Boutin ◽

...

Keyword(s):

Genetic Variation ◽

Natural Selection ◽

Maternal Effects ◽

Adaptive Evolution ◽

Genetic Effects ◽

Adaptive Potential ◽

Red Squirrels ◽

Trade Offs ◽

The Face ◽

North American Red Squirrels

Genetic variation in fitness is required for the adaptive evolution of any trait but natural selection is thought to erode genetic variance in fitness. This paradox has motivated the search for mechanisms that might maintain a population's adaptive potential. Mothers make many contributions to the attributes of their developing offspring and these maternal effects can influence responses to natural selection if maternal effects are themselves heritable. Maternal genetic effects (MGEs) on fitness might, therefore, represent an underappreciated source of adaptive potential in wild populations. Here we used two decades of data from a pedigreed wild population of North American red squirrels to show that MGEs on offspring fitness increased the population's evolvability by over two orders of magnitude relative to expectations from direct genetic effects alone. MGEs are predicted to maintain more variation than direct genetic effects in the face of selection, but we also found evidence of maternal effect trade-offs. Mothers that raised high-fitness offspring in one environment raised low-fitness offspring in another environment. Such a fitness trade-off is expected to maintain maternal genetic variation in fitness, which provided additional capacity for adaptive evolution beyond that provided by direct genetic effects on fitness.

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Symbiont-conferred immunity interacts with the effects of parasitoid genotype and intraguild predation to shape pea aphid immunity in a clone-specific fashion

10.1101/2021.05.01.442267 ◽

2021 ◽

Author(s):

Samuel Alexander Purkiss ◽

Mouhammad Shadi Khudr ◽

Oscar Enrique Aguinaga ◽

Reinmar Hager

Keyword(s):

Genetic Variation ◽

Intraguild Predation ◽

Species Interactions ◽

Acyrthosiphon Pisum ◽

Species Interaction ◽

Genetic Effects ◽

Pea Aphid ◽

Aphidius Ervi ◽

Indirect Genetic Effects ◽

Host Parasite

Host-parasite interactions represent complex co-evolving systems in which genetic variation within a species can significantly affect selective pressure on traits in the other (for example via inter-species indirect genetic effects). While often viewed as a two-species interaction between host and parasite species, some systems are more complex due to the involvement of symbionts in the host that influence its immunity, enemies of the host, and the parasite through intraguild predation. However, it remains unclear what the joint effects of intraguild predation, defensive endosymbiosis, within-species genetic variation and indirect genetic effects on host immunity are. We have addressed this question in an important agricultural pest system, the pea aphid Acyrthosiphon pisum, which shows significant intraspecific variability in immunity to the parasitoid wasp Aphidius ervi due to immunity conferring endosymbiotic bacteria. In a complex experiment involving a quantitative genetic design of the parasitoid, two ecologically different aphid lineages and the aphid lion Chrysoperla carnea as an intraguild predator, we demonstrate that aphid immunity is affected by intraspecific genetic variation in the parasitoid and the aphid, as well as by associated differences in the defensive endosymbiont communities. Using 16s rRNA sequencing, we identified secondary symbionts that differed between the lineages. We further show that aphid lineages differ in their altruistic behaviour once parasitised whereby infested aphids move away from the clonal colony to facilitate predation. The outcome of these complex between-species interactions not only shape important host-parasite systems but have also implications for understanding the evolution of multitrophic interactions, and aphid biocontrol.

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Control without controllers: Towards a distributed neuroscience of executive control

10.1101/077685 ◽

2016 ◽

Cited By ~ 3

Author(s):

Benjamin R. Eisenreich ◽

Rei Akaishi ◽

Benjamin Y. Hayden

Keyword(s):

Control Systems ◽

Executive Control ◽

Neural Control ◽

Group Living ◽

Neural Systems ◽

Large Numbers ◽

Alternative Approach ◽

And Behavior ◽

Control Modules ◽

Organizing Principles

AbstractExecutive control refers to the regulation of cognition and behavior by mental processes and is a hallmark of higher cognition. Most approaches to understanding its mechanisms begin with the assumption that our brains have anatomically segregated and functionally specialized control modules. The modular approach is intuitive: control is conceptually distinct from basic mental processing, so an organization that reifies that distinction makes sense. An alternative approach sees executive control as self-organizing principles of a distributed organization. In distributed systems, control and controlled processes are co-localized within large numbers of dispersed computational agents. Control then is often an emergent consequence of simple rules governing the interaction between agents. Because these systems are unfamiliar and unintuitive, here we review several well-understood examples of distributed control systems, group living insects and social animals, and emphasize their parallels with neural systems. We then re-examine the cognitive neuroscience literature on executive control for evidence that its neural control systems may be distributed.

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An evaluation of genetic variation in gestation length, birthweight and early growth in Scottish Blackface sheep

Proceedings of the British Society of Animal Science ◽

10.1017/s1752756200593053 ◽

1996 ◽

Vol 1996 ◽

pp. 108-108

Author(s):

P Johnston ◽

J A Roden ◽

A Murray ◽

B Merrell ◽

W Haresign

Keyword(s):

Genetic Variation ◽

Birth Weight ◽

Litter Size ◽

Early Growth ◽

Genetic Effects ◽

Early Mortality ◽

Gestation Length ◽

Early Vigour ◽

Breeding Programmes

Birth weight (BW) and gestation length (GL) have important implications for the survival and early vigour of the lamb, in turn affecting the early growth. In hill sheep BW and early growth have low heritabilities, when considered as a trait of the lamb. They are highly influenced by maternal genetic effects and non genetic effects such as litter size, date of birth and the environment. When studying hill sheep there are also problems obtaining accurate records of birth weights and early growth and it is normally impossible to obtain accurate measures of GL. Exploitation of the genetic variation in the traits BW, GL and early growth could be useful in breeding programmes to reduce early mortality and improve vigour in lambs.

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Partitioning plant genetic and environmental drivers of above and belowground community assembly

10.1101/173500 ◽

2017 ◽

Author(s):

Matthew Barbour ◽

Sonya Erlandson ◽

Kabir Peay ◽

Brendan Locke ◽

Erik S. Jules ◽

...

Keyword(s):

Genetic Variation ◽

Phenotypic Plasticity ◽

Host Plant ◽

Environmental Effects ◽

Natural Variation ◽

Plant Traits ◽

Genetic Effects ◽

Environmental Drivers ◽

Leaf Quality ◽

Wind Exposure

Host-plant genetic variation affects the diversity and composition of associated above and belowground communities. Most evidence supporting this view is derived from studies within a single common garden, thereby constraining the range of biotic and abiotic environmental conditions that might directly or indirectly (via phenotypic plasticity) affect communities. If natural variability in the environment renders host-plant genetic effects on associated communities unimportant, then studying the community-level consequences of genetic variation may not be warranted. We addressed this knowledge gap by planting a series of common gardens consisting of 10 different clones (genotypes) of the willow Salix hookeriana in a coastal dune ecosystem and manipulated natural variation in ant-aphid interactions (biotic) and wind exposure (abiotic) in two separate experiments. We then quantified the responses of associated species assemblages both above (foliar arthropods) and belowground (rhizosphere fungi and bacteria). In addition, we quantified plant phenotypic responses (plant growth, leaf quality, and root quality) to tease apart the effects of genetic variation, phenotypic plasticity, and direct environmental effects on associated communities. In the ant-aphid experiment, we found that willow genotype explained more variation in foliar arthropod communities than aphid additions and proximity to aphid-tending ant mounds. However, aphid additions modified willow genetic effects on arthropod community composition by attracting other aphid species to certain willow genotypes. In the wind experiment, wind exposure explained more variation than willow genotype in structuring communities of foliar arthropods and rhizosphere bacteria. Still, willow genotype had strong effect sizes on several community properties of arthropods and fungi, indicating that host-plant genetic variation remains important. Across both experiments, genetic variation in plant traits was more important than phenotypic plasticity in structuring associated communities. The relative importance of genetic variation vs. direct environmental effects though depended on the type of environmental gradient (G > E-aphid, but E-wind > G). Taken together, our results suggest that host-plant genetic variation is an important driver of above and belowground biodiversity, despite natural variation in the biotic and abiotic environment.

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