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403 Review Questions
1
...

A chromosomal analysis is used to detect chromosome abnormalities and
structure
...
Chromosomal analysis is important to our
understanding of genetics and determining which genes are absolutely essential
for life, and which will cause defects
...
The three main types of Chromosomal
abnormalities that are determined by analysis are Polyploidy, aneuploidy and
chromosomal rearrangement
...

For example, instead of the usual 23 pairs of 2 chromosomes, a triploidy cell will
have 69 chromosomes, or 23 groups of 3, which does not allow proper
development of a fetus and would result in a miscarriage
...

Down syndrome is an example of aneuploidy, where there is trisomy at
chromosome 21
...
Among the most common characteristics of
Down syndrome are mental impairment, stunted growth, low muscle tone, large
tongue, and slanted eyes
...
Phenotypes include small testes,
feminized physique, more of a female patterned hair growth, and in some cases
breast development
...

iii) Chromosomal rearrangements:
Chromosomal rearrangements encompass several different classes of events:
deletions, duplications, inversions; and translocations
...

In the situation of reciprocal translocation, since an individual will essentially have
all of the genetic information, they will generally have no problems
...


Robertsonian translocation is similar to reciprocal translocation except instead of
retaining all of the information, the smaller fragment is usually lost
...
Other
abnormality
Ring chromosome: epileptic seizures, mental retardation, behavior disorders
...
(Turner’s syndrome, epilepsy)
...
Describe how the process of genomic imprinting can lead to a genetic
disorder and describe a genetic disorder caused by genomic imprinting
...
Epigenetics changes the structure or chemical affinity of the DNA without changing
the code or the transcript of the protein
...
This alters their chemical
affinity for binding to DNA and will aid or repress RNA polymerase interactions
...
This does not involve the
silencing of a full chromosome, just individual genes, and the process is relatively rare
...

This usually does NOT occur in housekeeping genes (Where it does occur: the inactive X chromosome in
female mammals, silencing of X in XX, environmental influences)
...
Epigenetic mechanisms are the underlying
mechanisms that results in cells differentiating into their specific tissues during development, despite all
cells having come from a single somatic cell
...
In the eggs, all
imprints are erased and rewritten with the maternal imprint – even
the genes that came from the dad
...

Replication occurs with normal and non-methylated sites being
replicated, but DNA has ‘memory’ of previous modifications and the
enzyme methyl acetyltransferase adds a methyl group to cytosines

in the daughter strands and you end up with exact copies of the
original; methylated sites activate protein complexes that remove
acetyl groups from histones leading to transcriptional repression
...
Histone modifications are associated with either
repressing/silencing or increasing transcription
...

Undifferentiated gametes do not carry methylation, because the generation of germ cells
erases methylation imprinting
...
This does
NOT occur in spermatogenesis
...
In a particular recessive mutation of Igf2 (insulin growth factor 2, necessary for cell
to know how to enter mitosis to grow)
...
If the father passes on the
Igf-2 mutation, then the heterozygous mutant will display the mutant phenotype
...
When it passes through the male germ line it is always
demethylated
...
The male allele of the Igf2 gene is the only one that will get expressed
...
Both Angelman’s syndrome and Prader-Willi syndrome are a sequence of missing
DNA from chromosome 15
...
If it
is inherited from the mother: Angelman’s syndrome
...

Ex: Example of paternal imprinting is seen in Prader-Willi syndrome, where
70% of the paternal
chromosome 15 is silenced
...

• Individual missing gene activity normally coming from father
• Father’s copy is missing or there are two maternal copies
Ex: Example of maternal imprinting is seen in Angelman syndrome, a
neuro-genetic disorder, where 70% of the maternal chromosome 15 is
silenced
...

• individual missing gene activity normally coming from mother
• Mother’s copy is defective or missing or there are two parental
copies

Epigenetics and its code answers the presence of a small genome within the human
complexity because the presence of only 30,000 genes makes up a complex human being
...

The epigenetic code must be understood in order to know all the different combo’s of
switches that are present that alter gene expression
...

3
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-­‐  Mitochondria  have  their  own  DNA,  include  13  protein-­‐coding  genes  required  for  
oxidative  phosphorylation
-­‐  These  genes  are  not  solely  responsible  for  this  process,  still  need  genes  from  nuclear  
genome  that  code  for  transporters  involved  in  the  oxphos  process  that  affect  its  
functionality  (ie:  transporting  molecules  involved  into/out  of  mitochondria)
-­‐  Mutations  in  mitochondrial  genes  lead  to  disorders  that  are  associated  with  failure  in  
energy  production
-­‐  Two  critical  differences  between  mitochondrial  &  nuclear  inheritance:
1
...
 An  affected  woman  therefore  transmits  the  trait  to  all  of  her  
children  while  an  affected  man  will  not  pass  the  trait  to  any  of  his  offspring
...

2
...
 This  means  there  is  existence  of  normal  and  mutant  mtDNA  in  
the  same  individual,  tissue,  or  cell
...
 Proportions  of  
mutant  and  wild-­‐type  mito  can  change  dramatically  due  to  this  chance  
segregation;  this  can  lead  to  variation  in  the  proportion  of  affected  mitochondria  
in  different  tissues  or  different  individuals  within  a  family
...
There are several approaches to genetic sequencing, including targeted
DNA sequencing, exome sequencing, and whole genome sequencing
...
We can find specific variants/SNPs that we know are diseasecausing and use them as predictors of disease or of protection against a disease (example
– BRCA1/2 mutation for cancer)
...
The disadvantage of this method is that very few

diseases have a simple Mendelian course of inheritance and are often caused by several
mutations
...
It can identify rare variants of a gene
...
An advantage of both whole genome sequencing and
exome sequencing is that it provides the molecular pathogenesis of the phenotype by
identifying its exact genetic etiology
...
This is beneficial because the exome contains the majority (~85%) of the
known disease-causing mutations but it comprises of only about 1% of the genome,
therefore there is a lot less data to deal with
...
Rare variants usually have a greater effect than
common variants because they have shown up fairly recently (common varients have
been around for a long time, thus have been able to spread)
...


5
...
Can
reveal propensity for a disease currently lacking effective treatment options,
which could have psychological consequences
...
They may think that they’re
lowered risk allows them to make unhealthy life decisions simply on the basis of
probability
...

Benefits: Advancing medicine and global health by providing information
on the genetic basis of poorly understood diseases, self-curiosity, can take steps
to reduce the risk of acquiring a disease in which the individual is a higher risk of
...

Personalized nutrition could also be provided, that would aid in your ability to
combat metabolic diseases that are affected by diet
...
Describe and contrast the different goals and approaches to performing
nutrigenomic vs nutrigenetic research and describe examples of each
...
It is the study and identification of
genes that are involved in physiological responses to diet, and genes in which
SNP’s or polymorphisms have significant nutritional consequences
...

The goal of nutrigenomic research is to find the interaction between diet and a
network of genes, on a global scale
...

Nutrigenomics regulation of gene expression often occurs through common
transcription-factor pathways that are regulated by macronutrients,
micronutrients, and other food components
...

Nutrigenomics – Leptin hormone mutation that causes obesity
...

Functionally relevant SNP’s and their multiple variants are identified and filtered,
integrated with nutrient intake, and related back to the individual and their
resultant risk and susceptibility to diseases
...

An important application of nutrigenetics can be related to the Inuit population, in
which 35 SNP’s from 20 genes related to lipid metabolism have been identified
...
Increased
knowledge about the interplay between the multiple gene variants can allow for
tailoring of a personalized diet, that is low in saturated and trans fats, in order to
prevent and cure chronic disease in the Inuit population
...
It is due to a mutation in either the
ABCG5 or ABCG8 gene, which code for ATP-binding cassette transporter
proteins, impairing the ability of the liver to excrete plant sterols into the bile
...

7
...
What
is a cancer stem cell? Why is it difficult to target cancer stem cells and why
is it important that they be targeted? Found in Lecture 10 [slides 23-28]
Stem cell - a cell type found in most, if not all, multicellular organisms
...

Relationship between stem cells and tumour cells: The similarities in
mechanisms that regulate self renewal of normal stem cells and cancer cells;
second the possibility that tumour cells might arise from normal stem cells; and
third the notion that tumours might contain ‘cancer stem cells’ – rare cells with
indefinite proliferative potential that drive the formation and growth of tumours
...

Different types of Stem cells:
• Totipotent (can form all cell types in a body)
• Pluripotent (can give rise to all of the cell types that make up the body)
• Multipotent (can develop into more than one cell type)
(Don’t know if
we need to know the types of stem cells
...
A cancer stem sell has indefinite potential for
self-renewal that drives tumorigenesis, thus it makes a crucial target
...
– thus it is difficult to
treat cancer stem cell mutations
• Progenitor cell mutation = weak stemness, homogenous cancer (more
differentiated/specialized cell)
o Treatment - therapy is effective against progenitor cell mutations
and tumor is eliminated (not sure if it is important)
Two Types of Treatment:
1
...

2
...
Tumor shrinks and grows back
...
CML
• Imatinib - a drug that targets and treats CML (chronic myelogenous
leukemia) but ONLY affects cycling blood cells; normally unable to treat
quiescent CSCs (in a state of quietness or inactivity, the G0 phase of the
cell in the cell cycle, where the cell is not dividing)
...

• Plerixafor (CXCR4 antagonist) - detach the quiescent cells from the
stroma and sensitize to imatinib
...


...
How could genetic and environmental factors explain different
phenotypic expression caused by the same single base variation (a SNP) in
two individuals? How could phenomena such as penetrance and
expressivity relate to this process?
While an individual may possess the appropriate genotype to express a
phenotypic treat, there are several situations that could lead to lack of expression
of that gene
...

• Genetic factors:
-Gene silencing: the ability of the cell to prevent expression of a
particular gene that occurs either in transcription or translation - if the gene
silencing is not complete (as in there is SOME existing gene expression, this
is known as gene “knock down”) and accounts for varying levels of
expressivity
...
X-chromosome
inactivation, 2
...
silencing
as a result of environmental influence
-Alternate splicing: another mechanism of genetic material, that
does not occur as a direct result of DNA alteration, but instead occurs during
gene expression
...
This process leads to enhanced
diversity among progeny
...
In this situation, mutations in at
least one copy of each gene are required for the expression of a phenotype
...
They
can elicit their effects on protein expression by: cleaving mRNA, destabilizing
mRNA, or by decreasing mRNA translation rates
...
Complete
lack of expression in the methylated gene on various individuals of a
population, would lead to an alteration of disease penetrance
...
Histone modifications are associated with either
repressing/silencing or increasing transcription
...

•

•

•
•

•

Environmental effects (temperature, light, chemicals, and nutrition) (the
effect of nutritional genomics): dietary chemicals can act on the human
genome directly or indirectly to alter gene expression (nutrition is the most
important environmental factor modulating the action of genes and of the
phenotypes being considered)
...
While the dietary restrictions may be hard to follow, an
individual can avoid the phenotypic traits of the disease (such as
intellectual disabilities, and mental retardation), by reducing phenylalanine
consumption (present in most meat and dairy products)
Ex
...

Ex
...
Lack of toxicity in adults, profoundly detrimental
effect on developing fetuses
...
Temperature affecting C gene expression in Himalayan rabbits,
differential phenotypic expression of coat color

In some cases, the presence of a particular SNP may increase or decrease an
individual’s susceptibility to the development of a phenotypic trait or a disease, as
opposed to directly generating the phenotype
...
For example, a SNP leading to lighter skin tone
may be present in two individuals, thus putting them both at a heightened risk for
skin cancer development
...
This same example could
apply if one of the SNP possessors also had genetic variants that produced light
hair and eyes (2 genetic factors), further enhancing their chances of developing

skin cancer – and thus leading to a greater chance of phenotype expression
...
Expressivity
(the degree of phenotypic expression of a genetic trait, the extent of gene
expression in an individual) may also be altered by coexisting risk factors – a
SNP that enhances an individual’s ability to develop a tan from sun exposure,
would be expressed to varying degrees depending on their level of sun exposure
(an environmental factor)
...
What is meant by a genetic map and how have the available maps
changed over time? How have such maps been used to identify the genes
responsible for diseases? What are the advantages and disadvantages of
this approach?
A genetic map is a collection of genetic markers and gene loci, based on
genetic linkage information
...
Known DNA sequences (genetic markers)
throughout the genome are used as reference points
...
The Human Genome Project is
an international scientific research project with the goal of determining the
sequence of chemical base pairs which make up human DNA, and then
identifying and mapping all of the genes of the human genome from both a
physical and functional standpoint
...
An accurate draft
was accomplished in 2003
...

The majority of advancements have been with rare single gene or
chromosomal disorders, whereas the study of multiple genes involved in multiple
disorders has proven to be more challenging
...

Old School method: Restriction fragment length polymorphisms (RFLP), first
proposed for genetic mapping
...
These enzymes cut
the DNA at that locus if the right base pair is present, and then run separate them
based on lengths by gel electrophoresis
...
Advantage is that any source of DNA can be

used for the analysis, and many markers can be mapped in a population that is
not stressed by the effects of phenotypic mutations
...

PCR: Polymerase chain reaction, most mapping of the HGP used PCR
...

Next came variable number of tandem repeat markers
...
The
differences between the two homologous chromosomes are in the number of
repeats present (and thus the length of the locus)
...
Advantage: Have many alleles on each paired chromosome at a
VNTR (variable number of tandem repeats) locus, which allows more families to
give recombination information, as each VNTR acts as an inherited allele
...

These markers are made of repeats of two, three or four base pairs, with the
variation being the number of repeats
...

Advantage: Microsatellite markers are easy to genotype, and have multiple (but
not large numbers) of alleles
...

Most recent: Single nucleotide polymorphisms (SNP’s), variations at a single
base on the chromosome
...
SNP’s as genetic markers allows for the map to be
much smaller, and to nail down the location of the mutation rather than having to
use the entire map
...
Can be used to study multiple genetic markers
simultaneously
...
If the disease is of late-onset with a high mortality,
finding families with more than one affected generation will be difficult
...

Linkage mapping has been extremely successful in mapping genes and gene variants

affecting Mendelian traits (e
...
, single-gene disorders), Mapping loci underlying
common diseases and, in particular, identifying causative mutations have had
much less success
...
One reason is that the
effect sizes (“penetrance”) of individual causal variants are too small to allow
detection via co segregation within pedigrees

10
...
5% of their DNA
...
5% difference,
78% can be attributed to SNP’s
...
The more
distant a common ancestor is, the smaller each shared chromosome segment
will be, until eventually the only shared DNA is that of the actual location of the
mutation
...
A specific haploblock was
analyzed to have 8 different sites of SNP’s found within it, which results in 256
different possibilities of variants
...
These two separate strands come from
only 2 different ancestors, while adjacent haplotype blocks show the same
pattern of limited diversity with contributions from 4 or less ancestors
...
This is a result of a population
bottleneck that resulted in a severe reduction of allele frequencies, and less
genetic variation in the surviving population
...

Since all populations originated in Africa, the African populations have the
greatest genetic diversity, with more haplotypes per haploblockblock (5
...
6)
...
What is meant by the terms dominant and recessive? Why do some
genetic variants exert a dominant effect while for others the effect is
recessive? (refers to lecture 13
...
)
Genes are made up of two alleles and these alleles come in two forms: dominant
and recessive
...
A recessive trait is only manifested in the phenotype if the individual is
homozygous for the recessive trait (carries two recessive alleles for that trait)
...

Recessive mutations often involve a loss-of-function gene so the gene no longer
specifies a polypeptide or it specifies a nonfunctional polypeptide
...
It will only show up in a homozygous
recessive individual for that mutation
...
This variant may arise
because the mutation specifies a different polypeptide to be produced that shouldn’t be
...

Some mutant variant alleles exist as conditional mutations, in which a mutant allele
causes a mutant phenotype in only a certain environment, called the “restrictive
condition”, but causes a wild-type phenotype in some different environment, called the
permissive condition
...
In a heterozygote with a wildtype allele and a mutant allele, the single wild-type allele may be able to provide enough
normal gene product to produce a wild-type phenotype
...
In others, the cell is able to ‘up-regulate’ the level of activity of
the single wild-type allele so that in the heterozygote the total amount of wild-type gene
product is more than half that found in the homozygous wild type
...
In such cases, the single wild-type allele in the
heterozygote cannot provide the amount of gene product needed for the cells and the
organism to be wild type
...

Harmful alleles that are recessive have an advantage by hiding in their heterozygous
form, and preventing their elimination
...
A deleterious mutation is one that doesn’t
perform as well as the wild-type and is thus detected and selected against by natural
selection preventing their propagation
...
Differential expression of a mutant genotype due to epigenetics: Undifferentiated gametes do not carry
methylation, because the generation of germ cells erases methylation imprinting
...
This does NOT occur in spermatogenesis
...
If the mother passes on the Igf-2
mutation, then the heterozygous mutant will display the wild-type phenotype
...
This is because the Igf2

gene that passes through the female germ line is ALWAYS methylated
...
The female allele, as far as gene expression is concerned, becomes
useless and remains silenced due to the methylation, which always causes repression of transcription
...


12
...
Discuss and compare the alternative models of the genetic basis of
common diseases
...

-

Small number of specific variants that together will add up to the heritability of disease
...
A small number of moderate effect loci would produce several percent of
genetic variance
...
Small effect, but large variance
...


INfintesimal: Large variance, small effect
...

Rare Allele Model:
- Many rare alleles of large effect
...

-Under this model, expressivity may be modified by other loci or by
the environment, but the notion is that the rare susceptibility
genotype is largely responsible for disease
...

- Penetrance does not need to be anywhere near 100%
- Vast majority of unaffected individuals are expected to carry one or
more risk alleles
- Disease such as schizophrenia is actually a collection of hundreds,
or possibly even thousands, of similar conditions that are
attributable to rare variants at individual loci
- If each of the variants explains most of risk in just a handful of
people, their effects will not explain enough of variance in total
population to be detected by standard GWAS procedures
- For disease with high heritability, under a multiplicative model,
relative risks rise steeply as number of contributing rare alleles in
individual increases, but only very small fraction of individuals have
sufficiently large number of alleles to ensure high sibling relative
risks
Broad Sense Heritability Model:
- The broad sense heritability model posits that additive
contributions of common variants and large effects of rare variants
are insufficient to explain the missing heritability
...

- GxG = genotype-by-genotype interactions: otherwise known as
epistasis, refers to situation in which the effect of one genotype is
conditional on genotypes at one or more other unlinked loci
- GxE = genotype-by-environment interactions: refers to situation in
which effect of genotype is conditional on environment, which may
include abiotic (temperature), biotic (viral exposure) and
cultural/behavioural influences

- Parent-of-origin genetic contributions: genetic effects that are only
seen when the allele is transmitted either from the mother or from
the father
- Broad sense states that you may have to look at the broader
picture, other than just gene-gene interactions
...
The association
between the mutant gene/SNP and the disease that you are looking
for may only be present under a specific environmental factor
...
If you
don’t account for the environmental trigger, you may be missing out
on a large amount of people that are contributing to the disease but
not showing the phenotype
Taken straight for “Box 1” from the article given…
Arguments for rare alleles:
Evolutionary theory predicts that disease alleles should be rare (if a
variation gives a disease, then it would be wiped out, and thus needs to be
rare)
Empirical population genetic data show that deleterious variants are
rare
Rare copy number variants contribute to several complex
psychological disorders
Many rare familial disorders are due to rare alleles of large effect
Synthetic associations may explain common variant effects
Arguments against rare alleles:
Simulation of the allele frequency distribution of data from genomewide association studies
(GWASs) is not consistent with rare variant explanations
Genome-wide associations are consistent across populations (ex
scitzophrenia is found everywhere, thus not ‘rare’)
Sibling recurrence rates are greater than the postulated effect sizes
of rare variants (If it was rare varients, then illnesses should have
such high heritability)
Epidemiological transitions cannot be attributed to rare variants
Rare variants do not have obviously additive effects
Arguments for common alleles:
GWASs have successfully identified thousands of common variants
Model organism research supports common variant contributions to
complex phenotypes
Variation in endophenotypes is almost certainly due to common
variants
The infinitesimal model is standard quantitative genetic theory
Common variants collectively capture most of the genetic variance in
GWASs

Arguments against common alleles:
The missing heritability has not been accounted for
Demographic phenomena suggest more than a simple common
variant model
The quantitative trait locus (QTL) paradox: QTLs that are
consistently detected in pedigrees and in experimental crosses are
not observed in outbred populations
Absence of blending inheritance
Very few common variants for diseases have been functionally
validated

14
...
Once you find the
candidates, then you can use these in a physiological system
...
This is from that d00d’s stuff, Wikipedia
is synthetic lethality and the same example from d00d’s lecture
...

Synthetic lethality - a type of genetic interaction where the co-occurence of two
genetic variants results in cellular or organismal death
...
Phenotypic traits of cancer can be
brought about by genetic alterations such as: (1) gain-of-function mutations (2)
loss-of-function mutations
...
By amplifying shRNA (short
hairpin RNA) and probing, we can screen for these cancer causing mutations in
individuals before phenotypic traits of cancers even occur
...
Cancer
cells are marked by genetic instability, errors in DNA repair, and
uncontrolled transcription, which create new synthetic lethal partners
in cancer cells
...


Consequently, drugs that target synthetic lethal partners of mutations
in cancer cells may not be toxic to normal cells, which could avoid offtarget side effects of chemotherapeutics
...
For example, BRCA1 and BRCA2 are
important for repairing double-strand breaks in DNA, and mutations in
these genes predispose individuals to breast cancer and ovarian
cancer
...
Synthetic lethality is also useful for
screening libraries of molecules to detect drugs that selectively inhibit
cancer cells
...
[13]
15
...
Michael Joyner of the
Mayo Clinic expressed scepticism about the new initiative on “precision
medicine” that the Obama administration intends to propose
...
 (Sorry  for  the  length!)      
1
...

-­‐  Unexpected  data  revealed  in  Human  Genome  Project  (HGP);  widespread  
diseases  like  diabetes/heart  disease/most  cancers  have  no  clear  genetic  story  for  
vast  majority  of  cases
...
 Age,  sex,  weight,  blood  tests  –  better  predictors  of  some  diseases  (Type  II  diabetes)  
than  your  DNA,  and  the  advice  of  more  exercise/better  eating  remains  the  same  either  
way  you  achieve  the  diagnosis
...
 Predictive  power  of  higher-­‐risk  variants  frequently  dependent  on  environment,  culture  
and  behavior  (ie:  obesity  -­‐-­‐  main  genetic  variant  only  seen  in  population  born  post  
WWII,  most  likely  result  of  low-­‐physical-­‐activity  &  high-­‐calorie  world  that  emerged  after)
4
...
 The  identified  variants  have  small  effect  sizes,  and  
have  explained  the  relatively  little  of  the  heritability  of  most  complex  traits
...
 Clinical  trials  have  failed  to  use  genetic  variants  to  target  patients  with  commonly  
used  drug  therapies,  and  researchers  have  found  how  a  patient  metabolizes  drugs  (from  
genetic  information)  does  not  improve  the  standard  way  of  adjusting  dosages  based  on  
other  factors  such  as  age/weight/blood  tests
...
 No  fix  for  defective  genes  via  gene  therapy  as  originally  hoped
                ie:  cystic  fibrosis  drugs  have  been  developed  from  genetic  info  to  aid  treatment
but  no  ‘cure’  or  reversal  potential  has  been  developed  as  a  result  of  genomic  
sequencing
...
 Unintended  consequences  from  human  response  to  risk  perceptions:
-­‐  If  people  feel  they  are  at  less  risk  for  a  disease,  they  might  engage  in  more  risky  
behavior  (as  they  feel  excessively  protected)  only  increasing  their  risk
...

-­‐  Worriers:  excessive  diagnostic  testing  and  procedures  “just-­‐in-­‐case”,  wasteful  
use  of  resources,  $$$
...
 *
16
...
Talked about it during the first lecture
...

The initial impact of the sequencing of the human genome was starting a
movement towards better understanding of human variation and study of
diseases
...
In 2000 when the HGP paper was published, much
of the information was incorrect and had little information with it compared to
today
...
In just three years the paper in
2004 gave 99
...
The initial genome was thought mainly to only consist of
protein coding sequences (30-40000 genes), but is now limited to about 21,000
...
With the advances in technology and assay mechanisms, a more
accurate representation of gene structure and the detection of variations was
vastly improved
...
The goal was to sequence and map the
human genome for better understanding of inheritance of traits and diseases and
which genotypes led to which phenotype
...
We can also use the genome for
mapping human history and ancestral lines
...

-The human genome encodes for aprox 21,000 protein coding genes
...
So what does? Epigenetics, and
the variability that results from different imprinting and turning genes on and off,
and SNP’s
...
5%) in all people
...

Humans have only about twice the number of genes as a fruit fly and barely more
genes than a worm
...
Some influence development of diseases, susceptibility to
certain drugs, toxins and infectious agents
...

The HapMap project
...

Can help us understand diseases
...
The figure below shows gene expression (mRNA) profiles of samples
from a normal lung (A) and from a cancerous lung (B and C)
...
) How would you interpret the data
shown above? Second lecture slides 8-12 in lecture 11
...
Gene expression
profiling is looking at the expression of a lot of genes
...

Gene expression profiling is an attempt to measure the activity (expression) of a
large number of genes at the same time, in order to create a comprehensive
overview of cellular function in a sample
...
Evidence of gene
expression is based on the concentration of mRNA that is being produced by a
particular gene, in order to interpret whether a gene is “on or off”
...
When a genetic sample is combined with the chip,
complementary sequences will interact, producing a mRNA concentrationdependent level of fluorescence, indicative of enhanced activity by a particular
gene
...


The data above represents the level of differential gene expression between lung
and lung tumor tissues
...
To the
right, heightened gene expression is demonstrated in the Cy5 (tumor tissue), as
opposed to the Cy3 (healthy tissue) -- genetic material expressed by the tumor
tissue is in red
...

18
...

GWAS is an approach that involves rapidly scanning markers across the
complete sets of DNA or genomes of a number of people in order to find genetic
variations that are associated with a specific disease
...
The GWAS is conducted by taking all the patients that
have a genetic disorder, and sequencing their genomes
...
Then
take the healthy individuals and sequencing their genomes and look for SNPs in
those genomes
...

The advantages of GWAS are the fact that the biological pathway
of the trait does not necessarily have to be known
...

There are a number of shortcomings of GWAS as it has been found that
the genetic components of different disorders are much less than originally
predicted
...
Secondly, some of the variants are difficult to detect in
the diseased individuals
...
Lastly, it is quite possible that heritability is over estimated for
some genetic disorders (environment + gene gene interactions count for more)
...


Limitations of GWAS:
•

Results need replication in independent samples in different populations
...


•

GWAS studies detect association not causation
...
Many variants
identified in GWAS are nowhere near a protein-coding gene, or are within
genes that were not previously believed to associated with a trait or
condition
...


The issue with genome wide association is that often there is a much smaller
genetic component involved in the production of a disease than would probably
be estimated when looking at heritability trends or twin studies (because
heritability has been overestimated in many cases, as opposed to recognizing the
role of environment etc)
...
Sometimes genetic variants are difficult to
detect, even in large case-control studies
...

Thus, 100% of cases would be prevented either by removing the mutation or
by adopting a low phenylalanine diet
...
Thus, the genetic and environmental components
are inseparable
...


19
...
Monogenic variation in drug
metabolism has been studied extensively
...
However,
an individual’s genetic profile affects the rate at which they metabolize drugs
...
Gene variations that can account
for these differences in metabolism rates include single nucleotide
polymorphisms, deletion of an allele, and multiple copies of an allele
...

Ex
...
They concluded that polygenic variation was to blame
...
Personalized medicine could
lower the cost of therapy, and prevent ‘cocktail’ remedies, for which each drug is
added only to mask the adverse effects that came about from the drug before it
...
Psychological effects on patients due to
their genetic testing results could also be grave, and includes not only the patient
but their lifestyle decisions for having a family, and their family members that may
be predisposed to due heritability
...
However, I do
believe that the therapeutic benefits from genetic testing will outweigh the
possible societal constraints

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Title: Physiological Genomics and Pharmacogenetics Midterm Study Notes
Description: Advances in Genetics, and Pharmacogenetics (PHPY 403): 4th year physiology and pharmacology course in the bachelor of science program at the University of Saskatchewan. Midterm review notes, in a question and essay answer format -Topics include: Chromosomal analysis, genomic imprinting, nutrigenomics and nutrigenetics, mitochondrial genome mutations and inheritance, genetic sequencing (advantages and disadvantages of each technique), genome sequencing consequences, cancer stem cell therapies, single base variations (SNP's) and differences in penetrance and expressivity due to environmental and hereditary factors, epigenetics, genetic maps, relatedness of the human race, dominant vs recessive (gene function, loss of function, different pathways, toxic effects), alternate models of genetic bases of common diseases (common disease - common variant model, infinitesimal model, rare allele model, broad sense heritability model, synthetic lethality, precision medicine, impacts of the human genome project, gene expression profiling, genome wide association study (GWAS)

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