Are The Differntces Bettween Animal And Human Blood Becuse Of Genectic Makeup?

Obesity (Silver Spring). Author manuscript; available in PMC 2009 Jun 29.

Published in last edited course as:

PMCID: PMC2703433

NIHMSID: NIHMS111171

Animate being Models of Factor–Nutrient Interactions

Danielle R. Reed

^aneMonell Chemical Senses Center, Philadelphia, Pennsylvania, USA

Abstract

Nutrient intake of humans is governed by the food's nutritional value and pleasing sense of taste, just besides by other factors such equally food toll and availability, cultural imperatives, and social condition. The biological determinants of human food intake are non easily parsed from these other factors, making them difficult to study against the whirligig aspects of human life in a modern historic period. The study of animals provides a useful culling. Humans have a history of studying animal food intake, for agronomical reasons (e.yard., pigs and cows), and for personal reasons (e.m., dogs and cats), and these practical concerns have been joined with the appreciation that other models tin can teach u.s.a. the principles of behavior, genetics, and nutrition. Thus there is a steady use of the traditional animal models in this type of research, likewise equally growth in the utilise of other systems such as worms and flies. Rats and mice occupy a special niche as animal models for two reasons; first, they share with humans a love of the same types of food, and second, they are the target of a number of well-developed genetic tools. The available genetic tools that make mice a popular model include a well-annotated genome (Mouse Build 37), profiles of RNA expression from many tissues, a various panel of inbred strains, and the power to manipulate genes in the whole animal, including removing a gene only in specific tissues (e.g., Cre-lox system). Mice have been harnessed to find genotypes that contribute to sweet-liking, and other studies are underway to understand how genetic variation might at to the lowest degree partially explain other puzzles of human appetites. Animate being models provide a way to written report the genetic determinants of food selection with experimental rigor and therefore complement homo genetics studies.

The human food environment has changed dramatically in the concluding few hundred years, and some humans now have the broadest range of food choices ever in the history of the species. This increment in the number of available foods has led to a concomitant increment in the number of variables that can determine food selection. These influences include subject characteristics such as sex and age, too equally more than subtle environmental and experiential variables, such as the easy availability of certain foods, and expectations most food created past advert and branding (1,ii). Another contributor to human being nutrient preferences is genetic makeup (iii). Genetic variation among people can lead to differences in taste perception, digestion, and metabolism (four), but how these differences interpret into food option are not well understood. The study of human food intake has been handicapped by the unavoidable problems of authentic measurement of behavior amongst complimentary-living people. It is possible to study human food intake in a controlled environment, merely laboratory measures may not generalize to the globe outside. There are further difficulties in the study of human being behavior because each person has idiosyncratic experiences and beliefs about food. To circumvent these difficulties, animal models have been developed to effort to sympathise how nutrient preferences are formed. These models are desirable because the environment and experiences of an animal tin can be controlled and studied over the life bridge. The theme of this article is how genetic variation influences food choice, and how animal models can exist used to understand the details of genotype–phenotype relationships.

Definition of Genotype

The employ of vocabulary in genetics is changing, and and so it is useful to define what is meant by the term "genotype." The DNA inside the nucleus of cells provides the template to be transcribed into a messenger molecule, which is translated into a particular protein, and this template is stored inside cells in two copies, the paired autosomal chromosomes. A region of transcribed genomic Deoxyribonucleic acid that results in a protein or functional RNA product is called a gene. The DNA sequence of the same gene may differ between people, and these regions are called alleles or polymorphisms. Differences among individuals in DNA sequence may outcome in RNA or proteins that differ in function. The consequences of these changes in function differ depending on the specific gene and the specific allele; some changes are undetectable, whereas others cause a total loss of role of the poly peptide. Even so others create unusual products that interfere with pathways not unremarkably associated with the gene. Also protein coding and other known RNA genes, we have recently learned that some regions of genomic Deoxyribonucleic acid are transcribed but non translated to poly peptide, and are therefore known as noncoding RNA (5). Although the function of these noncoding RNAs is not well understood, they may regulate the expression of protein-coding genes (5). Genotype has two meanings. Start, information technology is used as a general term that refers to the genetic makeup of an individual, and this concept is sometimes chosen "genetic background." Genotype also refers to the specific combination of alleles at a particular location. A mutual method of studying the role of a specific genotype on behavior is to grouping subjects co-ordinate to their particular genotype, and compare the groups for a dependent variable such as nutrient intake. In Figure 1, there is a schematic illustrating an interaction between genotype and the type of food preferred by an individual. A recent (November 2007) query of the largest repository of human genetic variation suggests that there are approximately 11,751,216 polymorphisms in the human genome (come across Electronic Resource one). Each of these polymorphisms is a potential genotypic site worth studying, simply the effect of these millions of alleles and their influence on normal beliefs largely unexplored.

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The bespeak illustrated is the hypothetical effect of detail genotypes on the intake of sure types of food. "Yummy" refers to nutrient that is regarded by nearly people as specially desirable to eat, similar sweet foods or savory meats, whereas "Yucky" refers to food that is regarded by near people as less desirable, like bitter vegetables or unripe fruit. A definition of "genotype" is establish in the text.

The point illustrated is the hypothetical effect of detail genotypes on the intake of certain types of food. "Yummy" refers to food that is regarded by most people every bit peculiarly desirable to eat, similar sweet foods or savory meats, whereas "Yucky" refers to food that is regarded by virtually people as less desirable, like bitter vegetables or unripe fruit. A definition of "genotype" is establish in the text.

Pop Brute Models for Nutrition and Genetics Research

Given the complexity of homo behavior and the complexity of the human genome, the written report of animals provides a useful pick to acquire about genetic influences on nutrient selection. The use of animals to report food intake is a natural extension of long-continuing interest in animal nutrition for practical reasons, like raising animals for apply equally food (e.g., dairy cows), animals that do farm work (east.g., sheepdogs), or every bit companion animals (eastward.m., cats). Therefore the apply of animals for food intake research was a natural outgrowth of the applied study of animal nutrition. I prerequisite for the genetic analysis of behavior is that the brute model should have a well-characterized genome; indeed, the number of model organisms with sequenced genomes is big and continues to grow. Some animals are oftentimes used in food intake inquiry and others are used infrequently, although all models take some advantages. A summary of the number of studies of animals with sequenced genomes and their popularity for study in the genetics of nutrition is shown in Figure 2 (and Electronic Resource 2). Humans are the most studied species, followed by the workhorses of laboratory inquiry (mice and rats), and then animals used for human being food (pigs and cows), and fruit flies. Past comparing the genomes of species as disparate as flies and humans, we accept learned that many genes are conserved in their DNA sequence and their function, and then flies and worms are becoming well-accepted model systems to conduct translational inquiry (6,7,viii).

An external file that holds a picture, illustration, etc. Object name is nihms111171f2.jpg

The results of a query of a database of biomedical research (PubMed, encounter Electronic Resources) using the common species proper noun (e.g., human being or cow), "nutrition" and "genetics" equally keywords. The number of publications returned from the query is shown on the Y-axis. Species are displayed alphabetically on the X-axis. Note the log calibration.

The results of a query of a database of biomedical research (PubMed, see Electronic Resources) using the common species name (e.g., man or cow), "nutrition" and "genetics" every bit keywords. The number of publications returned from the query is shown on the Y-centrality. Species are displayed alphabetically on the X-axis. Annotation the log scale.

Mice and Rats are Well Suited equally Models for Human Nutrient Choice

Rats and mice live commensurably with humans and exploit the trend of humans to store nutrient. The colloquial name for the type of mouse used most ofttimes in laboratories is the "house mouse, " so information technology was a small step from living in our homes and eating our food to living in the laboratory and existence fed by humans. Firm mice are common in almost all places that humans live, and co-ordinate to one source, there is a specific word for "firm mouse" in almost all man dialects (9). Mice and rats also get fat when offered homo junk nutrient (the term "junk nutrient" is employed to describe processed foods high in fatty and calories with added carbohydrate and common salt). Laboratory animals are fed junk food to brand them fatty, a epitome known as the "cafeteria" or "supermarket" nutrition (10). This state of affairs may seem unremarkable, just consider whether a diet of man junk food would make other animals fat, e.thou., cats or snakes. Rats and mice are partially apt models for human being food selection considering they are close to us in nutrient likes and dislikes, and this useful property of mice and rats is apt to be overlooked and unappreciated.

Studies in Mice Can Exploit Extensive Genetic Resources

The mouse is 2d merely to the man in the largess of the genetic toolbox for study of variation and behavior. The mouse was the beginning animate being genome to exist described by comprehensive sequencing (11). Gene targeting methods now permit usa to remove a particular gene or add a particular gene (12). For instance, human genes can be added into the mouse genome, resulting in the "humanization" of taste beliefs then that these mice tin can sense of taste a chemical compound that humans tin can only normal mice cannot (thirteen). New technologies also allow genes to be expressed at a fourth dimension controlled by the experimenter (14) or using other methods, genes can exist deleted just from sure tissues (xv). Another key genetic tool is the cosmos of inbred mice strains, which are genetically identical at each locus. In that location is picayune or no heterozygosity within these inbred lines, then every mouse of a specific strain is genetically identical. If we compare two or more than inbred strains for a trait, variation within a strain will be due to nongenetic factors whereas the departure between strains is ascribed to the genetic differences (16). Therefore the cosmos of more 180 inbred mouse strains, each with a different behavioral repertoire, physiology, and set up of traits is a valuable resource (run across Electronic Resource 3). There is a program to comprehensively examine inbred mouse strains and to appraise their genetic and behavioral differences, and these data are nerveless and organized in the Mouse Phenome Database (17). The availability of these strains and the organization of the data into a comprehensive database is a tool that tin can be used in the study of nutrient pick in mice.

Experimental Approaches to Observe Genes that Influence Behavior such every bit Nutrient Option

Inbred strains of mice can be used to study the genetics of food selection. As a beginning stride in a genetic assay, differences among inbred strains are identified. For case, some inbred strains of mice like saccharin much more other inbred strains (18). Once these strain differences were identified, the details almost which genotypes account for the behavioral differences could be studied by interbreeding the parental strains of mice, and and then testing the offspring. Some regions of DNA inherited from the parents will be shared among mice that drink more saccharin, and these regions will not exist shared by mice that drink less saccharin. These genomic segments incorporate genes and the genetic variation that account for the strain differences. In the example of saccharin preference, nosotros found that regions of chromosome 4 were shared by the sweet-preferring grandchildren (or the F₂, a term used by mouse geneticists to describe the second filial generation) (nineteen). Examining the DNA sequence on chromosome four, a new factor was identified that later proved to be a component of the sweet receptor (20). This arroyo to finding genes that influence a particular trait is called quantitative trait loci (QTL) mapping.

Strain Surveys and QTL Mapping for Nutrient Preference and Intake in Mice

The discovery of the sweet receptor is an example of how the report of behavioral differences among inbred strains can identify genes for a trait that is as seemingly complex as sweet preference. Earlier strain surveys have been done for susceptibility to dietary obesity (21), total caloric intake (22), the preference for taste solutions (23,24,25,26,27,28, 29,thirty,31,32,33), and fat preference (34,35). Because these surveys were useful, larger studies are underway, with a panel of 40 of the most widely used inbred mouse strains. These strains will be assessed for physiological, metabolic, neurological, and behavioral traits. Strain surveys can exist followed past QTL mapping studies designed to find genes involved in nutrient choice, such as the overconsumption of high-saccharide or high-fat diets (36,37). I unexplored expanse of enquiry using these methods is to focus on the genetic control of the preference for compounds found in fruits and vegetables, e.m., malic acid in apples and sinigrin in kale (38). This arroyo may agree clues to the uneven consumption of fruits and vegetables amidst members of the homo population.

Beyond Single Gene Effects

The genetic locus described before, which influenced saccharin preference in mice, had a large effect on mouse sweet preference. It is joined past many other genes of smaller effect to determine this trait, and these remaining genes are currently unknown. How to discover genes with smaller effect sizes is one of the main challenges facing geneticists. In addition to the effects of single locus and its alleles, there are gene–gene interactions and epigenetic influences on food selection. At the moment, in that location is no way to estimate the number of genes that participate straight in a behavior as circuitous as food option, just if nosotros look at a simpler instance, body weight, a recent genetic survey indicates that upwards to 6,000 genes may be capable of influencing how much a mouse weighs (D.R. Reed et al., submitted). Likewise, at that place is currently no fashion to estimate the number of gene–gene interactions for food selection. Even so, because they are function of a homeostatic biological arrangement (finding and metabolizing food for energy), genes and their alleles are likely to interact with others in their item pathway. Considering little is known about gene–gene interactions and food option, we tin once again turn to body weight to provide clues, and from this type of data nosotros learn that over 30% of the genetic variance in torso weight is due to gene–gene (as well chosen epistatic) interactions (39). Finally, epigenetic influences have been studied in animate being models. The word "epigenetics" has several definitions, but we use it here to hateful changes in cistron expression that are stable and can be transmitted during mitosis and meiosis. Epigenetics is specially relevant because genes involved in the perception of gustatory modality and scent, likewise every bit those involved in food metabolism, are susceptible to these furnishings (40,41). Taken together, the number of genes, their interactions, and modifications of cistron expression through experience will all be present in humans and in fauna models. However by controlling the breeding and surround, these influences can be assessed more easily in animal models than would be possible when studying humans.

Creature Models of Human Food Selection

As humans, nosotros choose among a variety of foods: apples or cake, hot dogs or tofu, butter or margarine, and there are more choices available now than ever before in our history. In the face of all the choices available, there is a superficial uniformity of human food likes and dislikes (e.g., ice cream and pizza), just if nosotros look deeper we encounter that individuals differ, and not everyone has a sweet molar (42) or prefers high-fat foods (43). The determinants of what people similar and what people eat are necessarily complex, just i of the influences is the genetic makeup of the field of study. Every bit an illustration, recent piece of work has determined that alleles in taste genes such equally those for bitter perception can influence taste perception, food preference, and choice in humans (44,45,46,47). If we can empathise why people differ in food choice, we have the capability to harness this information to amend human health (48). Although animals will never perfectly recapitulate the behavioral repertoire of humans, they do provide several advantages in the study of nutrient choice, such as the ability to absolutely control the nutrient choices available, to measure food intake accurately and for long periods of time, to control the creature'south experience and environment, and to dispense their genomes in means that are not possible in humans. Therefore ane pathway to understand human food selection and its genetic control is through the use of fauna models.

Acknowledgments

Alexander A. Bachmanov, Julie A. Mennella, Ian Tarr, and Michael Thousand. Tordoff provided helpful comments and discussion. This work was supported past a grant from the National Institutes of Health (R01 DK58797). This publication was sponsored by the National Cancer Constitute (NCI) to present the talks from the "Factor–Diet and Gene–Physical Activity Interactions in the Etiology of Obesity" workshop held on 24–25 September 2007. The opinions or assertions independent herein are the views of the authors and are not to be considered equally official or reflecting the views of the National Institutes of Health.

Footnotes

Disclosure

The author alleged no conflict of involvement.

Electronic Resources

To assess the number of known human polymorphisms, a query was made of this database on 8 Nov 2007 (Build 128): http://world wide web.ncbi.nlm.nih.gov/sites/entrez?db=snp.
To assess the number of biomedical research papers published for each animal species, a query was made of this database on 9 August 2008: http://www.ncbi.nlm.nih.gov/sites/entrezPubMed.
The number of inbred strains listed in the online catalogue at the Jackson Laboratory was counted on 8 November 2008: www.jax.org.

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