lecture 12- human genetics 2

Question 1

Genetic origins of disease

Answer 1

Over 5,000 human diseases and disorders are presently known to have genetic origins
-Recessive gene: PKU, sickle-cell anemia, Tay-Sachs disease, cystic fibrosis
-Single dominant gene: Huntington’s disease, neurofibromatosis
-Polygenic inheritance: cancer, heart disease, asthma, psychiatric disorders, behavior disorders
-Sex-Linked inheritance: male-pattern baldness, red-green color blindness, hemophilia, Duchenne muscular distrophy, fragile-X syndrome
-Chromosomal anomalies: Down syndrome (trisomy 21), Kleinfelter syndrome (XXY), Turner syndrome (XO)
Regulator gene defects: genetic male with female genitalia
-Unidentified (poorly understood) genetic basis: autism spectrum disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD) (most likely polygenic

Question 2

Tay-Sachs disease

Answer 2

Is a fatal, autosomal recessive neurodegenerative disease of infancy and early childhood
Rare in most populations
Caused by mutations of HEXA gene on chromosome 15q23-q24.
First identified in 1969

Question 3

tay sachs population studies

Answer 3

Population studies and pedigree analyses suggest that mutations may have arisen from small founder populations:
Carrier frequency is 1:25 in Ashkenazi Jews
Same mutation is found in Cajun population in southern Louisiana
Two different mutations are common in French Canadians
Higher carrier frequency in Irish-American and Pennsylvania Dutch communities compared with general population
Incidence in unscreened Jewish populations is 1 in 3,900 births

Question 4

tay sachs population screening continued

Answer 4

Internationally, screening has reduced the incidence of Ashkenazi Jews with TSD-affected children by more than 90%
Australian high-school-based preconception genetic screening programs help young people through screening and education
Aim is to optimise reproductive choices for participants
Choosing a partner not at risk
IVF, Donor gametes, adoption
Selective terminations
Child-free
Plans to extend the program into the more general Ashkenazi Jewish community

Question 5

Huntington’s disease is a progressive neurodegenerative disorder- onset, prevalence

Answer 5

Autosomal dominant
Huntingtin gene isolated in 1993, on chromosome 4 at 4p16.3
> 40 repeats of CAG (cytosine, adenine, guanine) trinucleotide in coding region of gene
Mean onset ~40 yrs, death 12-15 yrs afterwards
Prevalence 5-10 per 100,000

Question 6

hungtingtons disease symptoms and therapeutic research

Answer 6

Symptoms include
Cognitive deterioration
Personality change, memory loss and depression
Choreic and slow movement
Therapeutic research
Mechanisms of neuronal death
Cell replacement therapy

Question 7

Chorea and bradykinesia characterise movement control in HD: involuntary

Answer 7

Involuntary ‘dance-like’ choreic movement

Abates in advance stages of disease, when akinetic and bradykinetic movements become clearer

Question 8

voluntary

Answer 8

Voluntary movement
Bradykinetic (finger, saccades, gait)
Inconsistent and inefficient movement
Abnormal co-contractions of muscles
Prolonged EMG bursts
Less efficient and more variable movements in handwriting
Sequential and simultaneous movement difficulties

Question 9

Broader sub-cortical and cortical damage in HD, compared with Parkinson’ Disease

Answer 9

Neuronal and astrocyte loss in the basal ganglia (caudate, putamen, global pallidus and other areas)
Selective degeneration of GABAergic neurons of striatum
As disease progresses, greater cortical atrophy occurs

Question 10

Broader sub-cortical and cortical damage in HD, compared with Parkinson’ Disease
continued..

Answer 10

The gene contains an expanded trinucleotide repeat (CAG) that ranges from 9-35 in healthy adults, and from 36 to 180 in HD
Alleles with 36-39 repeats show “reduced penetrance”-only some individuals will go on to develop clinical symptoms
Individuals with juvenile onset (Westphal variant) usually have expansions >55 repeats and develop HD before 20 years
Onset appears to be earlier when the transmission is from the father

Question 11

Schizophrenia

Answer 11

Fundamental and characteristic distortions of thinking, perception and affect that are inappropriate or blunted
Psychopathological thoughts
Hallucinations, paranoid or bizarre delusions, and disorganised speech and thinking leading to significant social and occupational dysfunction
Onset typically occurs in young adulthood
Affects ~ 0.5% of population
Course of schizophrenic disorders can be continuous or episodic
Not due to depression or manic symptoms unless it is clear that schizophrenic symptoms antedate the affective disturbance; not due to drug intoxication or withdrawal

Question 12

Schizophrenia continued

Answer 12

Genetic risk for schizophrenia is more likely to be continuous than categorical
The last 5 years of genetic research has produced evidence that genetic risk for SCZ is largely polygenic
“The efforts to ground a categorical biomedical model of schizophrenia in Mendelian genetics have failed. The genetic risk for SCZ is widely distributed in human populations so that we all carry some degree of risk”

Question 13

Fragile-X syndrome

Answer 13

FXS is the most common inherited form of intellectual disability
Expansion mutation of a CGG repeat sequence in the FMRI gene
Leads to silencing of the gene and absence of the gene product - the fragile X mental retardation protein
This protein is essential for synaptic plasticity, development of the shape of the brain, and cognitive development
Boys are typically more severely affected than girls
FMRI gene is on the X chromosome; girls have a second X chromosome (back-up)

Question 14

Phenotype and genotype

Answer 14

Normal human development will only occur if a given gene is turned on and off at the correct time, in the right place and for the right length of time
Some genes are only turned on in a few cells and for only a few hours and then are switched off permanently (e.g. during development of the embryo)
Other genes are involved in the basic functioning of almost all cells almost all of the time
Regulator genes control the switching on and off of genes

External factors can affect the switching on and off of genes
There is a continuous interaction between the environment and the genotype
The range of reaction refers to all the phenotypes that could theoretically result from a given genotype, given all the environments in which it could survive and develop…

Question 15

Range of reaction

Answer 15

The phenotype is the unique consequence of a particular genotype developing in a particular environment

Question 16

eviroment on phenotype

Answer 16

A child with a given genotype would probably develop quite differently in a loving, supportive family compared with growing up in an alienated, abusive family
The child actively creates and explores the environment in which s/he lives
By virtue of their nature, they evoke different responses from others
Squirmy babies are more difficult to cuddle
Children with ADHD-like behaviours often hear the words “no”, “stop”, “don’t do that” many more times that typically developing children
Children actively seek out things that they inherently enjoy
This increases as they age – so children at school will become friends with people who have similar energy levels and interests

Question 17

Phenylketonuria

Answer 17

• Children with phenylketonuria (PKU) are unable to metabolize phenylalanine.
• Phenylalanine is an amino acid found in high-protein foods (e.g. meats, eggs, fish, nuts) and in some artificial foods (e.g. diet drinks, artificial sweeteners)
• PKU is a disorder that is related to a defective gene on chromosome 12, in which the body cannot break down this amino acid. It builds up in the body and can cause problems with brain development
• With early diagnosis and a properly restricted diet, however, mental retardation resulting from PKU can be avoided.

Question 18

Genome:

Answer 18

record of the genetic material of an organism encoded in DNA

Question 19

Epigenome:

Answer 19

record of the chemical changes to the DNA and histone proteins of an organism

Question 20

Epigenetics

Answer 20

Study of heritable (but reversible) changes in gene expression that are not coded in the DNA sequence but by post-translational modifications in DNA, histone proteins and in microRNA
Epigenetic change is a mechanism by which the environment can produce persistent alterations in the phenotype through altering gene expression
There are three different mechanisms involved in the regulation of genes
Histone modification
DNA methylation
microRNA

Question 21

Histone modification

Answer 21

Histones act as spools around which the DNA winds. These histones are protein complexes
The winding of DNA has at least two functions:
It is a mechanical way of stocking and protecting the DNA
It is a very efficient way to switch on and off genes, depending on their geometric location, allowing access of transcriptional factors to promoter regions on the genes
Any changes in the packing of the DNA can lead to changes in accessibility of different genes for transcription…and therefore gene function
The structures of the histones can be modified by 3 different chemical processes (active methylation, acetylation, simple phosporylation)
These represent highly efficient systems to control gene expression

Question 22

DNA methylation

Answer 22

DNA has many areas that are rich in CpG elements/islets
If a CpG islet in a promoter region of a gene is methylated (has a CH3 group added), this interferes with the transcription of the gene
High methylation means reduced access to transcription factors in the promoter region
Low/absent methylation results in accessibility and gene transcription
On/off process
Process is tightly controlled by a complex enzyme machinery

Question 23

Micro-RNA

Answer 23

MicroRNAs are small non-coding RNA molecules
This is a rapidly expanding family of molecules: area of new research
About 1/3 of coding genes are regulated by microRNAs
This regulatory process is down-stream from transcription

Question 24

Epigenetic modification

Answer 24

These 3 forms of complementary modifications of genetic code are forms of “epigenetic modification”
Regulation is at the post-DNA level
These epigenetic modifications are involved in
The differentiation of cells and tissues during development of the foetus
The adapation to internal and external influences
Epigenetic modifications can be permanent
Epigenetic modifications are heritable during cell division, particularly during mitosis
E.g. “ ‘epigenetic’ histone lysine methylation is not maintained in a precise manner during mitotic division”*

Question 25

Processes involved

Answer 25

-Epigenetics occurs in processes that required a stable control of gene expression
-E.g. selective gene-silencing during cell differentiation
Parent-of-origin specific silencing (imprinting)
Suppressing the transposition of mobile elements (DNA sequences that can copy themselves throughout the genome)
-Environmental influences and stochastic events can cause changes in the epigenetic processes
-As we age, we accumulate changes in these processes
The Developmental Origins hypothesis suggests that there is a link between adverse conditions in early development (in specific windows of time) and the occurrence of disease later in life

Question 26

Epigenetics - summary

Answer 26

The “epigenome” comprises DNA methylation, histone modifications and non-coding RNAs
These all influence transcription, and therefore, protein production, cell functioning, system functioning and behaviour
The epigenome is in a metastable state
It is stable enough to maintain cells, but dynamic enough to respond to developmental and environmental cues
Alterations to the epigenome can lead to epi-mutations that are transmitted to daughter cells
These mutations can have a significant effect on cell functioning and can lead to disease (e.g. cancer)
Epigenetic mechanisms regulate gene expression and are sensitive to external stimuli – bridging the gap between environmental and genetic factors

Question 27

Autoimmune disorders

Answer 27

Autoimmune diseases encompass > 80 disorders, affecting ~7% of population
Rheumatoid arthritis, Lupus, Type 1 diabetes, Multiple sclerosis
Monozygotic twin studies often show discordance of these diseases, suggesting a role for environmental factors contributing to disease development
Interplay between genetic and environmental factors may predispose and progress autoimmune diseases
Exposure to UV radiation, infections, tobacco smoke, pollutants, alcohol consumption
Gender bias (females), age, latitude of country point towards environmental factors contributing to disease predisposition
Circulating immune cells are in constant exposure to environmental factors
At this stage, the precise epigenetic mechanisms involved in autoimmune disorders is unclear

Question 28

Psychiatric disorders

Answer 28

• Early development marks a time of rapid brain development and enhanced susceptibility to environmental insults
• Early-life exposures to stress or drugs may exert life-long effects on neuropsychiatric health
• Exposure to stress or drugs during neurodevelopment may have a broader impact on epigenetic states and brain circuits, than if they occur later in life
• Data from animal models and post-mortem human samples suggests a diverse array of epigenetic regulatory mechanisms
• Mediation of transcriptional abnormalities may underlie depression and addiction
• Challenge for the field of psychiatric epigenetics is to develop an integrated understanding of how the histone modifications, DNA methylation and non-coding RNAs, interact to orchestrate normal and abnormal gene expression

Question 29

Nutrition

Answer 29

Field of nutrigenomic research – how nutritional factors can impact the regulation of genes and therefore their functions without altering the genetic code – has advanced massively in the last few years
Cohort and epidemiological studies provide information about the role and timing of differences in nutrition on health, from an epigenetics perspective
During the Nazi occupation in Winter 1944, food supply was extremely shortened in parts of the Netherlands
Daily rations were

Question 30

nutrition continued

Answer 30

Prenatal exposure to the famine was associated with adverse metabolic and mental phenotypes later in life
Higher BMI
Elevated plasma lipids
Increased risks of schizophrenia
Increased risk of cardiovascular disease
Many of these associations were dependent on the sex of the foetus and the timing of exposure during gestation (first trimester in particular)

Question 31

Genetics and environment

Answer 31

The interplay between genes and experience is very complex.

This model of hereditary and environmental influences can help to simplify this interplay

Question 32

summary

Answer 32

Over 5,000 disorders have genetic origins
Recessive, dominant, polygenic, x-linked, chromosomal abnormalities
The phenotype is the unique consequence of a particular genotype developing in a particular environment
Epigenetic mechanisms regulate gene expression and are sensitive to external stimuli