Nutrition Society Silver Medal Lecture Nutrigenetics and personalised nutrition: how far have we progressed and are we likely to get there?

Nutrigenetics and personalised nutrition are components of the concept that in the future genotyping will be used as a means of defining dietary recommendations to suit the individual. Over the last two decades there has been an explosion of research in this area, with often conflicting findings reported in the literature. Reviews of the literature in the area of apoE genotype and cardiovascular health, apoA5 genotype and postprandial lipaemia and perilipin and adiposity are used to demonstrate the complexities of genotype-phenotype associations and the aetiology of apparent between-study inconsistencies in the significance and size of effects. Furthermore, genetic research currently often takes a very reductionist approach, examining the interactions between individual genotypes and individual disease biomarkers and how they are modified by isolated dietary components or foods. Each individual possesses potentially hundreds of 'at-risk' gene variants and consumes a highly-complex diet. In order for nutrigenetics to become a useful public health tool, there is a great need to use mathematical and bioinformatic tools to develop strategies to examine the combined impact of multiple gene variants on a range of health outcomes and establish how these associations can be modified using combined dietary strategies.

Identification and validation of candidate genes associated with domesticated and improved traits in soybean

Soybean, an important source of vegetable oils and proteins for humans, has undergone significant phenotypic changes during domestication and improvement. However, there is limited knowledge about genes related to these domesticated and improved traits, such as flowering time, seed development, alkaline-salt tolerance, and seed oil content (SOC). In this study, more than 106,000 single nucleotide polymorphisms (SNPs) were identified by restriction site associated DNA sequencing of 14 wild, 153 landrace, and 119 bred soybean accessions, and 198 candidate domestication regions (CDRs) were identified via multiple genetic diversity analyses. Of the 1489 candidate domestication genes (CDGs) within these CDRs, a total of 330 CDGs were related to the above four traits in the domestication, gene ontology (GO) enrichment, gene expression, and pathway analyses. Eighteen, 60, 66, and 10 of the 330 CDGs were significantly associated with the above four traits, respectively. Of 134 traitassociated CDGs, 29 overlapped with previous CDGs, 11 were consistent with candidate genes in previous trait association studies, and 66 were covered by the domesticated and improved quantitative trait loci or their adjacent regions, having six common CDGs, such as one functionally characterized gene Glyma15 g17480 (GmZTL3). Of the 68 seed size (SS) and SOC CDGs, 37 were further confirmed by gene expression analysis. In addition, eight genes were found to be related to artificial selection during modern breeding. Therefore, this study provides an integrated method for efficiently identifying CDGs and valuable information for domestication and genetic research.

Identifying adaptive genetic divergence among populations from genome scans

The identification of signatures of natural selection in genomic surveys has become an area of intense research, stimulated by the increasing ease with which genetic markers can be typed. Loci identified as subject to selection may be functionally important, and hence (weak) candidates for involvement in disease causation. They can also be useful in determining the adaptive differentiation of populations, and exploring hypotheses about speciation. Adaptive differentiation has traditionally been identified from differences in allele frequencies among different populations, summarised by an estimate of F-ST. Low outliers relative to an appropriate neutral population-genetics model indicate loci subject to balancing selection, whereas high outliers suggest adaptive (directional) selection. However, the problem of identifying statistically significant departures from neutrality is complicated by confounding effects on the distribution of F-ST estimates, and current methods have not yet been tested in large-scale simulation experiments. Here, we simulate data from a structured population at many unlinked, diallelic loci that are predominantly neutral but with some loci subject to adaptive or balancing selection. We develop a hierarchical-Bayesian method, implemented via Markov chain Monte Carlo (MCMC), and assess its performance in distinguishing the loci simulated under selection from the neutral loci. We also compare this performance with that of a frequentist method, based on moment-based estimates of F-ST. We find that both methods can identify loci subject to adaptive selection when the selection coefficient is at least five times the migration rate. Neither method could reliably distinguish loci under balancing selection in our simulations, even when the selection coefficient is twenty times the migration rate.

The challenges for molecular nutrition research 1: linking genotype to healthy nutrition

Nutrition science finds itself at a major crossroad. On the one hand we can continue the current path, which has resulted in some substantial advances, but also many conflicting messages which impair the trust of the general population, especially those who are motivated to improve their health through diet. The other road is uncharted and is being built over the many exciting new developments in life sciences. This new era of nutrition recognizes the complex relation between the health of the individual, its genome, and the life-long dietary exposure, and has lead to the realisation that nutrition is essentially a gene - environment interaction science. This review on the relation between genotype, diet and health is the first of a series dealing with the major challenges in molecular nutrition, analyzing the foundations of nutrition research. With the unravelling of the human genome and the linking of its variability to a multitude of phenotypes from " healthy'' to an enormously complex range of predispositions, the dietary modulation of these propensities has become an area of active research. Classical genetic approaches applied so far in medical genetics have steered away from incorporating dietary effects in their models and paradoxically, most genetic studies analyzing diet-associated phenotypes and diseases simply ignore diet. Yet, a modest but increasing number of studies are accounting for diet as a modulator of genetic associations. These range from observational cohorts to intervention studies with prospectively selected genotypes. New statistical and bioinformatics approaches are becoming available to aid in design and evaluation of these studies. This review discusses the various approaches used and provides concrete recommendations for future research.

Mind-reading difficulties in the siblings of people with Asperger's syndrome: evidence for a genetic influence in the abnormal development of a specific cognitive domain

Background: Previous research suggests that the phenotype associated with Asperger's syndrome (AS) includes difficulties in understanding the mental states of others, leading to difficulties in social communication and social relationships. It has also been suggested that the first-degree relatives of those with AS can demonstrate similar difficulties, albeit to a lesser extent. This study examined 'theory of mind' (ToM) abilities in the siblings of children with AS relative to a matched control group. Method: 2 7 children who had a sibling with AS were administered the children's version of the 'Eyes Test'(Baron-Cohen, Wheelwright, Stone, & Rutherford, 1999). The control group consisted of 27 children matched for age, sex, and a measure of verbal comprehension, and who did not have a family history of AS/autism. Results: A significant difference was found between the groups on the Eyes Test, the 'siblings' group showing a poorer performance on this measure of social cognition. The difference was more pronounced among female siblings. Discussion: These results are discussed in terms of the familial distribution of a neuro-cognitive profile associated with AS, which confers varying degrees of social handicap amongst first-degree relatives. The implication of this finding with regard to the autism/AS phenotype is explored, with some discussion of why this neuro-cognitive profile (in combination with corresponding strengths) may have an evolutionary imperative.

Gene-nutrient interactions with dietary fat modulate the association between genetic variation of the ACSL1 gene and metabolic syndrome

Long-chain acyl CoA synthetase 1 (ACSL1) plays an important role in fatty acid metabolism and triacylglycerol (TAG) synthesis. Disturbance of these pathways may result in dyslipidemia and insulin resistance, hallmarks of the metabolic syndrome (MetS). Dietary fat is a key environmental factor that may interact with genetic determinants of lipid metabolism to affect MetS risk. We investigated the relationship between ACSL1 polymorphisms (rs4862417, rs6552828, rs13120078, rs9997745, and rs12503643) and MetS risk and determined potential interactions with dietary fat in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1,754). GG homozygotes for rs9997745 had increased MetS risk {odds ratio (OR) 1.90 [confidence interval (CI) 1.15, 3.13]; P = 0.01}, displayed elevated fasting glucose (P = 0.001) and insulin concentrations (P = 0.002) and increased insulin resistance (P = 0.03) relative to the A allele carriers. MetS risk was modulated by dietary fat, whereby the risk conferred by GG homozygosity was abolished among individuals consuming either a low-fat (<35% energy) or a high-PUFA diet (>5.5% energy). In conclusion, ACSL1 rs9997745 influences MetS risk, most likely via disturbances in fatty acid metabolism, which was modulated by dietary fat consumption, particularly PUFA intake, suggesting novel gene-nutrient interactions.

The role of the international cocoa germplasm database and the international cocoa quarantine centre in information management and distribution of cocoa genetic resources

A range of physiological parameters (canopy light transmission, canopy shape, leaf size, flowering and flushing intensity) were measured from the International Clone Trial, typically over the course of two years. Data were collected from six locations, these being: Brazil, Ecuador, Trinidad, Venezuela, Côte d’Ivoire and Ghana. Canopy shape varied significantly between clones, although it showed little variation between locations. Genotypic variation in leaf size was differentially affected by the growth location; such differences appeared to underlie a genotype by environment interaction in relation to canopy light transmission. Flushing data were recorded at monthly intervals over the course of a year. Within each location, a significant interaction was observed between genotype and time of year, suggesting that some genotypes respond to a greater extent than others to environmental stimuli. A similar interaction was observed for flowering data, where significant correlations were found between flowering intensity and temperature in Brazil and flowering intensity and rainfall in Côte d’Ivoire. The results demonstrate the need for local evaluation of cocoa clones and also suggest that the management practices for particular planting material may need to be fine-tuned to the location in which they are cultivated.

Genetic responses to phosphorus deficiency

Background: Phosphorus (P) is an essential macronutrient for plants. Plants take up P as phosphate (Pi) from the soil solution. Since little Pi is available in most soils, P fertilizers are applied to crops. However, the use of P fertilizers is unsustainable and may cause pollution. Consequently, there is a need to develop more P-use-efficient (PUE) crops and precise methods to monitor crop P-status. Scope: Manipulating the expression of genes to improve the PUE of crops could reduce their P fertilizer requirement. This has stimulated research towards the identification of genes and signalling cascades involved in plant responses to P deficiency. Genes that respond to P deficiency can be grouped into 'early' genes that respond rapidly and often non-specifically to P deficiency, or 'late' genes that impact on the morphology, physiology or metabolism of plants upon Prolonged P deficiency. Summary: The use of micro-array technology has allowed researchers to catalogue the genetic responses of plants to P deficiency. Genes whose expression is altered by P deficiency include various transcription factors, which are thought to coordinate plant responses to P deficiency, and other genes involved in P acquisition and tissue P economy. Several common cis-regulatory elements have been identified in the promoters of these genes, suggesting that their expression might be coordinated. It is suggested that knowledge of the genes whose expression changes in response to P deficiency might allow the development of crops with improved PUE, and could be used in diagnostic techniques to monitor P deficiency in crops either directly using 'smart' indicator plants or indirectly through transcript profiling. The development of crops with improved PUE and the adoption of diagnostic technology could reduce production costs, minimize the use of a non-renewable resource, reduce pollution and enhance biodiversity.

Role of genetic polymorphism peroxisome proliferator-activated receptor-gamma2 Pro12Ala on ethnic susceptibility to diabetes in South-Asian and Caucasian subjects: Evidence for heterogeneity

OBJECTIVE: To determine whether the peroxisome proliferator-activated receptor (PPAR)-gamma Pro12ala polymorphism modulates susceptibility to diabetes in South Asians. RESEARCH DESIGN AND METHODS: South Asians (n = 697) and Caucasians (n = 457) living in Dallas/Forth Worth, Texas, and South Asians living in Chennai, India (n = 1,619), were enrolled for this study. PPAR-gamma Pro12Ala was determined using restriction fragment-length polymorphism. Insulin responsiveness to an oral glucose tolerance test (OGTT) was measured in nondiabetic subjects. RESULTS: The Caucasian diabetic subjects had significantly lower prevalence of PPAR-gamma 12Ala when compared with the Caucasian nondiabetic subjects (20 vs. 9%, P = 0.006). However, there were no significant differences between diabetic and nondiabetic subjects with reference to the Pro12Ala polymorphism among the South Asians living in Dallas (20 vs. 23%) and in India (19 vs. 19.3%). Although Caucasians carrying PPAR-gamma Pro12Ala had lower plasma insulin levels at 2 h of OGTT than the wild-type (Pro/Pro) carriers (76 +/- 68 and 54 +/- 33 microU/ml, respectively, P = 0.01), no differences in either fasting or 2-h plasma insulin concentrations were found between South Asians carrying the PPAR-gamma Pro12Ala polymorphism and those with the wild-type genotype at either Chennai or Dallas. CONCLUSIONS: Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that the PPAR-gamma Pro12Ala polymorphism is protective against diabetes in Caucasians but not in South Asians.

A simple syllogism-solving test: empirical findings and implications for g research

It has been reported that the ability to solve syllogisms is highly g-loaded. In the present study, using a self-administered shortened version of a syllogism-solving test, the BAROCO Short, we examined whether robust findings generated by previous research regarding IQ scores were also applicable to BAROCO Short scores. Five syllogism-solving problems were included in a questionnaire as part of a postal survey conducted by the Keio Twin Research Center. Data were collected from 487 pairs of twins (1021 individuals) who were Japanese junior high or high school students (ages 13–18) and from 536 mothers and 431 fathers. Four findings related to IQ were replicated: 1) The mean level increased gradually during adolescence, stayed unchanged from the 30s to the early 50s, and subsequently declined after the late 50s. 2) The scores for both children and parents were predicted by the socioeconomic status of the family. 3) The genetic effect increased, although the shared environmental effect decreased during progression from adolescence to adulthood. 4) Children's scores were genetically correlated with school achievement. These findings further substantiate the close association between syllogistic reasoning ability and g.

Genetic, structural, and molecular insights into the function of ras of complex proteins domains

Ras of complex proteins (ROC) domains were identified in 2003 as GTP binding modules in large multidomain proteins from Dictyostelium discoideum. Research into the function of these domains exploded with their identification in a number of proteins linked to human disease, including leucine-rich repeat kinase 2 (LRRK2) and death-associated protein kinase 1 (DAPK1) in Parkinson’s disease and cancer, respectively. This surge in research has resulted in a growing body of data revealing the role that ROC domains play in regulating protein function and signaling pathways. In this review, recent advances in the structural informa- tion available for proteins containing ROC domains, along with insights into enzymatic function and the integration of ROC domains as molecular switches in a cellular and organismal context, are explored.

Language in genetic syndromes and cognitive modularity

In recent years, research into the impact of genetic abnormalities on cognitive development, including language, has become recognized for its potential to make valuable contributions to our understanding of the brain–behaviour relationships underlying language acquisition as well as to understanding the cognitive architecture of the human mind. The publication of Fodor’s ( 1983 ) book The Modularity of Mind has had a profound impact on the study of language and the cognitive architecture of the human mind. Its central claim is that many of the processes involved in comprehension are undertaken by special brain systems termed ‘modules’. This domain specificity of language or modularity has become a fundamental feature that differentiates competing theories and accounts of language acquisition (Fodor 1983 , 1985 ; Levy 1994 ; Karmiloff-Smith 1998 ). However, although the fact that the adult brain is modularized is hardly disputed, there are different views of how brain regions become specialized for specific functions. A question of some interest to theorists is whether the human brain is modularized from the outset (nativist view) or whether these distinct brain regions develop as a result of biological maturation and environmental input (neuroconstructivist view). One source of insight into these issues has been the study of developmental disorders, and in particular genetic syndromes, such as Williams syndrome (WS) and Down syndrome (DS). Because of their uneven profiles characterized by dissociations of different cognitive skills, these syndromes can help us address theoretically significant questions. Investigations into the linguistic and cognitive profiles of individuals with these genetic abnormalities have been used as evidence to advance theoretical views about innate modularity and the cognitive architecture of the human mind. The present chapter will be organized as follows. To begin, two different theoretical proposals in the modularity debate will be presented. Then studies of linguistic abilities in WS and in DS will be reviewed. Here, the emphasis will be mainly on WS due to the fact that theoretical debates have focused primarily on WS, there is a larger body of literature on WS, and DS subjects have typically been used for the purposes of comparison. Finally, the modularity debate will be revisited in light of the literature review of both WS and DS. Conclusions will be drawn regarding the contribution of these two genetic syndromes to the issue of cognitive modularity, and in particular innate modularity.

Changes in physical activity following a genetic-based internet-delivered personalized intervention: randomized controlled trial (Food4Me)

Background: There is evidence that physical activity (PA) can attenuate the influence of the fat mass- and obesity-associated (FTO) genotype on the risk to develop obesity. However, whether providing personalized information on FTO genotype leads to changes in PA is unknown. Objective: The purpose of this study was to determine if disclosing FTO risk had an impact on change in PA following a 6-month intervention. Methods: The single nucleotide polymorphism (SNP) rs9939609 in the FTO gene was genotyped in 1279 participants of the Food4Me study, a four-arm, Web-based randomized controlled trial (RCT) in 7 European countries on the effects of personalized advice on nutrition and PA. PA was measured objectively using a TracmorD accelerometer and was self-reported using the Baecke questionnaire at baseline and 6 months. Differences in baseline PA variables between risk (AA and AT genotypes) and nonrisk (TT genotype) carriers were tested using multiple linear regression. Impact of FTO risk disclosure on PA change at 6 months was assessed among participants with inadequate PA, by including an interaction term in the model: disclosure (yes/no) × FTO risk (yes/no). Results: At baseline, data on PA were available for 874 and 405 participants with the risk and nonrisk FTO genotypes, respectively. There were no significant differences in objectively measured or self-reported baseline PA between risk and nonrisk carriers. A total of 807 (72.05%) of the participants out of 1120 in the personalized groups were encouraged to increase PA at baseline. Knowledge of FTO risk had no impact on PA in either risk or nonrisk carriers after the 6-month intervention. Attrition was higher in nonrisk participants for whom genotype was disclosed (P=.01) compared with their at-risk counterparts. Conclusions: No association between baseline PA and FTO risk genotype was observed. There was no added benefit of disclosing FTO risk on changes in PA in this personalized intervention. Further RCT studies are warranted to confirm whether disclosure of nonrisk genetic test results has adverse effects on engagement in behavior change.