Genetics and Public Health
summary
1
,Monogenetic (Mendelian) Inheritance 3
Genes and Diseases 4
Public Health and Genetics 7
Genetic Testing 10
Translation of Genomics into Healthcare 12
More than Mendel 14
Genetic Screening 17
Screening Criteria and Parameters 20
Clinical Genetics 21
Population Genetics 23
Prenatal Screening 25
Consanguinity 29
Preconception Care 31
Calculating Interactions Between Genes and Environment 32
From Genetics to Genomics and Further 34
Whole Genome Sequencing (WGS) 37
Ethical, Legal and Social Aspects of WES/WGS 40
Epigenetics 42
New Developments in Gene Editing 45
(In)equality in Genetics 48
Psychological and Behavioral Implications of Genetic Testing 51
The Shadow of Eugenics 54
Pharmacogenomics 57
Clinical Validity 59
New Possibilities of Genomics Outside of Clinical Genetics 61
Potential Use of Polygenic Risk Scores 63
Clinical Utility 65
2
, Monogenetic (Mendelian) Inheritance
PEDIGREE
- Children are portrayed in order of birth, with rst-borns at the left
- Pedigree symbols:
- ▢ = male
- ◯ = female
- ♢ = gender unknown
- ▢—◯ = mating
- ▢==◯ = consanguineous mating
- ◼ = a ected male
- ⚫ = a ected female
- ◧ = heterozygous male
- ◐ = heterozygous female
- ⧄ = deceased male
- ⁄ ⃝ = deceased female
- ● ⃝ = female carrier of X-linked trait
AUTOSOMAL DOMINANT INHERITANCE PATTERN
- Only 1 gene variant is needed to carry the disease (i.e. Aa)
- Characteristics of a pedigree of a family with a typical autosomal dominant inheritance
pattern:
- Several generations
- On average 50% of children of a ected parents are also a ected
- I.e. 1/2 chance for o spring to carry the disease
- Inheritance is not gender-related: from man to woman, woman to woman, man to man,
woman to man
- Examples of autosomal dominant disorders:
- Huntington’s disease, BRCA1 and BRCA2 (=breast cancer), Lynch syndrome (=colon
cancer), achondroplasia (=dwar sm)
AUTOSOMAL RECESSIVE INHERITANCE PATTERN
- Everyone carries around 2-3 recessive diseases
- Characteristics of a pedigree of a family with a typically autosomal recessive inheritance
pattern:
- On average, if both parents are carrier, 1/4th of their children are a ected
- Parents are usually healthy carriers (i.e. Aa)
- Families in which none of the children are a ected, but both parents are carriers, are not
observed
- Sometimes parents are consanguineous
- Usually just 1 generation
- Inheritance is not gender-related
- Examples of autosomal recessive disorders:
- Cystic brosis, hemoglobinopathies (sickle cell anemia, thalassemia), phenylketonuria
3
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, X-LINKED (SEX-LINKED) INHERITANCE PATTERN
- Characteristics of a pedigree of a family with a typical X-linked recessive inheritance pattern:
- Males are a ected, females pass on the disorder but are (usually) not a ected
- Sons are a ected
- Women are not a ected: they are carrier, they can pass on the predisposition
- No inheritance from man to man
- Fathers (if fertile) can have daughters who are carriers
- In general: no increased risk on X-linked disorder if there is a healthy male in between
- Examples of X-linked inherited disorder: Duchenne muscular dystrophy (DMD), hemophilia A
and B (=impaired blood clotting), color blindness
- NB: men with DMD mostly cannot get children to begin with due to infertility
Genes and Diseases
GENETIC VARIATION
- Genetics: science of genes, heredity and variation
- Genetics is a fast moving eld: once started with Mendel and peas, whereas nowadays
there are fast technological developments, and it is increasingly multidisciplinary
- Genetics can have high impact on individuals, families and populations (hypes and hopes)
- Gene: a functional unit that is regulated by transcription and encodes a product (protein or
RNA)
- ~20,000-25,000 genes in the human genome
- Located on chromosomes (23 pairs)
- Only 2% of genome codes for proteins (exons): ‘cut-and-paste’
- Determine hereditary traits
- Other 98% of DNA is non-coding (unexplained) and considered ‘junk DNA’: e.g. having
regulatory functions of distant gene, acting as ‘switch gene’
- Not just the number of genes makes humans who they are and determines the complexity
of a species; instead, the types of genes that are present code for multiple protein
complexes that determine the complexity of species
- Although humans and other apes both have the same amount of genes, there are
phenotypic di erences
- Human genetic variation is what makes us unique/di erent
- Classes of human genetic variants:
- Single nucleotide variant: 1 nucleotide changed from one individual to another
- Involvement of multiple nucleotides, thereby being structural variants:
- Insertion-deletion variant: 1(+) basepairs are present in some genomes, but
absent in others
- Block substitution: a string of adjacent nucleotides varies between 2 genomes
- Inversion variant: the order of the basepairs is reversed in a de ned section of a
chromosome
- Copy number variant: (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
- Genetic adaptation will lead to survival of the ttest, considering genetic variation
- 2 individuals each di er 1 base in 1000 basepairs (forensic, paternity testing)
- Polymorphism: change in DNA with frequency >1%
- In our genome: ~15,000,000 genetic variants (polymorphisms, e.g. SNPs)
- SNP: single nucleotide polymorphism
- Most polymorphisms have no phenotypic consequences, but some contribute to
common phenotypic traits (e.g. height)
- It is important to distinguish polymorphism from (pathogenic) mutations: normal
sequence variations vs. rare and deleterious changes
4
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summary
1
,Monogenetic (Mendelian) Inheritance 3
Genes and Diseases 4
Public Health and Genetics 7
Genetic Testing 10
Translation of Genomics into Healthcare 12
More than Mendel 14
Genetic Screening 17
Screening Criteria and Parameters 20
Clinical Genetics 21
Population Genetics 23
Prenatal Screening 25
Consanguinity 29
Preconception Care 31
Calculating Interactions Between Genes and Environment 32
From Genetics to Genomics and Further 34
Whole Genome Sequencing (WGS) 37
Ethical, Legal and Social Aspects of WES/WGS 40
Epigenetics 42
New Developments in Gene Editing 45
(In)equality in Genetics 48
Psychological and Behavioral Implications of Genetic Testing 51
The Shadow of Eugenics 54
Pharmacogenomics 57
Clinical Validity 59
New Possibilities of Genomics Outside of Clinical Genetics 61
Potential Use of Polygenic Risk Scores 63
Clinical Utility 65
2
, Monogenetic (Mendelian) Inheritance
PEDIGREE
- Children are portrayed in order of birth, with rst-borns at the left
- Pedigree symbols:
- ▢ = male
- ◯ = female
- ♢ = gender unknown
- ▢—◯ = mating
- ▢==◯ = consanguineous mating
- ◼ = a ected male
- ⚫ = a ected female
- ◧ = heterozygous male
- ◐ = heterozygous female
- ⧄ = deceased male
- ⁄ ⃝ = deceased female
- ● ⃝ = female carrier of X-linked trait
AUTOSOMAL DOMINANT INHERITANCE PATTERN
- Only 1 gene variant is needed to carry the disease (i.e. Aa)
- Characteristics of a pedigree of a family with a typical autosomal dominant inheritance
pattern:
- Several generations
- On average 50% of children of a ected parents are also a ected
- I.e. 1/2 chance for o spring to carry the disease
- Inheritance is not gender-related: from man to woman, woman to woman, man to man,
woman to man
- Examples of autosomal dominant disorders:
- Huntington’s disease, BRCA1 and BRCA2 (=breast cancer), Lynch syndrome (=colon
cancer), achondroplasia (=dwar sm)
AUTOSOMAL RECESSIVE INHERITANCE PATTERN
- Everyone carries around 2-3 recessive diseases
- Characteristics of a pedigree of a family with a typically autosomal recessive inheritance
pattern:
- On average, if both parents are carrier, 1/4th of their children are a ected
- Parents are usually healthy carriers (i.e. Aa)
- Families in which none of the children are a ected, but both parents are carriers, are not
observed
- Sometimes parents are consanguineous
- Usually just 1 generation
- Inheritance is not gender-related
- Examples of autosomal recessive disorders:
- Cystic brosis, hemoglobinopathies (sickle cell anemia, thalassemia), phenylketonuria
3
ffff
fi ff fiff fffi ff ff
, X-LINKED (SEX-LINKED) INHERITANCE PATTERN
- Characteristics of a pedigree of a family with a typical X-linked recessive inheritance pattern:
- Males are a ected, females pass on the disorder but are (usually) not a ected
- Sons are a ected
- Women are not a ected: they are carrier, they can pass on the predisposition
- No inheritance from man to man
- Fathers (if fertile) can have daughters who are carriers
- In general: no increased risk on X-linked disorder if there is a healthy male in between
- Examples of X-linked inherited disorder: Duchenne muscular dystrophy (DMD), hemophilia A
and B (=impaired blood clotting), color blindness
- NB: men with DMD mostly cannot get children to begin with due to infertility
Genes and Diseases
GENETIC VARIATION
- Genetics: science of genes, heredity and variation
- Genetics is a fast moving eld: once started with Mendel and peas, whereas nowadays
there are fast technological developments, and it is increasingly multidisciplinary
- Genetics can have high impact on individuals, families and populations (hypes and hopes)
- Gene: a functional unit that is regulated by transcription and encodes a product (protein or
RNA)
- ~20,000-25,000 genes in the human genome
- Located on chromosomes (23 pairs)
- Only 2% of genome codes for proteins (exons): ‘cut-and-paste’
- Determine hereditary traits
- Other 98% of DNA is non-coding (unexplained) and considered ‘junk DNA’: e.g. having
regulatory functions of distant gene, acting as ‘switch gene’
- Not just the number of genes makes humans who they are and determines the complexity
of a species; instead, the types of genes that are present code for multiple protein
complexes that determine the complexity of species
- Although humans and other apes both have the same amount of genes, there are
phenotypic di erences
- Human genetic variation is what makes us unique/di erent
- Classes of human genetic variants:
- Single nucleotide variant: 1 nucleotide changed from one individual to another
- Involvement of multiple nucleotides, thereby being structural variants:
- Insertion-deletion variant: 1(+) basepairs are present in some genomes, but
absent in others
- Block substitution: a string of adjacent nucleotides varies between 2 genomes
- Inversion variant: the order of the basepairs is reversed in a de ned section of a
chromosome
- Copy number variant: (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
- Genetic adaptation will lead to survival of the ttest, considering genetic variation
- 2 individuals each di er 1 base in 1000 basepairs (forensic, paternity testing)
- Polymorphism: change in DNA with frequency >1%
- In our genome: ~15,000,000 genetic variants (polymorphisms, e.g. SNPs)
- SNP: single nucleotide polymorphism
- Most polymorphisms have no phenotypic consequences, but some contribute to
common phenotypic traits (e.g. height)
- It is important to distinguish polymorphism from (pathogenic) mutations: normal
sequence variations vs. rare and deleterious changes
4
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