The relation of genes to nutrition is obviously a two-way relationship. Thus, not only genes profoundly affect nutrient metabolism but also, in turn, nutrients regulate gene expression. Before discussing their interrelationship, a brief review of gene structure and expression follows.
A. Genetic Structure
Genetic information is encoded in the sequence of a linear polymer of purine and pyrimidine bases termed deoxyribonucleic acid (DNA). This genetic message codes for the building and operation of the human body. The message is written in an alphabet that uses only four letters: A, C, G, T. Each of the letters represents one of the four bases that are chemical building blocks of DNA. A stands for adenine, C for cytosine, G for guanine, and T for thymine. The nucleotides, which spell out the genetic message, are arranged in a linear sequence in the double-stranded helical DNA molecule. The two
strands of DNA are complementary copies of each other to form two antiparallel polynucleotide strands that are twisted into a double helix. The nucleotides on one strand pair with the complementary nucleotides on the other strand; adenine is paired with thymine and guanine is paired with cytosine. The genetic message is read not as a single letter but rather it is grouped into a three-letter word. Each three-letter word is called a codon, which specifies one of the 20 possible amino acids that are the building blocks for all proteins.
Human DNA is estimated to consist of about 3 billion base pairs per haploid genome. Because humans are diploid organisms two copies of DNA exist. Therefore, the actual number of base pairs is 6 billion. DNA strands are covered with histone and nonhistone proteins that allow them to be supercoiled and twisted into compact structures termed chromosomes. There are 23 pairs of chromosomes per somatic nucleus: 22 pairs of autosomes numbered by descending size and one pair of sex chromosomes (XX, female; XY, male). These chromosomes are located in the nucleus of the cell.
During mitosis the chromosomes are unwound; the DNA helix is split apart and copied. Each replicated strand creates a complementary copy of the original double helix, allowing the transmission of a complete set of genetic information into each daughter cell. In meiosis, a reduction division of genetic information occurs. Homologous chromosomes are paired, duplicated, and separated. Only one member of each pair of chromosomes is allowed to segregate into a gamete. Thus a diploid germ cell gives rise to a haploid sperm or egg that contains an assortment of one of each of the 23 pairs of homologous chromosomes in the parental cell. During fertilization, sperm and egg unite to create a zygote with a complete set of 46 chromosomes.
In its simplest form, a gene is a segment of a DNA molecule containing the specific code for the amino acid sequence of a polypeptide chain and the regulatory sequence necessary for expression. A gene product is usually a protein, but can occasionally consist of a ribonucleic acid (RNA) that is not translated. The human genome contains enough base pairs to make a million average-size proteins, but there are only about 30,000–60,000 genes. Genes are composed of coding spaces (exons) intercepted by noncoding sequences (introns). Only about 10% of the entire human genome is composed of exons.
Gene expression refers to the process whereby a gene gives rise to its product, namely, its unique polypeptide. It consists of three phases: (a) transcription; (b) translation; and (c) posttranslational modification. This is a highly controlled process.
Transcription is the process whereby messenger (m) RNA is synthesized in the nucleus using a strand of the double helix DNA as a template. The mRNA and other RNAs are then transported from the nucleus to the cytoplasm where the RNA sequence is decoded or translated to determine the sequence of amino acids in the protein being synthesized. The process of translation occurs in ribosomes. Translation involves transfer (t) RNAs, which provide the molecular link between the coded base sequence of the mRNA and the amino acid sequence of the protein. Many proteins undergo extensive posttranslational modifications. The polypeptide chain that is the primary translation product is folded and bonded into a specific three-dimensional structure that is determined by the amino acid sequence itself. Two or more polypeptide chains, products of the same gene or of different genes, may combine to form a single, mature protein complex. Other modifications may involve cleavage of the protein to remove specific amino-terminal sequences, addition of phosphate, or various amino acid modifications.
Fundamentals of Nutrition 11
B. Effects of Nutrients on Gene Expression
The formation of purine and pyrimidine bases in the DNA and RNA require the participation of folic acid, vitamin B12, and other nutrients. Mechanisms that regulate gene expression play a critical role in the function of genes. The transcription of genes is controlled by a group of DNA-binding proteins (transcription factors) that determine which regions of the DNA are to be transcribed. Nutrients bind to these proteins to form nutrient–protein complexes that target small (8–15 nucleotides) DNA regions.
Transcription control is exerted by that portion of the DNA, called the promoter region, to which transcription factors bind. Several nutrients have a role in the transcription process. In many instances, the specific DNA-binding protein contains zinc. Zinc binds to histidine and cysteine residues in the linear portions of these proteins. This binding results in the formation of a loop ‘‘finger’’ in the protein that permits the folded region to bind DNA sequences in the promotion region. Thus, without zinc the transcriptor factors cannot bind and stimulate transcription of the gene.
Nutrients such as vitamins A and D and some hormones have their effects on the expression of specific genes because they bind to these zinc fingers that in turn bind to specific DNA sequences.
The gene remains turned-on, directing the synthesis of more protein until some-thing causes it to be switched off. A common mechanism of gene regulation is negative feedback. The presence of a large amount of the protein product from the gene can interfere with the binding of transcription factors (inducers) that originally turned the gene on. When this happens, the gene is turned off. There are several nutrients that also control the transcription or translation processes. For example, dietary cholesterol exerts an inhibitory effect on the transcription of the gene for hydroxymethylglutaryl CoA reductase, a key enzyme in cholesterol synthesis. Alterations in the diet have striking effects on the expression of a number of genes. Polyunsaturated fatty acids regulate the expression of many genes that are involved in lipid metabolism. Vitamin A, in the form of retinoic acid, modulates the expression of a variety of genes that encode for many types of proteins, including growth factors, transcription factors, and enzymes. Copper appears to stimulate the transcription of superoxide dismutase gene.
Nutrients and hormones may affect the synthesis of specific proteins by regulating several steps in the translation and posttranslational processing. For example, cellular iron concentration directly affects the translation and stability of mRNA for ferritin and transferrin receptor proteins. The synthesis of proteins in the translation process depends on the availability of constituent amino acids and energy. The changes required in the posttranslational process are dependent on the availability of vitamins K and C and several other nutrients. Thus, nutrients serve as regulators of the gene expression.
C. Genetic Variation and Nutrition
Genetic predisposition is known to contribute to variations in the incidence and prevalence of chronic nutritional diseases among individuals, families, and nations.
The lifetime risk of non-insulin-dependent diabetes mellitus is about 40% in children with one diabetic parent. Studies in the United States have shown that 50% of the variance in plasma cholesterol concentration is genetically determined. Also, 30% to 60% of the variations in blood pressure is genetically determined. Studies in coronary artery disease suggest 15% variance in the U.K., whereas it is 51% in the Hawaiian
population, indicating significant differences between populations. The variance in bone density is genetically determined. Osteoporosis is a metabolic bone disease with strong genetic predisposition.
Mutations in the genes are known to cause several disorders. Some of the disorders can be treated nutritionally. Well known are the single-gene disorders that are expressed as phenylketonuria, lactose intolerance, and celiac disease. A diet restricted in phenyl-alanine largely circumvents the neurological damage in classic PKU. Lactose intolerance can be managed by dietary lactose exclusion, and celiac disease can be managed by dietary exclusion of gluten-containing foods.
In several metabolic disorders there is altered binding of a cofactor (often a vitamin) to the mutant enzyme. It may be possible to provide a large excess of the cofactor and overcome the altered binding ability to the enzyme impaired by mutation.
Examples are biotin in some types of multiple carboxylase deficiencies, and vitamin B1 with some forms of lactic acidosis. In fact, the vitamin-responsive inborn errors are among the most successfully treated of all genetic diseases. The vitamins used are remarkably nontoxic, generally allowing the safe administration of amounts several times greater than those required for normal nutrition.
PHENYLKETONURIA—A CASE
A 41/2-year-old girl was admitted to a hospital because of retardation of development and possible neurological problem. She began to sit up at 1 year of age and could use a few words.
She learned to walk at the age of 2 years but did not develop further in language ability and gradually lost the few words she had acquired. She was stiff-legged and hypertonic. She had been hyperactive and noisy, frequently banging her head on the wall, slapping her face, voluntarily falling down, biting her tongue, and screaming. There had been no episodes of unconsciousness or convulsions.
Physical examination revealed an above normal weight child with extensive red scaling dermatitis of the forearm and legs and the characteristic odor of phenylacetic acid. She was extremely hyperactive and her attention span was short. She grated her teeth together nearly continually and frequently uttered unrecognizable cries but no words. She responded to attention but did not play with toys or feed herself.
Neurological examination showed that her muscular tone was somewhat increased generally and reflexes were hyperactive. No objective evidence of sensory impairment was apparent. Electroencephalogram showed no seizure discharges. The usual blood and urine examinations were normal. Fasting serum phenylalanine was 42 mg/dl (normal 0.5–2 mg/dl).
Acidified urine developed green color on addition of ferric chloride (positive for PKU).
She was placed on artificial formula diet containing all of the amino acids in adequate amounts except phenylalanine. Her urinary phenylalanine fell promptly from 14 to about 3 mg/
mg creatinine, and serum phenylalanine came down to 20 mg/dl. During the next 2 weeks, her urinary ketoacids and serum phenylalanine continued to fall but her weight also declined.
Phenylalanine in an oral dose of 90 mg/day was started on the 13th day, but the dose was increased to 500 mg/day in order for growth to resume. During the first few weeks of her dietary regimen, she showed some improvements in behavior. There was moderate decrease in hyperactivity and increase in attention span. She also engaged in activities of her own choosing for periods as long as 15 to 20 min. The dermatitis disappeared after the first week of the diet and her skin remained clear during her stay in the hospital. She was discharged after 13 weeks on this diet.
Fundamentals of Nutrition 13
On a natural home diet, serum phenylalanine rose to 30 mg/dl and phenylpyruvic aciduria and dermatitis recurred. She continued to grow normally during the following 22 months.
This case of PKU was one of the first to be investigated for the possible salutary effect of phenylalanine restriction in the diet. PKU is characterized by reduced activity of phenylalanine hydroxylase (less than 2% of normal activity). The disease manifests between the third and sixth months of age and is characterized by mental retardation, abnormal electroencephalogram, dermatitis, hyperactivity, and reduced attention span. Although the exact pathogenesis of mental retardation in PKU is unknown, the accumulation of phenylalanine or its metabolites up to 5 to 10 times normal levels, or the deficiency of tyrosine or its products, or a combination of the two, cause irreversible damage to the central nervous system. High phenylalanine appears to interfere with decarboxylation of dihydroxyphenylalanine (DOPA) and 5-hydroxy tryptophan, which could impair neurotransmitter synthesis. This effect causes hyperactivity, short attention span, and dermatitis, which can be reversed by reducing serum phenylalanine levels, as was seen with this case.
In PKU, phenylalanine levels are elevated and tyrosine levels tend to be depressed. The rational therapy, therefore, is to reduce phenylalanine to just enough for growth requirements and increase tyrosine intake to the level required for growth. Tyrosine becomes a dietary essential amino acid for patients with PKU. The estimated requirement for infants less than 6 months of age is 140 mg/kg of body weight/day. This drops with time to 70 mg at 2 years and about 20 mg/kg of body weight/day with maturity. The diet should be started as soon as possible, preferably by the time the child is 3 weeks old. The diet’s effectiveness is remarkable.
In almost every case, it can prevent the devastating array of symptoms described above.
DEFINITIONS
Allele An alternative form of a gene that may occupy a given locus.
Autosomes All chromosomes other than the X and Y chromosomes.
Chromosome A highly ordered structure composed of DNA and proteins that carries the genetic information. In humans, there are 46 chromosomes ordered in pairs.
Dominant allele An allele that is expressed when present at only a single copy (i.e., it dominates over the other allele present).
Gene A sequence of nucleotides that represent a functional unit of inheritance.
Heterozygous The two alleles are different.
Homozygous Both alleles at a locus are the same.
Locus Position of a gene on a chromosome.
Mutation A permanent heritable change in the sequence of DNA.
Recessive allele An allele that is only expressed when homozygous.
X-Linkage The distinctive inheritance pattern of alleles at loci on the X chromosome.
REFERENCES
A.I. Arieff and R.A. Defronzo (Eds.): Fluid, Electrolytes and Acid–Base Disorder. Churchill Livingstone, New York, 1985.
F.M. Atkins and D.D. Metcalf: The diagnosis and treatment of food allergy. Annu. Rev. Nutr. 4: 233, 1984.
C.D. Berdanier: Nutrient–gene interaction. Nutr. Today 35 (1): 8, 2000.
G.F. Cahill, Jr.: Starvation in man. Clin. Endocrinol. Metab. 5: 397, 1976.
N. Clark: How to pack a meatless diet full of nutrients. Physician Sports Med. 19: 31, 1991.
S.D. Clark and S. Abraham: Gene expression: Nutrient control of pre- and post translational events.
FASEB J. 6: 3146, 1992.
L.J. Filer: Recommended dietary allowances: How did we get where we are? Nutr. Today 26 (5): 25, 1991.
Food and Nutrition Board of the National Academy of Sciences: Recommended Daily Allowances, 10th ed. National Academy of Sciences, Washington, DC, 1989.
E.E. Goldberger: Water: Electrolyte and Acid–Base Syndrome, 4th ed. Lea and Febiger, Philadelphia, 1975.
F. Guttler: Hyperphenylalaninemia: Diagnosis and classification of the various types of phenylalanine hydroxylase deficiency in childhood. Acta Paediatr. Scand. Suppl. 280: 7, 1980.
R.G. Hansen: An index of food quality. Nutr. Rev. 32: 1, 1973.
A.E. Harper: Evolution of recommended dietary allowances—New direction? Annu. Rev. Nutr. 7:
509, 1989.
S. M. Kleiner. Water: An essential but overlooked nutrient. J. Amer. Diet. Assoc. 99: 200, 1999.
L.G. Leksell and M. Rundgren: Regulation of water intake. Annu. Rev. Nutr. 2: 73, 1982.
C.A. Monturo: Enteral access device selection. Nutr. Clin. Pract 5: 207, 1990.
J.M. Saavedra and J.A. Perman: Current concepts in lactose malabsorption. Annu. Rev. Nutr. 9: 475, 1989.
H.A. Sampson and A.W. Burks: Mechanisms of food allergy. Annu. Rev. Nutr. 16: 161, 1996.
N.S. Scrimshaw and V.R. Young: The requirements of human nutrition. Sci. Am. 235: 50, 1976.
L. Share and J.R. Claybaugh: Regulation of body fluids. Annu. Rev. Physiol. 34: 235, 1972.
G.F. Sheldon, R.P. Scott, and R. Sanders: Hepatic dysfunction during TPN. Arch. Surg. 113: 504, 1978.
S.G. Shipley: Glutamine in total parenteral nutrition. Nutr. Today. 31 (2): 74, 1996.
H. Silberman: Parenteral and Enteral Nutrition 2nd ed. Appleton & Lange, Norwalk, CT, 1989.
A.P. Simopoulos: Genetic variation and nutrition. Nutrition Today 30 (4): 157, 1995.
N.W. Souba. Nutritional support. N. Engl. J. Med. 136: 41, 1997.
T.P. Stein: Why measure the respiratory quotient of patients in total parenteral nutrition? J. Am. Coll.
Nutr. 4: 501, 1985.
T. Vokes: Water homeostasis. Annu. Rev. Nutr. 7: 383, 1987.
Case Bibliography
M.D. Armstrong and F.H. Tyler: Studies in Phenylketonuria. I. Restricted phenylalanine intake in phenylketonuria. J. Clin. Invest. 34: 565, 1955.
Clinical nutrition cases. The dietary treatment of phenylketonuria. Nutr. Rev. 41: 11, 1983.
O. de Freitas, C. Izumi, M.G. Lara and L.J. Greene: New approaches to the treatment of phenylketonuria. Nutr. Rev. 57: 65, 1999.
Fundamentals of Nutrition 15