Lecture 3- Nature vs Nurture (Genomic vs Environmental Factors)

Question 1

What were the positions on nature vs nurture in antiquity?

Answer 1

-Biological determinism/ Genetic determinism:

Plato: all knowledge is innate and environment and emotions only allow access to it -

-Social determinism:

Aristotle: tabula rasa, every person is a blank slate on which society and environment writes

-ongoing debate as to the extent an individual is responsible for his/her actions

Question 2

What is biological determinism?

Answer 2

-the interpretation of humans and human life from a strictly biological point of view, and it is closely related to genetic determinism.

Question 3

What is social determinism?

Answer 3

-the theory that social interactions and constructs alone determine individual behavior

Question 4

When are concepts usually the easiest to see?

Answer 4

• at their extremes
• many human characteristics behave as per Gaussian distribution (height, weight, intelligence etc.)
• same with some diseases and causes of diseases
• at one extreme have diseases that are fully caused by environmental factors (teratogens) and on the other extreme have monogenetic diseases (fully genetically caused)

Question 5

What are monogenetic conditions?

Answer 5

• 100% penetrance during life
• fault within one gene

Question 6

PIC2What are some of the monogenetic conditions?

Answer 6

• dysmorphic syndromes
• congenital anomalies
• developmental delay
• TAR syndrome
• Classical genetic disorders (Neurofibromatosis NF1, Marfan)
• Genetic forms of common disorders: Familial cancers, Neurogenetics

Question 7

What is the TAR syndrome?

Answer 7

• monogenetic disorder
• autosomal recessive disorder
• characterized by the absence of the radius bone in the forearm, and a dramatically reduced platelet count

Question 8

What is a dysmorphic syndrome?

Answer 8

-belief that one’s own appearance is unusually defective and is worthy of being hidden or fixed

Question 9

What is neurofibromatosis (NF1)?

Answer 9

• covers a number of inherited conditions that are clinically and genetically distinct and carry a high risk of tumor formation, particularly in the brain.
• it is an autosomal dominant disorder
• 25% of cases are de novo mutations, ie no family history

Question 10

What is Marfan?

Answer 10

• a genetic disorder of connective tissue. It has a variable clinical presentation, ranging from mild to severe systemic disease.
• the most serious manifestations involve defects of the heart valves and aorta, which may lead to early death

Question 11

What is familial adenomatous polyposis coli (APC)?

Answer 11

• APC is a protein that in humans is encoded by the APC gene
• APC is classified as a tumor suppressor gene
• defects cause uncontrolled tumour growth and eventually one will turn malignant
• AD cancer syndrome
• Cancer occurs in multiple polyps which form from

Question 12

What is the Peutz- Jeghers syndrome?

Answer 12

• Intestinal polyposis (hamartomas)
• Mucocutaneous pigmentation (increased pigmentation of the lip)
• lower risk of colon cancer than in APC but have a high probability of a number of cancers incl. colorectal, gastric, pancreatic, breast and ovarian cancer
• STK11 gene mutations

Question 13

What are teratogens?

Answer 13

-substances or environmental agents which cause the development of abnormal cell masses during fetal growth, resulting in physical defects in the fetus.

Question 14

What is teratology?

Answer 14

-study of birth defects caused by in utero exposure to a)Drugs b)Environmental toxins

Question 15

What was one of the main reasons for the emergence of teratology?

Answer 15

• thalidomide
• 1961 -2 papers described limb defects in babies whose mothers had taken thalidomide between days 35 and 48 from LMP
• This observation sparked search for association between other drugs and birth defects

Question 16

What are some of the environmental teratogens?

Answer 16

• Infections
• Maternal diabetes
• Environmental toxins (methylmercury)
• Hyperthermia
• Ionizing radiation
• Recreational drugs

Question 17

How does susceptibility to teratogens vary with developmental stage of the foetus?

Answer 17

• Susceptibility to teratogenesis varies with the developmental stage at the time of exposure to the adverse influence
• red= when very susceptible
• problem is that many women are unaware of their pregnancy in the beginning stages of the foetal development -this is when lot of the damage occurs

Question 18

What are the causation criteria for teratogenicity?

Answer 18

• Correlation does not prove causation
• Human experimentation (usually not an option)
• Strength of association (magnitude of relative risk)

Question 19

What is an example of an infection that causes severe disability in the offspring?

Answer 19

• Rubella embryopathy
• Risk of infection of the foetus from the mother:

100% in first 8weeks

Question 20

What is an example of a recreational drug that causes severe disability in the offspring?

Answer 20

• alcohol -FAS -the effects of a drug may be more subtle than those seen with thalidomide.
• This infant has a small head, some distinctive facial features, developmental delay, short stature and a heart abnormality and was exposed to large amounts of alcohol in the first trimester.
• Alcohol use in pregnancy has been extensively studied and a characteristic set of abnormalities, foetal alcohol syndrome is now recognisable.
• Note also Alcohol-related neurodevelopmental disorder (ARND)

Question 21

What is the importance of folate during pregnancy?

Answer 21

• Folate supplementation reduces risk of NTD by 70% both as primary prevention and secondary prevention
• loss of this pathway associated with spina bifida and other NTDs
• now we know that some drugs have effect as are antimetabolites of folateso it is recommended to take folate in the preconception prerion until at least 12 weeks of gestation
• Some drugs associated with folate antagonism!

Question 22

What is the take-home message?

Answer 22

-birth defects caused by teratogenic exposures are preventable when you are cautious and receive pre-pregnancy counselling

Question 23

What is an example of an environmental factor that can be modified or avoided in terms of pregnancy and childhood development?

Answer 23

• Mutation in both copies of the phenylalanine hydroxylase gene
• In PKU, phenylalanine levels rise damage brain causing:
  a) Severe learning difficulties.
  b) Also decreases hair, skin and eye pigmentation
• Postnatal condition as in utero maternal PKU level protect embryo
• Tested and diagnosed at post natal check
• Diet restriction prevents learning difficulty
• preventable if the diet is changed
• monogenetic conditions are preventable but have to be diagnosed early and modification must be made
• Positive environmental modification of monogenetic disorder

Question 24

What are the two major ways of assessing the intrinsic genetic versus the extrinsic environmental component of more variable traits?

Answer 24

1. Twin and adoption studies
2. Genome wide association studies

Question 25

How and why do you use twin and adoption studies?

Answer 25

-to obtain evidence that a trait may have a genetic component

• Twin studies

-Monozygotic twins - same genome and environment

• Dizygotic twins • 50% similar genome and environment
• Adoption studies
• Same or 50% genome different environment
• can compare these to tease out how much of a trait is genetically determined (then should be much more prevalent among monozygotic compared to dizygotic)
• Twin studies can quantify how much of a trait has a genomic component
• Around 30% of Breast cancer has a familial component
• Currently clinical genetic testing can account for only around 14%

Question 26

What happened after the genome was sequences in terms of genetic research?

Answer 26

-could ask bigger questions, not just concerned with one gene but many and the interactions between genes

Question 27

What was the 100 genome project?

Answer 27

• sequencing of 1092 genomes from 14 populations
• Low coverage whole genome and exome sequencing
• discovered 38 million single polymorphism, 1.4 million small insertions and 14,000 Larger deletions

Question 28

What does genetic effect mean?

Answer 28

-an effect that is significant enough to interpret by itself “mutation” “pathological” “unique or rare

Question 29

What does genomic effect mean?

Answer 29

-An effect that can only be interpreted correctly in the context of other similar variants “variant or polymorphisms” “normal” “common”

Question 30

What are the case control studies and how do you perform them?

Answer 30

• Collect 1000s of cases with one quantifiable trait: height, diabetes, depression
• Collect age controlled age and gender matched controls
• Quantify each genomic variation in both cohorts
• Any SNP in which case > control may represent a possible genomic influence on that trait

Question 31

What is a SNP?

Answer 31

• Single Nucleotide Polymorphism is a DNA sequence variation occurring commonly within a population (e.g. 1%) in which a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes.
• For example, two sequenced DNA fragments from different individuals, AAGCCTA to AAGCTTA, contain a difference in a single nucleotide. In this case we say that there are two alleles. Almost all common SNPs have only two alleles

Question 32

What is a genome wide association study?

Answer 32

• an examination of many common genetic variants in different individuals to see if any variant is associated with a trait.
• GWAS typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major diseases.
• These studies normally compare the DNA of two groups of participants: people with the disease (cases) and similar people without (controls). -gives us probability of having diseases etc.
• genomic variation may not be directly causative but may modify the risk of developing a certain trait

Question 33

What is pharmacogenomics?

Answer 33

• the study of the role of genetics in drug response. It deals with the influence of acquired and inherited genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with drug absorption, distribution, metabolism and elimination, as well as drug receptor target effects

Question 34

What is the significance of Cytochrome P450 2D6 (CYP2D6)?

Answer 34

• an enzyme responsible for metabolising nearly 25% of all drugs (50% of top 100)
• 6-10% caucasians carry 2 null alleles
• 70 variant alleles -ultra rapid metabolisers have up to 13 copies of the gene

Question 35

What are the 3 types of metabolisers with respect to CYP2D6?

Answer 35

• Poor metaboliser:  ( 50-1000 x ↓) =Side effects may outweigh benefit at ‘stand. dose’
• Intermediate metab:  ( 5-400 x ↓) =Side effects may outweigh benefit at ‘stand. dose’
• Extensive metaboliser: normal
• Ultra-rapid metaboliser: 4 x ↑ =may never reach therapeutic levels on stand. dose

Question 36

What are some of the drugs that are affected by the CYP2D6?

Answer 36

• Beta blockers, eg propanaolol, nifedipine
• Tricylclics antidepressants SSRIs (eg paroxetine, fluoxetine)
• Anti-psychotics (haloperidol, risperidone, thioridazine)
• others: Codeine, Amphetamine, Tamoxifen

Question 37

How was the effect of decreased MAO discovered?

Answer 37

• X-linked (only men affected) Dutch family with learning difficulties and prominent behavioral abnormalities; aggressive violent behaviour, arson attempted rape and exhibitionism
• Functional: Decreased monoamine monoamine oxidase (MAO) activity in affected men ( MAO metabolises neurotransmitters, good functional candidate)
• Cause: Mutation in the MAO gene
• an example of a monogenetic disorder affecting behavior

Question 38

What did the genomic analysis of the MAO show?

Answer 38

• 1,037 individuals with data on childhood maltreatment (MT) and adult antisocial behaviour
• Genotype a MAO polymorphism assoc. with decreased MAO activity.
• Result:
• MT (maltreatment in childhood or development) + Low MAO activity = significantly increased risk of antisocial behaviour compared to
• MT + high MAO activity or No MT +low MAO= not as much antisocial behaviour
• Genomic predisposition IN PRESENCE OF MT ONLY

Question 39

Are the brains of of MAO deficient people different?

Answer 39

• yes
• Data suggest that MAO may function though regulation of anatomical Brain development during childhood

•Brain development continues through childhood

Question 40

What are the ethical implications of the whole MAO issue?

Answer 40

scenario:

• It is 2015, Joe Schmoe has been charged with assault. The physical evidence supporting his guilt.
• Joe’s lawyer asks him to undergo a series of genetic tests to determine whether he carries any of four genetic mutations that have been associated in research literature with violent behavior. The tests, while controversial, show that Joe’s DNA does, in fact, contain all four mutations.
• Based on these results, Joe’s lawyer will argue that Joe should be sent to a psychiatric facility rather than to state prison. He claims that because Joe’s genetic status predisposed him to this violent act, it would be unfair to sentence him as a criminal for behavior over which he had essentially no control.

• If you were the judge would the results of this controversial genetic test influence your decision?
• How would your decision be influenced if Joe had only 1 of the 4 mutations associated with violent behavior?
• What would be your decision if Joe was shown to suffer from a mental illness such as schizophrenia? How come?
• Should the fact that he may have a genetic predisposition to violent behavior be used to keep him in prison, should all newborn babies be screened to determine if they have genetic mutations that could be linked to violent behavior?
• What if a medication became available to treat people with these mutations?