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Department of Kinesiology, College of Health and Human Development, The Pennsylvania State University, University Park, PA 16802
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONGenetic diversity in human...Some sources of genetic...Practical implications of...Comparative genomicsREFERENCES |
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KEY WORDS: • biochemical individuality • euphenics • genetic polymorphisms • genomics • molecular evolution
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONGenetic diversity in human...Some sources of genetic...Practical implications of...Comparative genomicsREFERENCES |
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-chain
found in fetal hemoglobin as a replacement for the 
-chain variant
that is protective against malaria in single dose but produces sickle
cell anemia in double dose (Cerami and Washington 1974
).
Regulation of gene expression will lead eventually to control of tissue
differentiation and regeneration of organs from somatic cells.
The hemoglobin variants are among many genes (Woolf 1996
) initially characterized as defective, yet proving
beneficial in certain environmental settings, undercutting a major
thesis of the earlier eugenic movement (Eckhardt 1992
).
Genetic research also holds great promise for progress in another
realm, i.e., euphenics. First conceived in contradistinction to
eugenics, the euphenic approach to human health holds that knowledge of
individual nucleotide sequences can be used to optimize elements of
each person’s lifestyle. Strategies of this sort have been employed to
a limited degree for several decades with the objective of maximizing
the human potential of patients with rare genotypes, such as those
underlying the expression of phenylketonuria (Scriver et al. 1996
). It is now evident that significant improvements in human
health can be made by nutritional scientists using knowledge about the
human genome but emphasizing manipulation of environmental factors,
particularly dietary elements.
As amply documented by other contributions to this symposium, some nutritionists already are working at the cutting edge of genetic research, in a conceptual framework that sees our expanding knowledge of human diversity as broadening the concept of normality rather than as documenting an expanded array of infirmities. In reading these papers, many other researchers in the field of nutrition science may come to realize that they are in the same metaphorical position as the character in Molière’s (1670) classic French farce "Le Bourgeois Gentilhomme" who exclaims "Good Heavens! For more than forty years I have been speaking prose without knowing it." Although not generally realized, the concept of nutritional (or biochemical) individuality has been virtually coeval with the evolution of genetics as a field of science, and contributions to conceptual progress have been made by nutritionists and physicians as well as by geneticists.
The primary purpose of this paper is to provide a general conceptual framework for the further integration of genetic and nutritional research, first by making explicit some of the important steps that already have been taken toward this end, and then by making suggestions about future prospects. Several key questions are posed here and answered in the course of the paper:
1. What is the extent of gene-based diversity in nutritional requirements?
2. Why do these levels of diversity exist?
3. What are the practical implications of nutritional individuality—both in general, and in the specific context of understanding the basis of biological variation in connection with obesity, diabetes and cardiovascular disease?
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Genetic diversity in human nutritional requirements |
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TOPABSTRACTINTRODUCTIONGenetic diversity in human...Some sources of genetic...Practical implications of...Comparative genomicsREFERENCES |
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expressed the view
that alkaptonuria was "an alternative form of metabolism" belonging
to a category "... of variations of chemical behavior which are
probably present everywhere in minor degrees and just that as no two
individuals of a species are absolutely identical in bodily structure
neither are their chemical processes carried out on exactly the same
lines."
Half a century later, this same theme was picked up by Williams (1956)
in a book titled Biochemical Individuality.
This work was published just three years after the discovery by
Watson and Crick (1953)
of the double helical structure
of DNA, and several years before the work of
Livingstone (1957)
and 1958
and others confirmed the
hypothesis of Haldane (1949)
concerning the importance
of balanced polymorphisms for the maintenance of genetic variation. In
a premolecular era, Williams could not draw upon the wealth of
knowledge now available; he had to posit it. His thesis was as follows:
"Individuality in nutritional needs is the basis for the
genetotrophic approach and for the belief that nutrition applied with
due concern for individual genetic variations, which may be large,
offers the solution to many baffling health problems"
(Williams, 1956
). He noted that the most commonly
accepted line of demarcation between "normal" and "abnormal" in
biological work is the 95% level, with any individual lying outside
this limit being regarded as a deviate. Yet a paradox arises when
multiple requirements exist (as in the case of a human diet requiring
various vitamins, minerals, essential amino acids and so on). By the
stated criterion of normality, if 100 uncorrelated attributes are
considered jointly, the probability of meeting all of the criteria
together is < 1% (0.95100 = 0.0059). This
realization was the basis for Williams’ "... hypothesis that
practically every human being is a deviate in some
respect ... with an important bearing upon the susceptibility
of the individual ... to disease later in life."
(Williams 1956
). The data that Williams had to support
these powerful ideas were limited to anatomical variants (in the form
and placement of the stomach and other internal organs) and physiologic
observations (including inorganic and organic composition of the blood
concentrations of vitamins in it as well as variations in salivary
amino acid patterns), many of which showed sample ranges exceeding 50%
of the mean values.
We are now in a strikingly different era of knowledge. The human genome
has just been completely sequenced. Approximately 3 billion nucleotides
are distributed sequentially among 23 pairs of chromosomes in the
nucleus of each body cell. Current estimates are that this mass of
material holds 
80,000 operational genes as well as large stretches
of unknown function. The activities of 8000 of these loci already
are known, and the race is on to understand the rest as rapidly as
possible. In the nutritional realm, progress has been swift. We already
are aware of inherited variants affecting metabolism of the sugar
fructose (producing disorders known as fructosuria and fructose
intolerance), protein components such as the amino acid phenylalanine
(leading to phenylketonuria), and fats (resulting in
hypobetalipoproteinemia, associated with lower than average risk of
cardiovascular disease but higher risk for several cancers as well as
pulmonary and gastrointestinal disorders; and related conditions that
result in vitamin E deficiency). Variants of this sort are so common
that The Journal of Nutrition now includes a category of
articles titled Nutrient-Gene Expression; from January through
April 2000, four such papers have appeared (Bonnet et al. 2000
, Kudo et al. 2000
, Metón et al. 2000
, Sciaudone et al. 2000
).
The latest nutritional guidelines (Murphy 2001
)
incorporate recommended daily allowances for some 30 nutrients. If the
metabolic pathway influencing nutritional requirements for each of
these nutrients was affected independently by only two alternative
alleles at a single genetic locus (almost certainly a substantial
underestimate of systemic complexity), then we should expect that the
number of alternative genotypes would be 330 or
in excess of 200 trillion; three alternative alleles would raise the
level of potential diversity to 6 30, i.e., over
a billion times higher. The advancing wave of knowledge about the human
genome has confirmed the idea that each of us must be genetically
unique in our nutritional needs.
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Some sources of genetic influence on human nutritional requirements |
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TOPABSTRACTINTRODUCTIONGenetic diversity in human...Some sources of genetic...Practical implications of...Comparative genomicsREFERENCES |
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). Jukes and King (1975)
proposed that this loss occurred as a result of neutral evolutionary
change in which sporadically arising mutations were fixed by genetic
drift in some vertebrate populations but not in others, as long as
adequate dietary sources of the compound were available continuously. A
question might be raised as to whether changes of this sort are
strictly neutral because the loss of an unused metabolic pathway can
confer a minute gain in energy efficiency, but that is too complex a
question to pursue here.
Evidence that inherited influences on nutritional requirements have
entered the gene pool of our species at very different times is
supported by the hemoglobin alleles. The most widely known expression
of these inherited variants is sickle cell disease, which has a genetic
trigger and broad systemic ramifications, some with nutritional
implications. Compared with ascorbic acid, this marks a relatively new
metabolic change. The underlying -chain mutation became widespread
only 10,000 years ago; its pattern of distribution was attributable
chiefly to the origin of swidden horticulture in Africa
(Livingstone 1957
and 1958
), which replaced tropical
forests with clearings and altered the ecological balance in other ways
that promote the spread of malarial parasites by mosquito vectors. The
gene that causes sickle cell anemia in the homozygous condition confers
resistance to malaria in the heterozygous state, so that two
alternative alleles are retained in some populations as the result of
opposed selective forces. This is the classic example of balanced
polymorphism predicted by Haldane (1949)
and confirmed
by the work of Livingstone and others.
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Practical implications of nutritional individuality |
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TOPABSTRACTINTRODUCTIONGenetic diversity in human...Some sources of genetic...Practical implications of...Comparative genomicsREFERENCES |
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noted that in patients with sickle cell anemia, RBC
membranes are more oxidatively stressed than are those of normal cells.
Reportedly, sickle cells spontaneously generate more reactive oxygen
variants, including hydrogen peroxide, superoxide anions and hydroxy
radicals. Of 18 patients with sickle cell anemia, 50% had leukocyte
ascorbic acid levels sufficiently low to be considered consistent with
vitamin C deficiency. Given adequate dietary intakes of vitamin C in
these patients, utilization of vitamin C must have increased,
suggesting that alteration of a single nucleotide base is sufficient to
trigger an elevated vitamin requirement. The various metabolic consequences of hemoglobin variants also illustrate pleiotropy, the technical term for the concept that genes have multiple phenotypic effects. This complication commonly is ignored when we speak of a gene "for" some disease. Thus the allele coding for the hemoglobin S variant commonly is referred to as the "gene for sickle cell anemia," whereas it really is a gene that confers malarial resistance in single dose and has increased in frequency for this reason.
Above all, the hemoglobin variants illustrate that multiple genetic
alternatives at polymorphic frequencies (by common convention, >1%)
signal functional significance, although under the influence of neutral
theory (Kimura 1983
) it has been convenient for several
decades to ignore this point. Genes are there because they do things,
and as a corollary, alternative alleles are there because there is a
value to performing common functions in slightly different ways (e.g.,
enzymes with different pH or temperature optima) that are made possible
by sections of DNA that have slightly different base sequences
(Gillespie 1991
, Eckhardt 2000
).
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Comparative genomics |
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TOPABSTRACTINTRODUCTIONGenetic diversity in human...Some sources of genetic...Practical implications of...Comparative genomicsREFERENCES |
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, when sequencing of
the human genome first began to be contemplated seriously around 1985,
the project seemed both logistically unlikely and informationally
unpromising. In the context of the 3 billion DNA bases comprising the
human genome, technological ability to sequence only 300 bases at a
time seemed daunting. Similarly, with as much as 95% of the human
genome commonly labeled "junk DNA," believed not to either encode
for proteins or to hold regulatory information, it seemed that much
work would be required for little scientific or practical reward.
Nevertheless, investigators pressed on, passing the following
milestones: In 1995 sequencing of the first bacterial genome, that of
Haemophilus influenzae, with 1.8 million bases (1.8 Mb) was
completed (Fleischmann et al. 1995
). In 1996,
collaboration among laboratories around the world produced the sequence
of the first eukaryote, the yeast Saccharomyces cerevisiae
with a genome of 12 Mb (Clayton et al. 1997
). The next
year saw completion of sequencing for the first multicellular organism,
the roundworm Caenorhabditis elegans, with a genome of 97 Mb
(The C. elegans Sequencing Consortium 1998
).
In the week of 24 March, 2000 the Drosophila genome sequence
was published in the form of three largely complementary papers
(Adams et al. 2000
, Myers et al. 2000
,
Rubin et al. 2000
). In the week of June 26, 2000 the
human genome sequence was accomplished.
Each genome sequenced represented a gain in size over ones done
previously, yet some of the greatest implications for human health lie
in the commonalities rather than in the differences. About 30% of
Drosophila genes have orthologs (proteins in different
organisms that show significant sequence similarities over 80% of
their lengths) in the worm Caenorhabditis. Nearly 20% of
fly proteins have orthologs in both worms and yeast. To date,
Drosophila shows orthologs to 177 of 289 human genes that
influence diseases. In the context of this symposium, note that there
are Drosophila homologs for insulin, somatostatin,
vasopressin, leutotropin and a number of hormones. The future of
nutritional studies will in all likelihood be tied to the study of such
loci, with data on their variations supplementing family histories and
baseline physiologic data already available. The results will be
unbelievably rewarding (Sander 2000
).
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONGenetic diversity in human...Some sources of genetic...Practical implications of...Comparative genomicsREFERENCES |
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1.
Adams M. D., et al The genome sequence of Drosophila melanogaster. Science (Washington, DC) 2000;287:2185-2195
2.
Bonnet M., Leroux C., Faulconnier Y., Hocquette J.-F., Martin P., Chilliard Y. Lipoprotein lipase activity and mRNA are up-regulated by refeeding in adipose tissue and cardiac muscle of sheep. J. Nutr. 2000;130:749-756
3. Cerami A., Washington E. Sickle Cell Anemia 1974:27 The Third Press New York, NY.
4. Clayton R. A., White O., Ketchum K. A., Venter J. C. The first genome from the third domain of life. Nature (Lond.) 1997;387:459-462[Medline]
5. Eckhardt R. B. Human quantitative genetics: a century of research. Seth P. K. Seth S. eds. Human Genetics 1992:21-34 Omega Scientific Publishers New Delhi, India.
6. Eckhardt R. B. Human Paleobiology 2000 Cambridge University Press Cambridge, UK.
7.
Fleischmann R. D. et al. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science (Washington, DC) 1995;269:496-512
8. Garrod A. E. The incidence of alkaptonuria: a study in chemical individuality. Lancet 1902;11:1616-1620
9. Gillespie J. H. The Causes of Molecular Evolution 1991 Oxford University Press New York, NY.
10. Haldane J.B.S. The rate of mutation of human genes 1949 Proc. 15th Int. Congr. Genet pp. 267–273. Stockholm, Sweden.
11. Jukes T. H. Nutrition science from vitamins to molecular biology. Annu. Rev. Nutr. 1990;10:1-20[Medline]
12. Jukes T. H., King J. L. Evolutionary loss of ascorbic acid synthesizing ability. J. Hum. Evol. 1975;4:85-88
13. Kimura M. The Neutral Allele Theory of Molecular Evolution 1983 Cambridge University Press Cambridge.
14.
Kudo H., Doi Y., Nishino T., Nara S., Hamasaki K., Fujimoto S. Dietary zinc deficiency decreases glutathione S-transferase expression in the rat olfactory epithelium. J. Nutr. 2000;130:38-44
15.
Lander E. S., Weinberg R. A. Genomics: journey to the center of biology. Science (Washington, DC) 2000;287:1777-1782
16. Livingstone F. B. Sickling and malaria. Br. Med. J. 1957;1:762-763
17. Livingstone F. B. Anthropological implications of sickle-cell gene distribution in West Africa. Am. Anthropol. 1958;60:553-562
18.
Metón I., Caseras A., Cantó E., Fernández F., Baanante I. V. Liver insulin-like growth factor-I mRNA is not affected by diet composition or ration size but shows diurnal variations in regularly fed gilthead sea bream (Sparus aurata). J. Nutr. 2000;130:757-760
19.
Murphy S. P. How consideration of population variance and individuality affects our understanding of nutritional requirements in human health and disease. J. Nutr. 2001;131:361S-365S
20.
Myers E. W. A whole-genome assembly of Drosophila. Science (Washington, DC) 2000;287:2196-2204
21.
Rubin G. M., et al Comparative genomics of the eukaryotes. Science (Washington, DC) 2000;287:2204-2218
22.
Sander C. Genomic medicine and the future of health care. Science (Washington, DC) 2000;287:1977-1978
23. Sauberlich H. E. Pharmacology of vitamin C. Annu. Rev. Nutr. 1994;14:371-391[Medline]
24.
Sciaudone M. P., Chattopadhyay S., Freake H. C. Chelation of zinc amplifies induction of growth hormone mRNA levels in cultured rat pituitary tumor cells. J. Nutr. 2000;130:158-163
25. Scriver C. R., Byck S., Prevost L., Hoang L., the PAH Mutation Analysis Consortium The phenylalanine hydroxylase locus: a marker for the history of phenylketonuria and human genetic diversity. Chadwick D. Cardew G. eds. Variation in the Human Genome 1996:73-96 John Wiley & Sons New York, NY.
26.
The C. elegans Sequencing Consortium Genome sequence of the nematode C. elegans: a platform for investigating biology. Science (Washington, DC) 1998;282:2012-2018
27. Watson J. D., Crick F.H.C. Molecular structure of nucleic acids. Nature (Lond.) 1953;171:737-738[Medline]
28. Williams R. J. Biochemical Individuality 1956 John Wiley & Sons New York, NY.
29. Woolf L. I. The heterozygote advantage of phenylketonuria. American Journal of Human Genetics 1996;38:628-630
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