Genetic determinism, essentialism and reductionism: semantic clarity for contested science.

Research linking genetic differences with human social and behavioural phenotypes has long been controversial. Frequently, debates about the ethical, social and legal implications of this area of research centre on questions about whether studies overtly or covertly perpetuate genetic determinism, genetic essentialism and/or genetic reductionism. Given the prominent role of the '-isms' in scientific discourse and criticism, it is important for there to be consensus and clarity about the meaning of these terms. Here, the author integrates scholarship from psychology, genetics and philosophy of science to provide accessible definitions of genetic determinism, genetic reductionism and genetic essentialism. The author provides linguistic and visual examples of determinism, reductionism and essentialism in science and popular culture, discusses common misconceptions and concludes with recommendations for science communication.

The genomic case against genetic determinism.

Animal studies reveal that the molecular wiring of the brain can be altered by heredity, the environment, and their interaction. A deeper molecular understanding of these interactions could be a potent antidote to societal concerns of genetic determinism for human behavior, but this requires a paradigm that extends beyond traditional genome-wide association study (GWAS).

Beyond morphs: Inter-individual colour variation despite strong genetic determinism of colour morphs in a wild bird.

Categorizing individuals into discrete forms in colour polymorphic species can overlook more subtle patterns in coloration that can be of functional significance. Thus, quantifying inter-individual variation in these species at both within- and between-morph levels is critical to understand the evolution of colour polymorphisms. Here we present analyses of inter-individual colour variation in the Reunion grey white-eye (Zosterops borbonicus), a colour polymorphic wild bird endemic to the island of Reunion in which all highland populations contain two sympatric colour morphs, with birds showing predominantly grey or brown plumage, respectively. We first quantified colour variation across multiple body areas by using a continuous plumage colour score to assess variation in brown-grey coloration as well as smaller scale variation in light patches. To examine the possible causes of among-individual variation, we tested if colour variation in plumage component elements could be explained by genotypes at two markers near a major-effect locus previously related to back coloration in this species, and by other factors such as age, sex and body condition. Overall, grey-brown coloration was largely determined by genetic factors and was best described by three distinct clusters that were associated to genotypic classes (homozygotes and heterozygote), with no effect of age or sex, whereas variation in smaller light patches was primarily related to age and sex. Our results highlight the importance of characterizing subtle plumage variation beyond morph categories that are readily observable since multiple patterns of colour variation may be driven by different mechanisms, have different functions and will likely respond in different ways to selection.

Genome-wide association study reveals the genetic determinism of serum biochemical indicators in ducks.

BACKGROUND: The serum is rich in nutrients and plays an essential role in electrolyte and acid-base balance, maintaining cellular homeostasis. In addition, serum parameters have been commonly used as essential biomarkers for clinical diagnosis. However, little is known about the genetic mechanism of the serum parameters in ducks. RESULTS: This study measured 18 serum parameters in 320 samples of the F2 segregating population generated by Mallard × Pekin duck. The phenotypic correlations showed a high correlation between LDH, HBDH, AST, and ALT (0.59-0.99), and higher coefficients were also observed among TP, ALB, HDL-C, and CHO (0.46-0.87). And then, we performed the GWAS to reveal the genetic basis of the 18 serum biochemical parameters in ducks. Fourteen candidate protein-coding genes were identified with enzyme traits (AST, ALP, LDH, HBDH), and 3 protein-coding genes were associated with metabolism and protein-related serum parameters (UA, TG). Moreover, the expression levels of the above candidate protein-coding genes in different stages of breast muscle and different tissues were analyzed. Furthermore, the genes located within the high-LD region (r2 > 0.4 and - log10(P) < 4) neighboring the significant locus also remained. Finally, 86 putative protein-coding genes were used for GO and KEGG enrichment analysis, the enzyme-linked receptor protein signaling pathway and ErbB signaling pathway deserve further focus. CONCLUSIONS: The obtained results can contribute to new insights into blood metabolism and provide new genetic biomarkers for application in duck breeding programs.

Genome-wide association study reveals the genetic determinism of growth traits in a Gushi-Anka F2 chicken population.

Chicken growth traits are economically important, but the relevant genetic mechanisms have not yet been elucidated. Herein, we performed a genome-wide association study to identify the variants associated with growth traits. In total, 860 chickens from a Gushi-Anka F2 resource population were phenotyped for 68 growth and carcass traits, and 768 samples were genotyped based on the genotyping-by-sequencing (GBS) method. Finally, 734 chickens and 321,314 SNPs remained after quality control and removal of the sex chromosomes, and these data were used to carry out a GWAS analysis. A total of 470 significant single-nucleotide polymorphisms (SNPs) for 43 of the 68 traits were detected and mapped on chromosomes (Chr) 1-6, -9, -10, -16, -18, -23, and -27. Of these, the significant SNPs in Chr1, -4, and -27 were found to be associated with more than 10 traits. Multiple traits shared significant SNPs, indicating that the same mutation in the region might have a large effect on multiple growth or carcass traits. Haplotype analysis revealed that SNPs within the candidate region of Chr1 presented a mosaic pattern. The significant SNPs and pathway enrichment analysis revealed that the MLNR, MED4, CAB39L, LDB2, and IGF2BP1 genes could be putative candidate genes for growth and carcass traits. The findings of this study improve our understanding of the genetic mechanisms regulating chicken growth and carcass traits and provide a theoretical basis for chicken breeding programs.

QTL mapping: an innovative method for investigating the genetic determinism of yeast-bacteria interactions in wine.

The two most commonly used wine microorganisms, Saccharomyces cerevisiae yeast and Oenococcus oeni bacteria, are responsible for completion of alcoholic and malolactic fermentation (MLF), respectively. For successful co-inoculation, S. cerevisiae and O. oeni must be able to complete fermentation; however, this relies on compatibility between yeast and bacterial strains. For the first time, quantitative trait loci (QTL) analysis was used to elucidate whether S. cerevisiae genetic makeup can play a role in the ability of O. oeni to complete MLF. Assessment of 67 progeny from a hybrid S. cerevisiae strain (SBxGN), co-inoculated with a single O. oeni strain, SB3, revealed a major QTL linked to MLF completion by O. oeni. This QTL encompassed a well-known translocation, XV-t-XVI, that results in increased SSU1 expression and is functionally linked with numerous phenotypes including lag phase duration and sulphite export and production. A reciprocal hemizygosity assay was performed to elucidate the effect of the gene SSU1 in the SBxGN background. Our results revealed a strong effect of SSU1 haploinsufficiency on O. oeni's ability to complete malolactic fermentation during co-inoculation and pave the way for the implementation of QTL mapping projects for deciphering the genetic bases of microbial interactions. KEY POINTS: • For the first time, QTL analysis has been used to study yeast-bacteria interactions. • A QTL encompassing a translocation, XV-t-XVI, was linked to MLF outcomes. • S. cerevisiae SSU1 haploinsufficiency positively impacted MLF by O. oeni.

The many faces of psoriatic arthritis: their genetic determinism.

In this review, we propose a model of PsA as a complex genetically determined autoimmune-mediated disease having a heterogeneous variety of subphenotypes, with each subphenotype under the control of a different susceptibility-associated HLA allele. Since the specific HLA molecules encoded by each susceptibility allele dominantly select a T cell repertoire with the property of recognizing different peptides, we hypothesize each subphenotype reflects a distinct adaptive autoimmune response directed to different target molecules that is mediated by T cells within each selected repertoire. The interaction among the patients' susceptibility alleles in the selection of their T cell repertoires determines a spectrum of overall clinical disease severity, varying from mild to severe. We further speculate that these different immune responses may result in activation of different immune effector pathways, which might therefore respond differently to various specific biologic agents.

Free Will, Determinism, and Intuitive Judgments About the Heritability of Behavior.

The fact that genes and environment contribute differentially to variation in human behaviors, traits and attitudes is central to the field of behavior genetics. Perceptions about these differential contributions may affect ideas about human agency. We surveyed two independent samples (N = 301 and N = 740) to assess beliefs about free will, determinism, political orientation, and the relative contribution of genes and environment to 21 human traits. We find that lay estimates of genetic influence on these traits cluster into four distinct groups, which differentially predict beliefs about human agency, political orientation, and religiosity. Despite apparent ideological associations with these beliefs, the correspondence between mean lay estimates and published heritability estimates for the surveyed traits is large (r = .77). Belief in genetic determinism emerges as a modest predictor of accuracy in these lay estimates. Additionally, educated mothers with multiple children emerge as particularly accurate in their estimates of the genetic contribution to these traits.

Cross-Cultural Differences in the Influences of Spiritual and Religious Tendencies on Beliefs in Genetic Determinism and Family Health History Communication: A Teleological Approach.

Adopting a teleological approach, this study investigates how beliefs in genetic determinism, intentional spirituality, and religious tendencies are associated with family health history (FHH) communication among European American, Chinese, and Korean college students. The results indicate that intentional spirituality was negatively associated with beliefs in genetic determinism and FHH communication, while beliefs in genetic determinism were positively associated with FHH communication. Intrinsic and extrinsic religiosity and paranormal beliefs showed interesting dynamics with beliefs in genetic determinism and FHH communication. An interaction effect regarding cultural identity, beliefs in genetic determinism, and FHH communication was likewise found. The findings have meaningful implications for future studies about religious influences on health behaviors.

An epigenetic escape route.

Some of our fate is predetermined, by genetics and by the environment in the womb. Gestational environments are reflected in the DNA methylomes of newborns, in a manner that is often influenced by genotype. Therefore, DNA methylation serves as molecular mechanism linking the interplay of early life environments and genetics to later life health. As such, methylation marks are potential biomarkers of suboptimal developmental trajectories. Can DNA methylation also be used to construct an escape route from biological fate?

Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma.

BACKGROUND: Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood; both environmental and genetic risk factors could contribute to their aetiology. METHODS AND RESULTS: We performed whole-exome sequencing (WES) in a familial aggregation of three individuals affected with soft-tissue sarcoma (STS) without TP53 mutation (Li-Fraumeni-like, LFL) and found a shared pathogenic mutation in CDKN2A tumour suppressor gene. We searched for individuals with sarcoma among 474 melanoma-prone families with a CDKN2A-/+ genotype and for CDKN2A mutations in 190 TP53-negative LFL families where the index case was a sarcoma. Including the initial family, eight independent sarcoma cases carried a germline mutation in the CDKN2A/p16INK4A gene. In five out of seven formalin-fixed paraffin-embedded sarcomas, heterozygosity was lost at germline CDKN2A mutations sites demonstrating complete loss of function. As sarcomas are rare in CDKN2A/p16INK4A carriers, we searched in constitutional WES of nine carriers for potential modifying rare variants and identified three in platelet-derived growth factor receptor (PDGFRA) gene. Molecular modelling showed that two never-described variants could impact the PDGFRA extracellular domain structure. CONCLUSION: Germline mutations in CDKN2A/P16INK4A, a gene known to predispose to hereditary melanoma, pancreatic cancer and tobacco-related cancers, account also for a subset of hereditary sarcoma. In addition, we identified PDGFRA as a candidate modifier gene.

The fundamental theorem of natural selection with mutations.

The mutation-selection process is the most fundamental mechanism of evolution. In 1935, R. A. Fisher proved his fundamental theorem of natural selection, providing a model in which the rate of change of mean fitness is equal to the genetic variance of a species. Fisher did not include mutations in his model, but believed that mutations would provide a continual supply of variance resulting in perpetual increase in mean fitness, thus providing a foundation for neo-Darwinian theory. In this paper we re-examine Fisher's Theorem, showing that because it disregards mutations, and because it is invalid beyond one instant in time, it has limited biological relevance. We build a differential equations model from Fisher's first principles with mutations added, and prove a revised theorem showing the rate of change in mean fitness is equal to genetic variance plus a mutational effects term. We refer to our revised theorem as the fundamental theorem of natural selection with mutations. Our expanded theorem, and our associated analyses (analytic computation, numerical simulation, and visualization), provide a clearer understanding of the mutation-selection process, and allow application of biologically realistic parameters such as mutational effects. The expanded theorem has biological implications significantly different from what Fisher had envisioned.

Genetic Determinism and Evolutionary Reconstruction of a Host Jump in a Plant Virus.

In spite of their widespread occurrence, only few host jumps by plant viruses have been evidenced and the molecular bases of even fewer have been determined. A combination of three independent approaches, 1) experimental evolution followed by reverse genetics analysis, 2) positive selection analysis, and 3) locus-by-locus analysis of molecular variance (AMOVA) allowed reconstructing the Potato virus Y (PVY; genus Potyvirus, family Potyviridae) jump to pepper (Capsicum annuum), probably from other solanaceous plants. Synthetic chimeras between infectious cDNA clones of two PVY isolates with contrasted levels of adaptation to C. annuum showed that the P3 and, to a lower extent, the CI cistron played important roles in infectivity toward C. annuum. The three analytical approaches pinpointed a single nonsynonymous substitution in the P3 and P3N-PIPO cistrons that evolved several times independently and conferred adaptation to C. annuum. In addition to increasing our knowledge of host jumps in plant viruses, this study illustrates also the efficiency of locus-by-locus AMOVA and combined approaches to identify adaptive mutations in the genome of RNA viruses.

Aortic root dimensions are predominantly determined by genetic factors: a classical twin study.

OBJECTIVES: Previous studies using transthoracic echocardiography (TTE) observed moderate heritability of aortic root dimensions. Computed tomography angiography (CTA) might provide more accurate heritability estimates. Our primary aim was to assess the heritability of the aortic root with CTA. Our secondary aim was to derive TTE-based heritability and compare this with the CTA-based results. METHODS: In the BUDAPEST-GLOBAL study 198 twin subjects (118 monozygotic, 80 dizygotic; age 56.1 ± 9.4 years; 126 female) underwent CTA and TTE. We assessed the diameter of the left ventricular outflow tract (LVOT), annulus, sinus of Valsalva, sinotubular junction and ascending aorta. Heritability was assessed using ACDE model (A additive genetic, C common environmental, D dominant genetic, E unique environmental factors). RESULTS: Based on CTA, additive genetic effects were dominant (LVOT: A = 0.67, E = 0.33; annulus: A = 0.76, E = 0.24; sinus of Valsalva: A = 0.83, E = 0.17; sinotubular junction: A = 0.82, E = 0.18; ascending aorta: A = 0.75, E = 0.25). TTE-derived measurements showed moderate to no genetic influence (LVOT: A = 0.38, E = 0.62; annulus: C = 0.47, E = 0.53; sinus of Valsalva: C = 0.63, E = 0.37; sinotubular junction: C = 0.45, E = 0.55; ascending aorta: A = 0.67, E = 0.33). CONCLUSION: CTA-based assessment suggests that aortic root dimensions are predominantly determined by genetic factors. TTE-based measurements showed moderate to no genetic influence. The choice of measurement method has substantial impact on heritability estimates. KEY POINTS: • Aortic root dimensions are determined by genetic and environmental effects. • Transthoracic echocardiography (TTE) demonstrated moderate to no genetic effects on aortic root dimensions. • Computed tomography angiography might provide more accurate heritability estimates compared to TTE. • Three-dimensional imaging techniques are needed to reliably quantify aortic root dimensions.

Genetic Determinism vs. Phenotypic Plasticity in Protist Morphology.

Untangling the relationships between morphology and phylogeny is key to building a reliable taxonomy, but is especially challenging for protists, where the existence of cryptic or pseudocryptic species makes finding relevant discriminant traits difficult. Here we use Hyalosphenia papilio (a testate amoeba) as a model species to investigate the contribution of phylogeny and phenotypic plasticity in its morphology. We study the response of H. papilio morphology (shape and pores number) to environmental variables in (i) a manipulative experiment with controlled conditions (water level), (ii) an observational study of a within-site natural ecological gradient (water level), and (iii) an observational study across 37 European peatlands (climate). We showed that H. papilio morphology is correlated to environmental conditions (climate and water depth) as well as geography, while no relationship between morphology and phylogeny was brought to light. The relative contribution of genetic inheritance and phenotypic plasticity in shaping morphology varies depending on the taxonomic group and the trait under consideration. Thus, our data call for a reassessment of taxonomy based on morphology alone. This clearly calls for a substantial increase in taxonomic research on these globally still under-studied organisms leading to a reassessment of estimates of global microbial eukaryotic diversity.

Difficult temperament and negative parenting in early childhood: a genetically informed cross-lagged analysis.

A genetically informed longitudinal cross-lagged model was applied to twin data to explore etiological links between difficult temperament and negative parenting in early childhood. The sample comprised 313 monozygotic (MZ) and dizygotic (DZ) twin pairs. Difficult temperament and negative parenting were assessed at ages 2 and 3 using parent ratings. Both constructs were interrelated within and across age (rs .34-.47) and showed substantial stability (rs .65-.68). Difficult temperament and negative parenting were influenced by genetic and environmental factors at ages 2 and 3. The genetic and nonshared environmental correlations (rs .21-.76) at both ages suggest overlap at the level of etiology between the phenotypes. Significant bidirectional associations between difficult temperament and negative parenting were found. The cross-lagged association from difficult temperament at age 2 to negative parenting at age 3 and from negative parenting at age 2 and difficult temperament at age 3 were due to genetic, shared environmental, and nonshared environmental factors. Substantial novel genetic and nonshared environmental influences emerged at age 3 and suggest change in the etiology of these constructs over time.

Genetic determinants of voluntary exercise.

Variation in voluntary exercise behavior is an important determinant of long-term human health. Increased physical activity is used as a preventative measure or therapeutic intervention for disease, and a sedentary lifestyle has generally been viewed as unhealthy. Predisposition to engage in voluntary activity is heritable and induces protective metabolic changes, but its complex genetic/genomic architecture has only recently begun to emerge. We first present a brief historical perspective and summary of the known benefits of voluntary exercise. Second, we describe human and mouse model studies using genomic and transcriptomic approaches to reveal the genetic architecture of exercise. Third, we discuss the merging of genomic information and physiological observations, revealing systems and networks that lead to a more complete mechanistic understanding of how exercise protects against disease pathogenesis. Finally, we explore potential regulation of physical activity through epigenetic mechanisms, including those that persist across multiple generations.

CTLA-4 as a genetic determinant in autoimmune Addison's disease.

In common with several other autoimmune diseases, autoimmune Addison's disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR=1.37 (CI 1.13-1.66), P=0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68-3.51), P=0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.

Repressive histone methylation: a case study in deterministic versus stochastic gene regulation.

Transcriptionally repressive histone lysine methylation is used by eukaryotes to tightly control cell fate. Here we explore the importance of this form of regulation in the control of clustered genes in the genome. Two distinctly regulated gene families with important roles in vertebrates are discussed, namely the Hox genes and olfactory receptor genes. Major recent advances in these two fields are compared and contrasted, with an emphasis on the roles of the two different forms of histone trimethylation. We discuss how this repression may impact both the transcriptional output of these loci and the way higher-order chromatin organization is related to their unique control.

Genetic determinant for amino acid metabolites and changes in body weight and insulin resistance in response to weight-loss diets: the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial.

BACKGROUND: Circulating branched-chain amino acids and aromatic amino acids were recently related to insulin resistance and diabetes mellitus in prospective cohorts. We tested the effects of a genetic determinant of branched-chain amino acid/aromatic amino acid ratio on changes in body weight and insulin resistance in a 2-year diet intervention trial. METHODS AND RESULTS: We genotyped the branched-chain amino acid/aromatic amino acid ratio-associated variant rs1440581 near the PPM1K gene in 734 overweight or obese adults who were assigned to 1 of 4 diets varying in macronutrient content. At 6 months, dietary fat significantly modified genetic effects on changes in weight, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) after adjustment for the confounders (all P for interaction ≤0.006). Further adjustment for weight change did not appreciably change the interactions for fasting insulin and HOMA-IR. In the high-fat diet group, the C allele was related to less weight loss and smaller decreases in serum insulin and HOMA-IR (all P ≤ 0.02 in an additive pattern), whereas an opposite genotype effect on changes in insulin and HOMA-IR was observed in the low-fat diet group (P=0.02 and P=0.04, respectively). At 2 years, the gene-diet interactions remained significant for weight loss (P=0.008) but became null for changes in serum insulin and HOMA-IR resulting from weight regain. CONCLUSIONS: Individuals carrying the C allele of the branched-chain amino acid/aromatic amino acid ratio-associated variant rs1440581 may benefit less in weight loss and improvement of insulin sensitivity than those without this allele when undertaking an energy-restricted high-fat diet. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00072995.