LECTURES GENETICS AND PUBLIC
HEALTH
LECTURE 1: MEET & GREET: MENDEL
PEDIGREE SYMBOLS
AUTOSOMAL DOMINANT INHERITANCE PATTERN
Draw a pedigree with a typical autosomal dominant inheritance pattern
What are typical characteristics
- 50/50 → 50% chance → can also be that no children are affected → for each child 50%
- You only have to carry 1 gene to inherit it
- Not gender related
- Several generations
- On average 50% of children of affected parents are also affected
- Inheritance from man to woman, woman to woman, man to woman, woman to man
Autosomal dominant disorders
- Huntington disease
- BRCA1 & 2: breast cancer
- Lynch Syndrome: colon cancer
- Achondroplasia: dwarfism
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,AUTOSOMAL RECESSIVE INHERITANCE PATTERN
Draw a pedigree with a typically autosomal recessive inheritance patterns
What are typical characteristics?
- Usually parents are not affected
- Not sex related
- We are all carriers of 2 to 3 recessive diseases
- On average, if both parents are carrier, a quarter of their children are affected
- Families in which none of the children are affected, but both parents are carrier, are not observed
- Sometimes parents are consanguineous
- Usually just 1 generation
Autosomal recessive disorder
- Cystic fibrosis (CF)
- Hemoglobinopathies (sickle cel anemia, thalassemia)
- Phenylketonuria (PKU)
CASE PETER AND DANIELLE
Peter and Daniëlle have a relationship. A nephew of Daniëlle has
Duchenne Muscular Dystrophy (DMD). Peter does not want to have
children if his children have a high risk to have DMD. However,
Daniëlle would very much like to have children. Nephew Edward is
Daniëlle’s brother’s son.
- DMD shows an X-linked inheritance pattern
- Characteristics of a pedigree of a family with a typical X-
linked recessive inheritance pattern:
o Sons are affected
o Women are not affected: they are carrier, they can pass on the predisposition
o No inheritance from man to man
- In general: no increased risk on X-linked disorder if there is a healthy male in between
- Danniëlle’s brother has a “normal” X- chromosome, otherwise he would have had DMD as well.
Edward will have inherited the predisposition for DMD from his mother (or it is a ‘de novo’ (new)
mutation)
- Daniëlle does not have an increased risk to pass on the disorder to her children
- Referral to a clinical genetics center is not necessary
Chance is 0%
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,CASE JASPER AND LISA
Jasper and Lisa have a relationship. The cousin of Lisa, Tim, has DMD. Jasper does not want to have children if
they have a high risk to have DMD. However, Lisa would very much like to have children. Tim is the son of Henk
and Isabelle. Isabelle is the sister of Lisa’s mother
- In this pedigree there are only women between Lisa and Tim. Because Isabelle is a carrier, Lisa has a
25% chance to be a carrier as well.
- Here referral is necessary!
X-LINKED INHERITANCE PATTERN
- Characteristics of a pedigree of a family with a typical X-linked (sex-linked) recessive inherited
disorder:
o Males are affected, females pass on the disorder but are (usually) not affected
o No inheritance from man to man
o Fathers (if fertile!) can have daughters who are carriers
- X-linked inherited disorders: Duchenne Muscular Dystrophy, Hemophilia A and B (impaired blood
clotting), Color blindness
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,LECTURE 2: GENES AND DISEASES
GENES
Genetics: science of genes, heredity and variation
- Fast technological developments, increasingly multidisciplinairy
- Can have high impact on individuals, family and populations (hypes and hopes)
WHAT IS A GENE
Gene= functional unit that is regulated by transcription and encodes a product (protein or RNA)
- 20-25.000 genes in the human genome
- Located on chromosomes (23 pairs)
- Only 2% of genome codes for proteins (exons): cut and paste
- Determine hereditary traits
Large parts are non coding (unexplained). We call this junk DNA
Now we discovered that the other parts have more regulatory functions of distant gene: switch gene→ switch
on and switch of the gene
Phenotypic differences between human and other apes
- Both 20-25.000 genes → this is similar
- Puffer fish has 35.000 genes
- Sand rocket has 25.000 genes
➔ It is not just the number who determines who we are and the complexity of the species→ 1 gene
codes for multiple proteins or protein complex → determines complexity of the species
WHAT MAKES US UNIQUE
- We have human genetic variation
- This can be devided into multiple classes: makes us different
o Single nucleotide variant: one variant that is changed from one nucleotide to another (C base
changed for T)
o Insertion-deletion variant: occur when one or more base pairs are present in some genomes
but absent in others. Generally composed of only few bases
o Block substitution: cases in which a string of adjacent nucleotides varies between two
genomes
o Inversion variant: one in which the order of the base pairs is reversed in a defined section of
a chromosome
o Copy number variant: occur when identical or nearly identical sequences are repeated in
some chromosomes but not others
Genetic variation
- Genetic variation leads to phenotypic variation
- Genetic variation in a population increases the chance that some individuals will survive
- 2 individuals each differ 1 base in 1000 basepairs (forensic, paternity testing)
- Change in DNA with frequency >1% = polymorphisms
- In our genome: ca. 15.000.000 genetic variants (polymorphisms, e.g. SNPs)
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, - Polymorphism vs (pathogenic) mutations → these can cause disease
o Normal sequence variations vs rare and deleterious changes
MUTATIONS
- Defined as a change in the DNA (disturbs protein function→ can cause disease)
o DNA replication
o Chemical damage
o Ionizing radiation
- Origin
o Somatic cells
▪ Occur in nongermline tissues
▪ Cannot be inherited
▪ Mutation in tumor only (for example, breast)
o Germ line/sex cells
▪ Present in egg or sperm
▪ Can be inherited
▪ Cause cancer family syndrome
▪ Mutation in egg or sperm (in parent)→ all cells affected in offspring
- Types of mutations
o Chromosome mutation
▪ Loss (monosomy) or gain (trisomy: down syndrome) of whole chromosomes =
aneuploidy
▪ Structural changes within the
chromosome – translocation
(rearrangement of parts of the
chromosome, because of damage),
deletions etc.
o Gene mutation: alteration at gene level: point
mutation (single base), insertions, deletion
GENETIC DISEASE
What is the relevance of knowing something is hereditary?
Case 1: peter and his father at 10 months
- Age of 15 months, diagnosed at clinical genetics centre: retinoblastoma (eye tumour), mutation in RB
gene (AD)
- Father also had enucleated eye (never realized/had been told of possible genetic aetiology)
- If known about the genetic risk (for children): early screening and early detection possible
➔ The importance of taking an adequate family history and an appropriate follow-up of that
Case 2
- 2nd child of healthy parents
- From birth: colds, coughing
- 4 times antibiotics
- Does not grow well
- Pediatrician: cystic fibrosis (CF)
o Incurable disorder: lungs and nutritional malabsorption
o Daily physiotherapy, dietary supplements, intensive treatment for chest infections
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, o Limited life expectancy
- Is it hereditary?
- CF caused by mutations in CFTR gene
- Autosomal recessive
- 1 in 30 carrier (European descent)
- Birth prevalence: 1: 3600-4000
- Answer to parents: yes it is hereditary, risk next child is 1 in 4, also risk family members to be carrier
TERMINOLOGY
Hereditary: inherited, derived from parents (genetic disorder is usually, but not always inherited, e.g. acquired
mutations)
Congenital means apparent at birth
- Not all congenital disorders are genetically determined (e.g. fetal alcohol syndrome: mother drinks to
much alcohol during pregnancy, toxoplasmosis infection): 40-60% unknown cause
- Not all hereditary diseases are congenital (BRCA)
Hereditary disorders
- Cancer (oncogenetics), Cardiovascular diseases (cardiogenetics), Neurological disorders
(neurogenetics), storage diseases, errors of metabolism, skin disorders, blood disorders etc.
CLASSIFICATION OF GENETIC DISEASES
Chromosomal disorders and monogenic disorders are individually rare, but collectively common 1-2% birth
prevalence
CHROMOSOMAL DISORDERS
- Numerical (chromosome gain or loss) or structural changes (0,6% live born)
- Most affect autosome (= chromosomes other than sex chromosomes)
Generally
- Loss of chromosomal material= more dangerous than gain
- Abnormalities of sex chromosomes = better tolerated than autosomal
- Usually origin de novo (new) (both parents and siblings are normal)
Down syndrome: birth prevalence 1:700
Sex chromosome abnormality: Klinefelter, 47 XXY
- 1:500-1000 males
- Extra X is either of paternal or maternal origin
- Clinical characteristics e.g.:
o Disproportional long arms/legs
o IQ mostly normal
o Glynaecomasty: breast development
o Reduced body and facial hair
o Infertility
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,MONOGENIC DISORDER
- Most follow mendelian pattern of inheritance
- Single gene
Online mendelian inheritance in Man (OMIM)
- Mendelian disorders: caused by mutations in single genes of large effect (1% liveborn)
- In 2019
o 5281 autosomal
o 342 X linked
o 4 Y linked
o 33 mitochondrial
Mechanisms of single gene disorders
1. Enzyme defects (e.g. inborn errors of metabolism)
2. Defects in membrane receptors/transport systems
3. Alterations in structure, function, or quantity of non-enzyme proteins
4. Genetic variants leading to unusual drugs reactions
Enzyme defects: storage diseases
- Material to be degraded builds up in certain cells in the body and causes problems
- Example: Tay-Sachs disease
o Deficiencies of enzyme hexosaminidase
o GM2 ganglioside (waste) builds up
o Destroys nerve cells
o Children: loss of sight, hearing, movement etc, death age 4
Defects in membrane receptors/transport systems
- Example: familial hypercholesterolemia
o Receptor disease
o Mutation in gene encoding LDL receptor (involved in transport and metabolism of
cholesterol)
o Elevated cholesterol levels (artherosclerosis)
o Early onset heart disease
Alteration in structure, function or quantity of non enzyme proteins
- Example Marfan syndrome
o Prevalence 1:5000
o Disorder of connective tissues of the body (defect in extracellular glycoprotein fibrillin-1)
▪ Affects skeleton, eyes, and cardiovascular system (dilation of aorta → aneurysm)
o 80% of cases are familial (autosomal dominant)
Genetic variants leading to unusual drugs reactions
- E.g.: cytochrome P450
o Used by the liver to metabolize drugs
o Changes in CYP enzyme levels affect drug metabolism
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, o Rapid metabolization (you give higher dose of the drugs), if you have poor metabolization
(lower the dose)
MULTIFACTORIAL AND COMPLEX DISORDER
- Frequent, 10% life time risk to develop one of the diseases
Multifactorial etiology of disease: to develop the diseases: the environmental factors are very important
Multifactorial disorders
- Most common disorder are multifactorial
o Asthma, arthritis, dementia, depression, heart disease, cancer, cleft lip, spina bifida etc.
- Multi or polygenic: 1> gene, each convey low risk
- And environmental factors
- Complex interactions
GENETIC EFFECT VS. ENVIRONMENTAL EFFECTS
Mendelian subsets of common diseases: from the common diseases (heart disease, cancer), there is also a
subset that has the mendelian cause → breast cancer, Mendelian subset are BRACA 1 & 2 → disease are
common but cause is a single mutation
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