Lecture 2 - The Role of Genes as a Determinant of Lifetime Health Flashcards
1
Q
Define Nutrigenomics and Nutrigenetics
A
- Nutrigenomics = the effect of diet on genes. Some genes are more sensitive to nutrition
- Nutrigenetics = the study of how genetic differences arising from polymorphisms modify dietary effects (genes —–> metabolism)
- So, they are the opposite of one another as nutrigenomics have food influencing genes and then nutrigenetics are genes influencing our diet
- We are all different when it comes to these
2
Q
Explain how chromosomes - DNA - and genes are related
A
- Chromosomes exist within a cell nucleus
- Chromosomes are made of DNA strands that contain bases: adenine, guanine, cytosine, and tyrosine
- Genes make up DNA
- People have different alleles which have variations in bases
3
Q
What is the central dogma of biology?
A
- DNA is transcribed to RNA
- RNA is translated into proteins
4
Q
Explain genotype and phenotype via Mendel’s peas
A
- A yellow plump pea is AABB and thus dominant form. It is bred with the recessive wrinkly green form aabb.
- The green wrinkly: It’s genotype is aabb and its phenotype is green, wrinkled
- When bred with the dominant AABB form its genotype is AaBb (dominant genotype) and its phenotype is yellow, plump
4
Q
What is nutrigenetics the study of?
A
- Study of how genetic differences arising from polymorphisms modifies dietary effects
- Genes —-> Metabolism
5
Q
What are polymorphisms? What is a SNP?
A
- Polymorphisms are substitutions of a base pair
- SNP: single nucleotide polymorphism
6
Q
Explain single nucleotide polymorphism and how it can have varying impacts
A
- a single nucleotide is substituted for something else and it can cause changes
- With a normal protein (Person 1) you will have a DNA sequence. One nucleotide base may be substituted
- Person 2: Substitution but the protein is normal despite DNA variation and you will have no negative effects
- Person 3: Substitution can cause low or non-functioning protein. Can lead to disease (e.g. sickle cell) or increased susceptibility to disease (e.g. lung cancer)
7
Q
What is sickle cell disease?
A
- An example of a single nucleotide polymorphism that impacts genotype and phenotype
- Causes red blood cells to not have proper formation/function, originates at the level of DNA
- Base pairs are switched around so it forms Valine instead of Glutamic acid and leads to different formation
8
Q
Explain the HemoglobinS Allele and how they can impact RBCs
A
- Sickle cell is caused from autosomal recessive HbS + HbS
- 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 can sickle causing sickle cell disease)
9
Q
What is SREBP-1c?
A
- Sterol response element binding protein
- An example of a SNP in response to diet
- Gene that regulates lipid metabolism
- SNP + high fat diet = overexpression
- Overexpression associated with dyslipidemia, impaired glucose metabolism, Type-2 diabetes
- Need a lower fat diet in order to counteract the overregulation of lipid metabolism
10
Q
What is Apolipoprotein E4?
A
- An example of a SNP in response to diet
- Regulates lipoprotein-cholesterol clearance from plasma (rather than E1,E2,E3)
- ApoE4 allele + high fat diet results in higher LDL levels
- Higher risk of CV outcomes, and Alzheimers disease
11
Q
Define myostatin
A
Myostatin is a hormone that inhibits muscle protein synthesis
12
Q
Explain how whippets are impacted by SNPs
A
- Whippets = racing dogs
- MTSN gene variant mh (deletion)
- if myostatin inhibits muscle synthesis then it is a deletion of the myostatin so there would be increased muscle
- +/+ normal muscle and speed
- +/mh more muscle and faster speed = heterozygous
- mh/mh bulky muscle and slower. Mutant of both. Muscles are dysfunctional so they are slower
13
Q
Explain Prader-Willi Syndrome (PWS)
A
- An example of a snp related to genes and obesity
- chromosomal deletion with multiple genes affected
- hypothalamic dysfunction: growth hormone, hunger-satiety hormones, other endocrine
- short stature, lower lean mass, hyperphagia (lack of satiety leading to insatiable hunger), developmental delays
- Failure-to-thrive in infancy –> food seeking in early childhood (insatiable hunger)
14
Q
How does nutrigenetics impact metabolism and how can this be modified?
A
- Genetic differences arising from polymorphisms can alter metabolism
- Genetic polymorphisms can not be changed. They can go from generation to generation.
- Dietary modification can be made to amount of energy and nutrients and types of diet depending on the Snp
15
Q
Define nutrigenomics
A
- the application of nutrition to the entirety of gene expression: the interaction between diet and genes
- study of how nutrition influences gene expression (on/off)
- Food —-> Gene expression
- Change in phenotype (physical looks) without a change in genotype
16
Q
Explain the concept of epigenetics
A
- changes in gene expression (phenotype) caused by mechanisms other than changes in the underlying DNA
- Non-genetic factors cause the organism’s genes to be expressed differently
- Allows for adaptations to environment
- Changes remain through cell divisions
17
Q
What are examples of possible epigenetic modifications?
A
- DNA methylation
- Chromatin modifications including modifications to histones (by methylation, phosphorylation, acetylation, etc)
18
Q
What are histones?
A
Proteins that compact DNA and have a role in DNA regulation
19
Q
Epigenetic modifications can be caused by…
A
Chronic and acute exposures
20
Q
DNA ____________ + _________ modifications = __________________
A
DNA methylation + histone modifications = the epigenetic code
21
Q
What does the epigenetic code determine?
A
What genes are expressed
22
Q
What does DNA methylation mean?
A
- Methyl groups can be added at any place along DNA sequence
- Done via DNA methyltransferases
- Note: DNA methylation changes how things are folded together
23
Q
What can DNA methylation and histone modification do?
A
- DNA methylation and histone modification can cause genes to turn off for active DNA
- Which means that although they have the same DNA, a liver cell is a liver cell and a brain cell is a brain cell because they have different epigenetic codes
- Cells know what to become via DNA methylation and histones. DNA needs to be in a certain structure to be functional, if not then turned off.
24
Q
Can we have changes in phenotypes over our lifetime? Explain.
A
- Environmental factors such as diet, stress, exercise, smoking, alcohol drugs, pathogens, and weather can impact our DNA
- DNA methylation, histone modification, and chromatin remodeling will be impacted
- This then changed our phenotype in regards to physical shape, disease susceptibility, stress response, behavior, longevity
25
Q
What do studies on identical twins tell us?
A
- Identical twins begin with the same genome + epigenome
- Howver, over time, life events and the environment change the epigenome
- This contributes to differing appearances and disease risk as the twins age
- Signals from environment act on epigenome to activate and silence different genes
- Environmental signals include physical activity, toxins, stress, diet
26
Q
What do epigenetic tags do?
A
- Turn on or off genes (e.g. cause specialization, heart vs. muscle cells)
- Erased from mom and dad, but the ones that are left are known as imprinted genes
27
Q
Explain the life-course model
A
- As we age the risk of non-communicable diseases increases
- 4 life stages including fetal life, infancy and childhood, adolescence, and adult life
- By adult life there is an accumulated risk of non-communicable disease
- Demonstrates how lifetime exposures can increase risk
28
Q
Overall, what can alterations to epigenetic patterns do and can this be reversed?
A
- Alterations to epigenetic patterns may contribute to diseases that are more common with age
- Epigenetics may also contribute to the process of aging itself
- Reversibility remains unknown; would be positive as this could change one’s disease risk
29
Q
Explain the Barker Hypothesis
A
- The environment encountered during fetal life and infancy appears to be strongly related to risk of chronic disease in adult life
- The process through which a stimulus or insult during a critical window of development results in permanent responses that produce long-term changes in tissue structure or function
- Also called Developmental Origins of Disease Hypothesis
- Intra-uterine growth is associated with increased risk of chronic disease
30
Q
A retrospective study on a UK cohort demonstrates concepts of Barker Hypothesis. Explain how
A
- In a certain UK region, lower birth weights had higher prevalence of CVD
- As birth weight increased, death from CVD also increased
- demonstrated how fetal life later impacted adult life
31
Q
Inadequate growth in uterus increases risk of?
A
- Dyslipidemia, hypertension, glucose intolerance, CVD, type 2 diabetes, obesity (phenotypes)
32
Q
Excessive intrauterine growth increases risk of?
A
- Less well studied but evidence of dyslipidemia, hypertension, glucose intolerance, obesity
33
Q
What are other names for the barker hypothesis?
A
- Developmental origins of (adult) disease
- Development origins of health and disease
- Fetal Origins of (adult) disease
- Fetal (developmental) programming
- Epigenetic programming
34
Q
What does the dutch famine demonstrate?
A
- Times of rationing where there was an extreme decrease in caloric intake
- Changes in DNA methylation in genes related to growth (bc malnourished)
- Women were pregnant at this time and their offspring showed higher glucose levels, higher LDL/HDL ratios, CHD %, and microalbuminuria (impacts kidneys)
- Depended on time frame of when they were pregnant
- Before and after pregnancies the adults had normal results
35
Q
What is a potential problem with looking at the dutch famine and epigenetics?
A
- Retrospective, could be other factors leading to health risks in these individuals
- Stress, we don’t know the food they ate, etc.
36
Q
What nutrients are important in maternal diet and why?
A
- Choline, methionine, vitamin B12, and folate can donate methyl groups and are therefore involved in methyl-group metabolism. Deficiency or supplementation can alter DNA and histone methylation
37
Q
What can occur with choline deficiencies?
A
- have been associated with irreversible changes in brain structure and function
38
Q
What can occur with a low protein maternal diet?
A
- associated with many changes in offspring (pancreatic islet cells, GLUT 4 expression, adipose tissue, heart tissue, and leptin regulation)
39
Q
Energy restriction in-utero of animal models show changes in?
A
- Liver and pancreatic cell differentiation (alterations in metabolism)
- Distribution of muscle cell type and muscle cell glucose transport (insulin sensitivity)
- Number of nephrons in kidney (fluid and electrolyte balance)
- Endothelial function
- Bone density
40
Q
Explain the Thrifty Phenotype Model
A
- Fetus has been able to adapt in utero to pull more nutrients in from the blood because it is being malnourished
- nutrient restriction leaders to slow growth and a small baby and thrifty adaptation
- In a nutrient poor postnatal environment, thrift is a survival advantage
- In a postnatal environment that is nutrient rich, obesity and metabolic syndrome can result
41
Q
Does the father’s diet impact the offspring’s health?
A
- Yes an association has been found in animal models
- Males were put on a restrictive protein diet from weaning to puberty
- Offspring had increased gene expression for cholesterol/lipid synthesis
- In the female offspring only they showed a response to a high fat diet and they became more obese and insulin resistant
42
Q
What are the challenges of human research on epigenetics?
A
- Mostly retrospective studies, emerging prospective studies and recent findings
- Measuring exposures, ethics, establishing causation
