Genetics & Public Health
Lecture 1: Mendelian Inheritance
- Pedigree (symbol) charts:
o A pedigree is a chart that shows the presence or
absence of a trait within a family across generations.
o On top, the parents are displayed and on the bottom
the children in order of birth (first born on the left).
o Homozygous means that someone has two
identical alleles for a particular gene and when
someone has two different alleles for a particular
gene, which is called heterozygous.
o Monogenic diseases are variants in a single gene
and are enough to cause disease.
- Autosomal dominant inheritance pattern:
o An autosomal dominant trait is located on one autosome and is
phenotypically expressed over another allele because a single copy
of the mutated gene is enough to cause the disorder.
o On average, the trait expresses over several generations and 50%
of the children of affected parents are also affected. The trait can
be inherited from man to women, from women to women, and from
women to man.
o Examples: Huntington disease (brain disorder), BRCA1/2 (breast cancer), Lynch syndrome
(colon cancer), and Achondroplasia (short-limbed dwarfism).
- Autosomal recessive inheritance pattern:
o An autosomal recessive trait is located on one autosome
and is only expressed in absence of a dominant allele,
meaning that two copies of it causes the disease.
o On average, if both parents are carriers of the trait, a quarter
(25%) of their children are affected. It usually lasts for only
one generation. In case of a consanguineous marriage, two
blood-related individuals are married, and the chance of affected children is larger.
o Examples: Cystic fibrosis (lung disease), Hemoglobinopathies (sickle cell anaemia), and
Phenylketonuria (metabolic disease).
- Case Peter & Danielle – X-linked recessive inheritance pattern:
o “Peter and Danielle have a relationship. A nephew of
Danielle has Duchenne Muscular Dystrophy (DMD),
which is a X-linked trait. Peter does not want to have
children if his children have a high risk of having DMD.
However, Danielle would very much like to have children.
Nephew Edward is Danielle’s brother’s son.”
o X-linked recessive traits are usually only present in
males who cannot pass the variant on to their sons, but
they always pass their affected X chromosome to their
daughters who will be carriers.
o In general, there is no increased risk for an X-linked disorder if there is a healthy male in
between. In this case of Peter and Danielle, it means that Danielle’s brother has a ‘normal’ X-
chromosome and Edward inherited the predisposition from his mother. Danielle does not have
an increased risk to pass on the disorder to her children.
o Examples: Duchenne Muscular Dystrophy (muscle loss), Haemophilia A/B (impaired blood
clotting), and colour blindness.
, - Case Jasper & Lisa – X-linked inheritance pattern:
o “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 of having 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.”
o There is a 12,5% chance that Lisa passes the trait on to
her child and a 6,25% chance that the child will be
affected if it’s a boy.
o Examples: Duchenne Muscular Dystrophy (muscle loss),
Haemophilia A/B (impaired blood clotting), and colour
blindness.
- Punnett squares:
o Punnet squares help predict offspring traits by showing possible gene combinations from
maternal and paternal alleles → heterozygous (Bb), homozygous dominant (BB), and
homozygous recessive (bb).
o Capital letters represent dominant alleles and lower case letters recessive alleles. Dominant
traits will ‘overpower’ the recessive trait and will be expressed.
o A monohybrid cross is a type of genetic cross between two individuals
with homozygous genotypes and different alleles for a single trait, often
resulting in an opposite phenotype.
▪ The phenotypic ratio of phenotypes is 3:1 → 3 offspring
dominant for the trait and 1 recessive.
▪ The genotypic ratio is 1:2:1.
▪ The result of the cross occurs in the form of heterozygous hybrid offspring expressing
the dominant trait (Bb/BB).
o A dihybrid cross is a type of genetic cross between two
individuals with either homozygous or heterozygous
genotypes and with different alleles for two distinct traits.
This means that the genes aren’t linked.
▪ The phenotypic ratio is 9:3:3:1 → 9 offspring
dominant for both traits, 3 offspring dominant for
A trait only and 3 for B trait only, and 1 offspring recessive for both traits.
▪ The genotypic ratio is 1:2:2:4:1:2:1:2:1.
Lecture 2: Genes & Diseases
Part 1: Genes
- Genetics and genes:
o Genetics is a science of genes, hereditary and variation. In the earlier days, you would think
about Mendelian inheritance. Nowadays, due to fast technological developments, you see that
it’s also increasingly multidisciplinary.
o Genetics can have a high impact on individuals, families, and populations.
o A gene is a functional unit that’s regulated by transcription and encodes a product
(protein/RNA). In the human genome, we have ~20.000-25.000 genes, which is less than they
expected when they first studied the genome.
o The genes are located on the chromosomes, and we have 23 pairs.
o Only 2% of the genome codes for the proteins; exons translate into proteins and determine
hereditary traits. The other 98% is still unexplained and was called ‘junk DNA’. Recently it has
been discovered that other parts have more regulatory functions (switch on/off genes).
, - Phenotypic differences:
o It’s not just the number of the genes that makes us who we are and determines the complexity
of the species. It’s probably that one gene codes for multiple proteins/protein complexes that
determines the complexity of species.
- Human genetic variation – classification:
o Single nucleotide variants are DNA sequence variations in which only one nucleotide is
changed from one individual to another.
o Insertion-deletion variant can occur when one or more base pairs are present in the same
genomes but absent in others.
o Block-substitutions describe cases in which a string of adjacent nucleotides varies between
two genomes.
o Inversion variant includes the reversion of the order of base pairs in a defined section of a
chromosome.
o Copy number variants can occur when identical or nearly identical sequences are repeated in
some chromosomes but not in others.
o Genetic variations lead to phenotypic variations and in a population it also increases the
chance that some individuals will survive. If you compare two individuals, we differ in one base
in 1000 base pairs on average. This can be helpful in forensics or paternity testing.
o Changes in DNA with a frequency of >1% is called polymorphism. In our genome, there are
~15.000.000 genetic variants and most of them have single nucleotide polymorphism (SNP).
They are normal sequence variations when compared to (pathogenic) mutations, which are
rare and deleterious changes that can cause disease.
- Genetic mutations:
o Mutations are defined as a change in the DNA that disturbs protein function and eventually
can lead to disease. There are endogenous causes, such as DNA replication, and exogenous
causes, such as chemical damage and ionising radiation.
o The origin of the mutation can be either in somatic cells or in germ/sex cells.
▪ Somatic mutations occur in non-germline tissues, for example in breast tissue or in a
tumour. These mutations cannot be inherited since they occur during life.
▪ Germline mutations are present in egg/sperm cells and can be inherited from parent
to child, potentially being the cause of cancer.
o Chromosome mutations
▪ Loss (monosomy) or gain (trisomy) of whole chromosomes is called aneuploidy.
▪ Structural changes within the chromosome can occur, such as translocation/deletion.
o Gene mutations are alterations at gene level, such as point mutations (single base), insertion
or deletion.
Part 2: Diseases
- Case 1: Peter and his father at ten months:
o When the mother of Peter was taking pictures with a flashlight, she noticed that Peter’s eye lit
up. At 15 months, Peter was diagnosed with retinoblastoma (eye tumour), which is caused by a
mutation in the Retinoblastoma gene (Rb) that is autosomal dominant.
o The father of Peter once had an enucleated eye (removed), but he never realised that
Retinoblastoma was genetic and could be passed on to his son. If he had known about the
genetic risk, early screening and detection would have been possible, resulting in fast and
adequate treatment.
- Case 2: A couple and their second child:
o A healthy couple presented a second child that had a lot of colds and coughed a lot since birth,
therefore needing antibiotics four times. The paediatrician diagnosed the child with Cystic
Fibrosis, which is an incurable disorder with problems in the mucus of the lungs resulting in
nutritional malabsorption.
o Cystic Fibrosis is caused by mutations in the CFTR-gene, which is autosomal recessive. There
are about 2000 mutations involved in this gene, but the most common is the ∆F508 mutation.
o Approximately 1 in 30 people is carrier of this disease, mostly from European descent, and the
birth prevalence is 1:3600-4000.
o In Cystic Fibrosis, there usually is a lot of invasive treatment needed for the recurrent chest
infections and there is a limited life expectancy.
, - Terminology:
o Hereditary means inherited, derived from the parents. A genetic disorder is usually (but not
always) inherited, for example acquired mutations.
▪ Examples: cancer (oncogenetics), cardiovascular disease (cardiogenetics),
neurological disorders (neurogenetics), storage diseases, error of metabolism, skin
disorders or blood disorders.
o Congenital means apparent at birth. Not all congenital disorders are genetically determined
(e.g., foetal alcohol syndrome) and 40-60% has an unknown cause. Moreover, not all
hereditary diseases are congenital (BRCA) and apparent at birth.
- Classification of genetic diseases:
o Chromosomal and monogenic disorders are individually quite rare, but when added up they are
quite common (1-2% birth prevalence).
o Chromosomal disorders can be numerical or structural (0,6% liveborn), and mostly affect the
autosome (= chromosome other than sex chromosomes).
▪ A loss of chromosomal material is more dangerous than a gain of material.
▪ Abnormalities of sex chromosomes are better tolerated than autosomal abnormalities.
▪ Usually, the origin is ‘de novo’, meaning that both parents and siblings are normal.
▪ Most common chromosomal abnormality is Down syndrome (birth prevalence 1:700).
▪ An example of sex chromosome abnormality is Klinefelter disorder, which presents in
1:500-1000 males with an extra X chromosome of either paternal or maternal origin.
• Clinical characteristics: disproportional long arms/legs, IQ mostly normal,
gynaecomastia (breast development), reduced body and facial hair, and
infertility.
o Monogenic disorders often follow Mendelian patterns of inheritance and are caused by
mutations in single genes that have a large effect (1% liveborn).
- Mechanisms of single gene disorders:
o Enzyme defects (e.g., “inborn errors of metabolism”).
▪ Example: Tay-Sachs disease is a rare disorder that is seen more in people from
Jewish descent. Material that has to be degraded builds up in certain cells in the body
and causes problems because the enzymes don’t work. Waste builds up in the brain
(GM2 ganglioside) and destroys nerve cells. Thereby, children lose their sight or
hearing and their movement (death at age of 4).
o Defects in membrane receptors/transport systems.
▪ Example: Familial Hypercholesterolemia is caused by a mutation in the gene encoding
for the LDL-receptor. Cholesterol levels build up because these receptors don’t work
well, and therefore there are problems with early-onset heart disease (atherosclerosis)
and sudden death.
o Alterations in structure, function, or quantity of non-enzyme proteins.
▪ Example: Marfan syndrome is also a rare disorder with a prevalence of 1:5000. It is a
disorder of connective tissues of the body, with a defect in extracellular glycoprotein
fibrillin-1. It affects the skeleton, eyes, and cardiovascular system (dilation of aorta →
aneurysm). Around 80% of the cases are familial and caused by an autosomal
dominant mutation.
o Genetic variants leading to unusual drug reactions.
▪ Example: cytochrome P450 enzymes are used by liver to metabolise drugs. Genetic
variants in P450 change enzyme levels and can result in ultra-rapid metabolization
(give higher dose) of drugs or poor metabolization (give lower dose) of drugs.
- Multifactorial and complex disorders:
o These disorders are very frequent, and every person has a 10% lifetime risk to develop one of
these diseases. To develop these diseases, environmental factors are very important.
o Most common disorders are multifactorial: asthma, arthritis, dementia, depression, heart
disease, cancer, cleft lip, and spina bifida.
o Multi-or polygenic means that there is more than one gene involved in causing the disease; the
genes add up as a polygenic risk model and all together, they increase the risk of developing
the disease.
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