THE BASICS OF NUTRIGENOMICS

The heredity of traits is an essential phenomenon of biology: parents pass on some of their traits to their
offspring.
The material that contains and transfers the heritable information from one generation to the next is
deoxyribonucleic acid (DNA).
It consists of two very long complimentary polymers forming a helix structure, held together by hydrogen
bonds between the monomers.
There are four monomer molecules (nucleotides), each having a complementary partner: Adenine pairs with
thymine and guanine pairs with cytosine, typically abbreviated as A,T, G, C, respectively.
The biological information is encoded by the highly specific order of nucleotides.
A specific base at a specific position transfers information that is equal to the information of two binary bits.
In order to encode and transfer the complete biological information of a human, billions of nucleotides are
required.
The human genome: The reference set of DNA of the human genome consists of 3∗109 (three billion)
nucleotides. These are distributed over 23 polymers, called chromosomes. As humans inherit one set of
chromosomes from each of their parents, the number of basepairs that describes the biological heritage of
human beings is 6∗109. This amount of information can be expressed in about 1.5 gigabytes (GB). For
comparison: this is more information than the holy books of Bible and Quran together in plain text in
English (10 MB), but less information than is required to run a modern computer game like for instance
Grand Theft Auto 5 (that requires 65 GB of hard disk space).
A minority of 1-2% of the human genome encodes for protein molecules [Ohno, 1972].
Proteins are the workhorses of the cell, essential for catalyzing biochemical reactions, keeping structure,
regulating the expression of other genes and sensing the biological surroundings of the cell.
They are essentially polymers as well, fulfilling their functions when folded into highly specific 3D
structures. The protein monomers are amino acids. A
set of three nucleotides from the DNA, called a
codon, can code for one out of 21 amino acids.
The regions in the human genome where these
instructions for the creation of proteins are located
are called genes.
The protein-coding information of genes is usually
spread across several short regions called exons.
Exons are separated from each other by non-coding
introns, which are typically longer than exons.
Next to exons and introns, a typical gene is preceded
by a so-called promoter region containing
sequences that regulate the expression of a gene.
Upstream and downstream of the coding sequences
are untranslated regions that will not contribute to
the gene product.
In order to express the information encoded in a
gene, the gene is “read” during the process of transcription
For that, several proteins that regulate transcription bind to the promoter region of the gene, including an
RNA polymerase enzyme.
The RNA polymerase moves along the gene, separating the two DNA strands and generating a single-
stranded molecule very similar to DNA, called RNA.
The RNA, while it is being generated, is directly edited during the process of splicing: The intronic regions
are removed from the RNA copy of the gene and the exonic regions are linked together.
In a second step, the process of translation converts the genetic code of the RNA into a protein molecule.
As DNA is transcribed into RNA it needs to be edited to remove non-coding regions, or introns, shown in
green. This editing process is called splicing, which involves removing the introns, leaving only the yellow,
protein-coding regions, called exons.
Splicing is not a static process that always occurs in the same way, but it can generate several protein
versions from the same gene.
For example, the gene encoding the essential motor component that generates the movement of muscles,
Myosin Heavy Chain 11 (MYH11), has several ways of being spliced.
The resulting mRNA versions, called transcripts or isoforms, are essential for adapting the functioning of
the protein to the specific situation. In this way,
MYH11 transcripts in skeletal muscle cells generate
proteins specialized for moving quickly and strongly,
while other transcripts of MYH11 in smooth muscle
cells are specialized for keeping up a slow constant
tension [Alberts et al., 2008].

Besides the bare nucleotide sequence of the genome,

additional information lies in the modification,
packaging and spatial organization of the DNA.

First, the DNA itself can be modified by covalently adding methyl groups to the nucleotide molecules.
Two of the four bases can be methylated; these are cytosine and adenine [Wu et al., 2016]. These
modifications mark the DNA and transfer signals. For instance, the methylation of cytosine molecules in the
promoter region of a gene is associated with repression of transcription [Boyes and Bird, 1992].
Second, the DNA needs to be packaged in order to physically fit into the nucleus of the cell. The nucleus of
a human cell is about 1µm in diameter. This is in orders of magnitudes smaller than the sum of the lengths
of all chromosomes that are stored inside the nucleus.
If completely linearized, the human genome would be 2 meters long [Alberts et al., 2008]. In analogy, this is
like fitting a fine thread of yarn of 40 km length into a tennis ball, a process that is certain to end up in
chaotic knots if not tightly organized.
This is also true for our genome and therefore DNA strands are organized by specialized proteins, called
histones that wrap up the DNA.
If histones are densely spaced and tightly wrap up the DNA, the resulting fibers form heterochromatin,
which is unavailable for gene transcription. Contrary, in open euchromatin, where histones are spaced
widely from each other, the DNA is accessible [Gross and Garrard, 1988].

In reality, every human has a genome that is as distinct and unique as a fingerprint.
The fact that seven billion humans exist and the majority of them are free of genetic diseases implies that
there are at least seven billion different combinations of nucleotides that result in a functioning human
genome.
Most variations of the genomic sequence have little to no effect on the biology of the affected individual
A genetic variation can either affect one allele of the genome, in which case is called heterozygous, or both
alleles, in which case it is called homozygous. Special cases are mutations on the sex chromosomes in male
probands. As there is only one copy of each of the sex chromosomes these mutations will always be
hemizygous.
1. First, there is the group of single-nucleotide variants (SNVs) affecting only single nucleotides.
These variations can be substitutions, insertions and deletions.
2. Second, there is the group of variants affecting several (2-50) basepairs. Substitutions of several
base pairs are referred to as block substitutions; insertions and deletions are often grouped as small
indels.
3. Finally, a third group of variants is the structural variants (SVs), that typically affect more than 50
bp. Deletions and duplications of this group are called copy number variants (CNVs). In this group
of long variants it is also possible to observe inversions, where a streak of nucleotides is reversed
relative to the reference sequence. Translocations are sequences that migrated within the genome

Efforts to unveil the etiology of human disease often recapitulate the nature versus nurture debate. But
today’s biologists concede that neither nature nor nurture alone can explain the molecular processes that
ultimately govern human health. The presence of a particular gene or mutation in most cases merely
connotes a predisposition to a particular disease process. Whether that genetic potential will eventually
manifest as a disease depends on a complex interplay between the human genome and environmental and
behavioral factors.
Nutrigenomics therefore initially referred to the study of the effects of nutrients on the expression of an
individual’s genetic makeup. More recently, this definition has been broadened to encompass nutritional
factors that protect the genome from damage. Ultimately, nutrigenomics is concerned with the impact of
dietary components on the genome, the proteome (the sum total of all proteins), and the metabolome (the
sum of all metabolites).
Primarily, there are three types of nutrient gene-interactions that occur:
1. Direct interactions: Nutrients, sometimes after interacting with a receptor, behave as transcription factors
that can bind to DNA and acutely induce gene expression.
2. Epigenetic interactions: epigenetic changes are reversible and do not change your DNA sequence, but
they can change how your body reads a DNA sequence..
3. Genetic variations: Common genetic variations such as single-nucleotide polymorphisms (SNPs) can alter
the expression or functionality of genes. All of these mechanisms can result in altered metabolism and
altered dietary requirements for nutrients.
To date, more than 300 common single nucleotide polymorphisms (SNPs) affecting obesity and related
phenotypes have been identified from genome-wide association and candidate gene studies.

The key genes that have been implicated in obesity and related phenotypes are

 fat mass-and obesity-associated gene (FTO),

 melanocortin 4 receptor (MC4R),
 peroxisome proliferator activated receptor gamma (PPARγ),
 transmembrane protein 18 (TMEM18),
 brain derived neurotrophic factor (BDNF),
 pro-opiomelanocortin (POMC),
 neuronal growth regulator1(NEGR1),
 proprotein convertase subtilisin/kexin type 1 (PCSK1),
 SH2B adaptor protein1(SH2B1),
 leptin receptor (LEPR) and
 neurotrophic receptor tyrosine kinase 2 (NTRK2) with FTO showing the strongest and consistent
signal across age groups, genders and ethnicitie

DIABETES
To date, more than 70 genes have been identified as involved in T2DM, primarily by association analysis.

PPARG- Perioxisome Proliferator- Activated Receptor Gamma

The PPAR gene exists in gamma, alpha and delta subtypes
Major role- is related to glucose, lipid metabolism, insulin sensitivity, adipogenesis. It also has been
identified as the nuclear receptor for the thiazolidinedione class of insulin-sensitizing drugs.
Most significant polymorphism - Pro12Ala
ALA- associated with reduced risk of DM. It has a protective role in association with insulin sensitivity and
obesity.
Significant risk associated with PRO allele. Minimum 25 % of the population has affected PRO allele.

FTO gene
Located on the chromosome 16
Suggested to have a nucleic acid demethylation activity that may regulate the expression of genes involved
in metabolism leading to obesity.
Also associated with childhood obesity
A high saturated fat diet is strongly associated with an increase in obesity susceptibility and insulin
resistance and diabetes mellitus in individuals with the A allele, especially in children and adolescents.
 PCOS

PCOS is a complex disease and syndromic in pathology as the name indicates.

The disease is multifactorial and often of variable symptoms. The disease is grouped into four phenotypes:

A. By ultrasound, numerous polycystic ovaries, oligoanovulation, and hyperandrogenism.

B. By ultrasound, normal appearance of ovaries, oligoanovulation, and hyperandrogenism.
C. By ultrasound, polycystic ovaries with normal routine menses and hyperandrogenism.
D. By ultrasound, polycystic ovaries, oligoanovulation, without hyperandrogenism.

PCOS Phenotypes A and B: PCOS phenotypes A and B are termed classic PCOS. Women with the classic
PCOS phenotypes A and B present with more significant menstrual dysfunction, increased secretion of
insulin, increased insulin resistance, and increased risk for metabolic syndrome. A high incidence of obesity
and atherogenic dyslipidemia (AD) is prevalent in classic PCOS as compared to other PCOS phenotypes.An
increased risk of hepatic steatosis is also more common in PCOS phenotypes A and B in comparison with
normal healthy controls and other phenotypes of PCOS with normal androgen.The classic PCOS is also
characterized by a significantly elevated level of anti-mullerian hormone.
Classic PCOS (Phenotype-A and -B) Phenotype-A is often referred to as the ‘complete’ PCOS phenotype,
and both phenotypes-A and B are often called as ‘classic’ PCOS [25]. Women with classic PCOS appear to
be more hirsute and obese, show a more irregular menstrual pattern and more likely to have insulin
resistance, dyslipidemia, hepatic steatosis with an increased risk for metabolic syndrome compared with
ovulatory or nonhyperandrogenic phenotypes (C and D)

Phenotype C – Ovulatory PCOS: Mildly elevated serum insulin, atherogenic lipids, and androgen levels, and
high hirsutism scores are common in phenotype C (ovulatory PCOS) patients in comparison to classic and
non-hyperandrogenic PCOS. Metabolic syndromes are also common ovulatory PCOS as compared to other
types. In an Italian cohort of PCOS patients, the ovulatory phenotype was reported among individuals with
higher socioeconomic status. In high socioeconomic groups, tissue fat distribution and insulin level due to
eating habits could partially explain the difference in ovulation patterns. The 2006 AE-PCOS Society
criteria and the 2003 Rotterdam criteria include an additional phenotype, phenotype-C (HA þ PCOM, but
without OD), the so called ‘ovulatory’ PCOS [26]. Hirsutism scores, androgen and lipid levels, and risk of
metabolic syndrome of women with phenotype-C are in between classic PCOS and phenotype-D
Phenotype D – Nonhyperandrogenic PCOS: The classical characteristics of phenotype D include normal
androgen with slightly elevated other endocrine levels and the lowest metabolic dysfunction in comparison
to healthy controls. The endocrine finding includes an elevated level of sex hormone-binding globulin, a low
level of T3 and T4 and a lower LH/FSH ratio in comparison to individuals with classic PCOS. Normally,
individuals with PCOS phenotype D have regular menstrual cycles with intermittent irregularities. Non-
hyperandrogenic PCOS (Phenotype-D) Phenotype-D (OD þ PCOM, without HA), introduced by the 2003
Rotterdam criteria, termed as ‘nonhyperandrogenic PCOS’. These patients have normal androgen levels and
the mildest degree of endocrine dysfunction including insulin resistance and the lowest prevalence of
metabolic syndrome [26]. Patients with phenotype-D who have increased body mass index (BMI) might be
more insulin resistant compared with healthy women even though at a level lower than classic PCOS

Genes Involved in Steroid Hormone Effects

Androgen Receptor Gene The “q” arm of chromosome X contains the AR gene, which is composed of 11
exons and encodes a 90-kb long tridomain protein. Mutations and structural disruption of the gene are
reported to cause PCOS. “X” chromosome inactivation leads to disruption of the cellular pathway, causing
elevated androgen hormone resulting in PCOS. As the AR gene is located on the X chromosome, a change in
a single copy of the gene is sufficient to cause pathology.

Genes Involved In Insulin Action & Secretion

Calpain10 Gene CAPN10 is located on the long arm of “q” of chromosome 2 and consists of 12 exons. The
gene encodes calcium-dependent cysteine protease, which is a heterodimeric protein. The gene is associated
with diabetes mellitus type 1. The protein “calpain 10” interferes with insulin metabolism and secretion. The
impaired insulin level causes PCOS; thus, a mutation in calpain 10 also causes
PCOS. Hence, CAPN10 is a candidate gene causing PCOS.

SPORTS GENOMICS