The role of genes as a determinant of lifetime health Flashcards
What is nutrigenomics?
Study of how diet influences gene expression (on/off)
* some genes are more sensitive to certain nutrients
* Change in phenotype without a change in genotype
What is nutrigenetics?
Study of how genetic differences arising from polymorphisms modifies dietary effects
What are the nucleotide bases?
- adenine
- thymine
- guanine
- cysteine
What is the central dogma of biology?
What is the difference between phenotype and genotype?
- Genotype is a persons unique sequence of DNA. More specifically, this term is used to refer to the two alleles a person has inherited for a particular gene
- Phenotype is the detectable expression of this genotype – a patient’s clinical presentation
Genotype: aabb Phenotype: green, wrinkled
What is a polymorphism?
refers to the presence of two or more variant forms of a specific DNA sequence that can occur among different individuals or populations.
What is the most common type of polymorphism?
SNP - single nucleotide polymorphism
* involves variation at a single nucleotide whereby the replaced nucleotide may or may not produce a change in the phenotype
What are common examples of SNPs?
- sickle cell disease - HemoglobinS allele
- SREBP-1c
- Apolipoprotein E4
- Myostatin
- PWS
What is the SNP in sickle cell disease?
Autosomal recessive HbS+HbS; A nucleotide in the DNA sequence is flipped in the HgbS allele which expresses the protein valine instead of glutamic acid in the AA sequence resulting in malformation of RBCs such that it might not be functional inhibiting ability to carry oxygen
■ AA – homozygous for the ‘normal’ Hb allele
❑ disc-shaped RBCs
■ AT – heterozygous for the Hb/HbS alleles
❑ some disc-shaped and some with potential to sickle (no clinical symptoms)
■ TT – homozygous for HbS allele
❑ RBCs that can sickle (sickle cell disease)
What is the result of a SNP in the SREBP-1c?
changes in response to diet since this protein regulates lipid metabolism
* Snp present + high fat diet consumption leads to overexpression which is associated with dyslipidemia, impaired glucose metabolism, Type-2 diabetes
What is the result of a SNP in the apolipoprotein E4
Apo E4 egulates lipoprotein-cholesterol clearance from plasma so a SNP causes changes in response to diet
* ApoE4 allele + high fat diet results in higher LDL levels, cardiovascular outcomes and alzheimers disease
What is the result of a SNP in myostatin?
myostatin is a hormone that inhibits muscle protein synthesis so a SNP causes changes to body composition
Whippets (racing dogs) having MSTN gene variant mh (deletion)
▪ +/+ normal muscle and speed
▪ +/mh more muscle and faster speed
▪ mh/mh bulky muscle and slower
What is PWS?
prader-willi syndrome: chromosomal deletion with multiple genes affected
* hypothalamic dysfunction: growth hormone, hunger-satiety hormones, other endocrine
* short stature, lower lean mass, hyperphagia (lack of satiety), developmental delays
* failure-to-thrive in infancy
* food seeking in early childhood
What is epigenetics?
Changes in gene expression (phenotype) caused by mechanisms other than changes in the underlying DNA
What are the mechanisms by which epigenetics may induce a change?
non-genetic factors cause the organism’s genes to be expressed differently such as the environment in the organisms exists
* allows for adaptations to environment
* changes remain through cell divisio
How might epigenetics be described in terms of nutrition?
metabolic programming
* occurs when a nutritional stress/stimulus is experienced during the early developmental period, resulting in significant adaptations in target organs to enable the organism to survive the nutritional challenge
* Can also be in adulthood?
What are some possible epigenetic modifications?
- DNA methylation
- Chromatin modifications including
modifications to histones (by methylation,
phosphorylation, acetylation, etc)
What are histones?
proteins that compact DNA and
have a role in DNA regulation
What is the epigenetic code?
Determines what genes are expressed
* DNA methylation along with histone modifications
What is the enzyme for DNA methylation?
DNA methyltransferases
What micronutrients are involved in DNA methylation?
Both deficiency and supplementation can alter DNA and histone methylation
* choline
* methionine
* vitB12
* folate
Where does histone modifications occur and what nutrients are involved?
Typically on the histone tails involving amino acids such as lysine or arginine as well as serine, threonine, tyrosine, etc.
What are the main enzymes invovled in histone modifications?
- histone methyltransferases
- histone demethylases
- histone acetyltransferases
- histone deacetylases
How are cells differentiated between organs?
Although all cells have the same DNA, a liver cell is a liver cell and brain cell a brain cell because they have different epigenetic codes
What sort of environmental factors can result in modifications?
Exposure through the lifespan can cause phenotypical changes
* environmental toxins
* diet
* stress
* exercise
* smoking
* alcohol
* drugs
* pathogens weather
What is some insight into epigenetics from identical twins?
Identical twins begin with the same genome + epigenome but over time, life events and the
environment change the epigenome turning genes on and off which contributes to differing appearances and disease risk as the twins age
Are epigenetic tags passed from parent to offspring?
Epigenetic tags are typically erased but in some cases the tags can be passed on and are called imported genes
What is the influence of epigenetics on NCD risk?
Alterations to epigenetic patterns may contribute to diseases that are more common with age and may also contribute to the process of aging itself
* Chronic diseases often show up in adulthood and older age but that expression is often due to a lifetime of exposure to environmental factors. Even fetal life can effect this.
What is the Developmental Origins of Disease Hypothesis
The environment encountered during fetal life and infancy appears to be strongly related to risk of chronic disease in adult life where a stimulus or insult during a critical window of development results in permanent responses that produce long-term changes in tissue structure or function
Where did the Developmental Origins of Disease Hypothesis come from?
Barker hypothesis
* Found that certain regions of UK had higher death rate and chronic disease, those with lowest birth rates had higher disease risk. So somehow birth weight related to chronic disease later in life.
Effect of intra-uterine growth on chronic disease risk
- Inadequate growth SGA/LBW - dyslipidemia, hypertension, glucose intolerance, CVD, type 2 diabetes, obesity
- Excessive growth LGA - evidence of dyslipidemia, hypertension, glucose intolerance, obesity
What is intra-uterine growth potentially related to?
maternal nutrition status but other factors also might play a role
Describe the Dutch famine
During WWII there was a period of undernutrition during pregnancy and was associated with changes in DNA methylation in genes related to growth
* People are now 65+ and can see what their phenotype is with blood test. Those in EXPOSED late had higher incidence of T2D, early on there glucose was normal but LDL/HDL was higher and CHD was higher, with mid and late problems with kidney. So may be associated with timing of exposure and risk of disease alter in life.
What might be a problem with choline deficiency?
have been associated with irreversible changes in brain structure + function
* important for DNA methylation
What is low protein maternal diet associated with?
associated with many changes in offspring
* pancreatic islet cells
* GLUT4 expression
* adipose tissue
* heart tissue
* leptin regulation
What is the thrifty phenotype model?
Adaptation of the tissues of the baby that they have made to nutrient restriction during fetus life such as pulling nutrient from the blood so when born it pulls what it can from the environment
* nutrient poor environment it can be an advantage
* nutrient rich environment it becomes problematic
Impact of fathers diet on the offspring
An association has been seen in animal models
* Males were put on a restrictive protein diet from weaning to puberty and offspring had increased gene expression for cholesterol/lipid synthesis
developmental plasticity
The ability of an organism to develop in various ways depending on the environment
