Focus: Nutrigenomics

Cover illustration: Nutrigenomics aims to identify the genes that influence the risk of diet-related diseases on a genomewide scale, and to understand the mechanisms that underlie these genetic predispositions. This BTJ special issue edited by Taesun Park features articles uncovering ‘dietary signatures’ associated with obesity and metabolic diseases. Images copyright: Yellow, green, and red bell peppers. © Photodisc, Microarray; © http://genomics.energy.gov     

Nutrigenomics: goals and strategies

Nutrigenomics is the application of high-throughput genomics tools in nutrition research. Applied wisely, it will promote an increased understanding of how nutrition influences metabolic pathways and homeostatic control, how this regulation is disturbed in the early phase of a diet-related disease and to what extent individual sensitizing genotypes contribute to such diseases. Ultimately, nutrigenomics will allow effective dietary-intervention strategies to recover normal homeostasis and to prevent diet-related diseases.     

Nutrigenomics of hepatic steatosis in a feline model: effect of monosodium glutamate, fructose, and Trans-fat feeding

Nonalcoholic fatty liver disease begins with a relatively benign hepatic steatosis, often associated with increased adiposity, but may progress to a more severe nonalcoholic steatohepatitis with inflammation. A subset of these patients develops progressive fibrosis and ultimately cirrhosis. Various dietary components have been shown to contribute to the development of liver disease, including fat, sugars, and neonatal treatment with high doses of monosodium glutamate (MSG). However, rodent models of progressive disease have been disappointing, and alternative animal models of diet-induced liver disease would be desirable, particularly if they contribute to our knowledge of changes in gene expression as a result of dietary manipulation. The domestic cat has previously been shown to be an appropriate model for examining metabolic changes–associated human diseases such as diabetes. Our aim was therefore to compare changes in hepatic gene expression induced by dietary MSG, with that of a diet containing Trans-fat and high fructose corn syrup (HFCS), using a feline model. MSG treatment increased adiposity and promoted hepatic steatosis compared to control (P < 0.05). Exposure to Trans-fat and HFCS promoted hepatic fibrosis and markers of liver dysfunction. Affymetrix microarray analysis of hepatic gene expression showed that dietary MSG promoted the expression of genes involved in cholesterol and steroid metabolism. Conversely, Trans-fat and HFCS feeding promoted the expression of genes involved in lipolysis, glycolysis, liver damage/regeneration, and fibrosis. Our feline model examining gene–diet interactions (nutrigenomics) demonstrates how dietary MSG, Trans-fat, and HFCS may contribute to the development of hepatic steatosis.     

Nutrigenomics research for personalized nutrition and medicine

Current nutritional and genetic epidemiological methods yield 'risk factors' on the basis of population studies. Risk factors, however, are statistical estimates of the percentage reduction in disease in the population if the risk were to be avoided or the gene variant were not present. These measures are often assumed to apply to individuals who are likely to differ in genetic make-up, lifestyle, and dietary patterns than to the individuals in the study population. Developing individual risk factors in light of the genetic diversity of human populations, the complexity of foods, culture and lifestyle, and the variety of metabolic processes that lead to health or disease is a significant challenge for personalizing dietary advice for healthy or individuals with chronic disease.     

Fixed and dilutable benefits: female choice for good genes or fertility

Benefits accruing to females who exercise mate choice have been defined to be either 'direct' or 'indirect'. We suggest an alternative distinction: benefits can be considered 'fixed', meaning they are on average equal to all females mating with the same male (e.g. good genes' benefits) or 'dilutable', meaning they are shared between females mating with the same male, so that the more mates a male has, the lower the average benefit to each (e.g. fertility benefits or many forms of direct benefit). Using a simple model, we show that this distinction has a major effect on the form of female preference. We predict that mating skew will be far greater in species where the benefits are fixed when compared with those where the benefits are dilutable.     

Nutrigenomics: a case for the common soil between cardiovascular disease and cancer

The border between health and disease is often set by a complex equilibrium between two elements, genetics on one hand, lifestyle on the other, To know it better, means to give new weapons, often crucial, in the hands of the doctors and their patients. It also means to adjust therapies, to find out which drug is good for a patient and which prevention strategy will work better for him/her. Nutrigenomics is an approach to individualize or personalize food and nutrition, and ultimately health, by tailoring the food to the individual genotype. In this review, we present the interaction between certain genetic polymorphisms and diet and increased cardiovascular or cancer risk. It is, indeed, now clear that a large number of bioactive food components may provide risk or protection at several stages of both atherosclerosis and cancer formation processes. We are giving here few examples of gene-food interactions relevant for both the risk of cardiovascular disease and cancer, since a common soil could exist in the genesis of cardiovascular disease and of some types of cancer (mainly gastrointestinal tract and hormone-dependent).     

绵羊多胎主效基因研究进展

绵羊存在影响多胎性状的主效基因。BMPR-IB的突变体FecB对排卵数的增加具有增强效应,GDF-9的突变体FecGH和FecI及BMP-15的突变体FecXI、FecXH、FecXG、FecXB、FecXL和FecXR均为纯合子不育,杂合子增加排卵数,而GDF-9的突变体FecGE只有纯合子增加排卵数。Woodlands和Lacaune是遗传方式已知的多胎主效基因。Woodlands是与X染色体连锁的母系印迹基因,Lacaune与FecB类似对排卵数的增加具有增强效应。主效基因突变体单拷贝增加排卵数的效应具有差异性,FecB和FecXL的效应最高可增加1.5个,Woodlands最低可增加0.4个。研究绵羊多胎性状主效基因不仅有助于家畜的选种选育,提高绵羊繁殖力,而且为研究哺乳动物的繁殖机制开拓了新的方向。文章综述了绵羊多胎主效基因的来源、定位、表型、作用机制以及我国绵羊品种多胎主效基因的研究现状,旨在为深入研究绵羊多胎主效基因的作用机制及为绵羊多胎品种的选育提供参考。     

Y chromosomal fertility genes of Drosophila: a new type of eukaryotic genes

The Y chromosomal fertility genes of Drosophila are required for sperm differentiation. They are active only in primary spermatocytes where they form giant lampbrush loops. The molecular structure of these genes was investigated and revealed an unusual composition of DNA. Short, tandemly repeated sequence clusters are interrupted by longer and more heterogeneous sequences, which probably all represent transposable elements. No indication of the presence of protein-coding regions has been found within the fertility genes. However, the lampbrush loops bind site-specific proteins recognized by immunofluorescence techniques. This, together with other experimental data, led to the hypothesis that the Y chromosomal genes have a function in binding chromosomal proteins. The data and arguments in support of this gene model are summarized in this paper.     

Nutrigenomics: integrating genomic approaches into nutrition research

It has been suggested that the supermarket of today will be the pharmacy of tomorrow. Such statements have been derived from recognition of our increasing ability to optimize nutrition, and maintain a state of good health through longer periods of life. The new field of nutrigenomics, which focuses on the interaction between bioactive dietary components and the genome, recognizes that current nutritional guidelines may be ideal for only a relatively small proportion of the population. There is good evidence that nutrition has significant influences on the expression of genes, and, likewise, genetic variation can have a significant effect on food intake, metabolic response to food, individual nutrient requirements, food safety, and the efficacy of disease-protective dietary factors. For example, a significant number of human studies in various areas are increasing the evidence for interactions between single nucleotide polymorphisms (SNPs) in various genes and the metabolic response to diet, including the risk of obesity. Many of the same genetic polymorphisms and dietary patterns that influence obesity or cardiovascular disease also affect cancer, since overweight individuals are at increased risk of cancer development. The control of food intake is profoundly affected by polymorphisms either in genes encoding taste receptors or in genes encoding a number of peripheral signaling peptides such as insulin, leptin, ghrelin, cholecystokinin, and corresponding receptors. Total dietary intake, and the satiety value of various foods, will profoundly influence the effects of these genes. Identifying key SNPs that are likely to influence the health of an individual provides an approach to understanding and, ultimately, to optimizing nutrition at the population or individual level. Traditional methods for identification of SNPs may involve consideration of individual variants, using methodologies such as restriction fragment length polymorphisms or quantitative real-time PCR assays. New developments allow identification of up to 500,000 SNPs in an individual, and with increasingly lowered pricings these developments may explode the population-level potential for dietary optimization based on nutrigenomic approaches.     

Religion, fertility and genes: a dual inheritance model

Religious people nowadays have more children on average than their secular counterparts. This paper uses a simple model to explore the evolutionary implications of this difference. It assumes that fertility is determined entirely by culture, whereas subjective predisposition towards religion is influenced by genetic endowment. People who carry a certain 'religiosity' gene are more likely than average to become or remain religious. The paper considers the effect of religious defections and exogamy on the religious and genetic composition of society. Defections reduce the ultimate share of the population with religious allegiance and slow down the spread of the religiosity gene. However, provided the fertility differential persists, and people with a religious allegiance mate mainly with people like themselves, the religiosity gene will eventually predominate despite a high rate of defection. This is an example of 'cultural hitch-hiking', whereby a gene spreads because it is able to hitch a ride with a high-fitness cultural practice. The theoretical arguments are supported by numerical simulations.     

Short term thermal relief for improved fertility in dairy cattle during hot weather

Cooling dairy cows to basal body temperatures in a climatic-control barn before inseminating and for 1 to 6.5 days after, improved fertility during early summer in the hot desert climate of Arizona. The treatment was not as effective during later summer months when the animals had been exposed to high climatic temperature for a longer period. Physiological adaptation to heat stress, inimical to normal reproduction, is apparently irreversible over the short cooling period.Arizona Agricultural Experiment Station Technical Paper No 2622.     

Effect of hyperketonaemia and feeding on fertility in dairy cows

Fertility in relation to acetone concentration in milk and level of nutrition was studied in 38,624 lactations from 474 herds over a 3-year period. Herd-related data on nutrition were collected once each year. Milk acetone concentrations higher than 0.40 mM were deemed to be hyperketonaemic. The interval from calving to first service was about 5 days longer in cows with acetone concentrations >2.00 mM, while the interval to the last service was shortest at 0.40 to 1.00 mM. The risk for cystic ovaries was severely increased in first calving heifers with acetone concentrations >2.00 mM (odds ratio; 8.7). In herds with a high frequency of hyperketonaemic cows, primiparous cows had a 6-day longer period from calving to the first service and a 12-day longer period from calving to the last service. Increased feeding frequency of concentrate (2 vs 4 times/day) was related to shorter intervals from calving to first service and from calving to last service of 5 and 6 days, respectively, in mature cows. Increased total intake of energy in early lactation was related to shorter intervals from calving to last service in both primiparous and multiparous cows, 0.3 and 0.1 days per megajoule metabolizable energy, respectively. However, increased amounts of concentrate at calving in multiparous cows, and 15 days after calving in primiparous cows, were related to longer intervals from calving to last service and from calving to first service, respectively. The negative effect on these intervals was estimated to be approximately 2 days per kilogram of concentrate.     

An improved method for the study of apoptosis-related genes using the tet-on system

Inducible gene expression systems are particularly useful for the functional characterization of genes with putative toxic properties. In the course of studying the role of hypoxia-regulated gene expression on cell survival using the tetracycline-inducible (tet-on) system, the author noted that exposure to the inducing ligand doxycycline (dox) inhibited caspase-3 cleavage in control samples. To limit this confounding off-target effect, he devised an in vitro pulse dose, delayed-injury protocol testing both dox and a novel tetracycline analog 9-t-butyl doxycycline (9-TB). Although 9-TB induced higher transgene levels compared to matched concentrations of dox, continuous exposure to both drugs inhibited caspase-3 cleavage in hypoxic samples. Conversely, a 6-h pulse dose of 9-TB followed by a 40-h washout period prior to hypoxic challenge activated robust transgene expression and lessened the inhibitory effects on caspase-3 processing. It is anticipated that these protocol modifications will improve the performance of tet-regulated genetic screens, particularly in situations where cell death is used as a primary end point.     

Polymorphisms in candidate genes as markers for sperm quality and boar fertility

Alpha-actinins (ACTN1 and ACTN4) and gamma-actin (ACTG2), were investigated as candidate genes on the basis of their known functions, for their possible association with sperm concentration, motility, semen volume per ejaculate, plasma droplets rate, abnormal sperm rate and the fertility traits, non-return rate and number of piglets born alive. Polymorphisms were identified in intron 18 (G>A) of the porcine ACTN1 gene and in exon 22 (A>C) of the porcine ACTN4 gene by comparative sequencing of animals from the Pietrain (PI) and Hampshire (HA) breeds. Pietrain (n = 244) and crossbreed PI x HA (n = 112) boars from an artificial insemination boar station were genotyped for the single nucleotide polymorphisms (SNPs) within ACTN1 and ACTN4 as well as for a previously described microsatellite within ACTG2. The study provides evidence for effects of ACTN1 on fertility and of ACTG2 on sperm quality traits, while no indication of impact of ACTN4 on any of these traits was found.     

Analysis of spermatogenesis in Drosophila melanogaster bearing deletions for Y-chromosome fertility genes

The effects on spermatogenesis of a series of contiguous non-overlapping Y-chromosome deficiencies were examined using both the light and electron microscope. The deficiencies were constructed by combining elements of different X-Y translocations; they subdivide the Y into seven segments, six of which are required for male fertility (four in the long arm and two in the short arm). Spermatogensis was examined from the primary spermatocyte through to the formation of mature sperm and the earliest departures from normal development identified. Two deficiencies result in the absence of the same structure from the axoneme of the sperm tail-the dynein-containing outer arm extending from the A subtubule of the peripheral doublet; they also result in the absence from primary spermatocyte nuclei of aggregates of tubuli in one case and reticular material in the other. A third deficiency causes the appearance in the primary spermatocyte of the crystals characteristic of X0 males and the irregular distribution during meiosis of nuclear and cytoplasmic elements to the spermatids. The fourth deficiency results in the misalignment of the developing axoneme with the mitochondrial derivatives and is first detectable in the onion nebenkern stage of the spermatid. Finally for two deficiencies the first abnormalties detected were during later stages and comprise a syndrome found in most of the steriles. We attribute this phenotype to the indirect effects of earlier lesions.     

Genome-wide association study identifies candidate genes for male fertility traits in humans

Despite the fact that hundreds of genes are known to affect fertility in animal models, relatively little is known about genes that influence natural fertility in humans. To broadly survey genes contributing to variation in male fertility, we conducted a genome-wide association study (GWAS) of two fertility traits (family size and birth rate) in 269 married men who are members of a founder population of European descent that proscribes contraception and has large family sizes. Associations between ～250,000 autosomal SNPs and the fertility traits were examined. A total of 41 SNPs with p ≤ 1 × 10(-4) for either trait were taken forward to a validation study of 123 ethnically diverse men from Chicago who had previously undergone semen analyses. Nine (22%) of the SNPs associated with reduced fertility in the GWAS were also associated with one or more of the ten measures of reduced sperm quantity and/or function, yielding 27 associations with p values < 0.05 and seven with p values < 0.01 in the validation study. On the basis of 5,000 permutations of our data, the probabilities of observing this many or more small p values were 0.0014 and 5.6 × 10(-4), respectively. Among the nine associated loci, outstanding candidates for male fertility genes include USP8, an essential deubiquitinating enzyme that has a role in acrosome assembly; UBD and EPSTI1, which have potential roles in innate immunity; and LRRC32, which encodes a latent transforming growth factor β (TGF-β) receptor on regulatory T cells. We suggest that mutations in these genes that are more severe may account for some of the unexplained infertility (or subfertility) in the general population.     

Changes in feeding level during early pregnancy affect fertility in gilts

Modified feeding combining the benefits of restricted feeding after ovulation and abundant feeding during implantation in autumn was tested. Three groups of eight gilts were housed with individual feeding stalls and fed 40 MJ per day of a commercial ration. Following insemination gilts were fed 27 MJ per day (LLL) or 54 MJ per day (HHH) for 34 days or 27 MJ per day for 10 days, 54 MJ per day for 7 days followed by 27 MJ per day until day 34 (LHL). Blood for progesterone analysis was collected daily during the week of ovulation and then twice a week until the end of the study. For LH assay, blood was collected from five gilts from each group at 15 min interval for 10 h on the day 15 of pregnancy. Gilts were weighed three times at intervals of 4 weeks. The effect of dietary treatment was significant (P<0.05) on body weight gain from days 0 to 30 of pregnancy, 1201, 287 and 438 g per day for groups HHH, LLL and LHL respectively. The pregnancy rate at day 34 was significantly higher (P<0.005) in HHH-group (100%) compared with LLL (25%) and LHL (38%) although HHH group had significantly lower (P<0.05) progesterone concentration on days 9 and 12. The basal LH level was significantly higher (P<0.01) in HHH group compared to LHL group (mean±S.D.) (0.98±0.22 and 0.60±0.08, respectively). Gilts in HHH group had a significantly higher mean LH concentration (1.18±0.24) than those in group LHL (0.7±0.07) (P<0.05), but not in group LLL (0.93±0.15) (P=0.09). There was a tendency (P=0.058) for amplitude to be higher for gilts in HHH group. The LHL feeding strategy did not provide the benefits anticipated. Instead, it was the HHH feeding strategy that provided a disfinct advantage in pregnancy rate. The mechanism mediating supportive effect of high feeding level on the maintenance of early pregnancy is yet to be determined.