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Genes & Genomes – BMW20605
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Week 1
- Phenotypes in families S&R: 5.1, 5.2, 5.4, 11.3, 14.5, 15.1, 15.2, 15.3, 18.1
- Natural genomic variation
Week 2
- Organisation of the human genome S&R: 2.4, 7.1, 9.1, 9.2, 9.4
Week 3
- Sequencing technologies S&R: 6.3, 6.4, 6.5
Test
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Week 4
- Linkage S&R: 17
- De Novo gene mapping
Week 5
- Molecular pathology S&R: 16.1, 16.2, 16.3, 16.5
Week 6
- Comparative genetics S&R: 11.4, 13.1, 13.2, 13.5, 21.1, 21.2, 21.3
Week 7
- Functional studies S&R: 9.4, Alberts
Week 8
- Back to the patient S&R 21.1, 22.1 (intro)
- Cardiovascular genetics
Test
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Paper analysis
- Week 1 – ABCB6 gene (DUH disease)
Liu, Hong, et al. "Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic
gene of dyschromatosis universalis hereditaria." PLoS One 9.2 (2014).
- Week 2 – GRIN2A and GRIN2B mutations
Endele, Sabine, et al. "Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable
neurodevelopmental phenotypes." Nature genetics 42.11 (2010): 1021.
- Week 3 – Sequencing technologies – the next generation
Metzker, Michael L. "Sequencing technologies—the next generation." Nature reviews genetics 11.1 (2010): 31-46.
,Week 1
Phenotypes in families
A locus: unique chromosomal location, defining the position of a gene
Allele: alternative version of a gene
Genotype: a list of the alleles present at one or several loci
Phenotype: observable properties of an organism
Homozygous: two of the same alleles
Heterozygous: different alleles
Why do diseases/mutations exist?
- Novel variants are continuously created with every offspring
- De novo mutations
- Mutations occur at a relative constant rate across or through replications errors
- Mutations are essential for fitness of a species and the species ability to develop, evolve and adapt to
changing environment
Diseases and mutations
Rare diseases → caused by a single gene mutation
Common disease → caused by environmental factors and common genetic variants (hypertension, stroke, cancer,
diabetes, autoimmune diseases)
Susceptibility for infections can also be influenced by rare and common genetic factors
- See figure leprosy slide 7 (Example)
Sources of DNA
Peripheral blood
- T-lymphocytes culture for karyotyping
- Nuclear DNA isolation
Buccal swab
- Nuclear DNA isolation
Skin biopsy
- Fibroblast culture
- Karyotyping
- Nuclear DNA isolation
- Metabolic / Enzymological essays
Muscle biopsy
- Study mitochondrial genome
Heritability
‘The proportion of the causation of a character that Is due to genetic causes’ or ‘The proportion of the total variance
of a trait that is genetic’. Heritability is specific to a given population at a given time.
𝑣𝑎𝑟𝑖𝑎𝑛𝑐𝑒 𝑑𝑢𝑒 𝑡𝑜 𝑔𝑒𝑛𝑒𝑡𝑖𝑐 𝑐𝑎𝑢𝑠𝑒𝑠
𝐻2 =
𝑣𝑎𝑟𝑖𝑎𝑛𝑐𝑒 𝑑𝑢𝑒 𝑡𝑜 𝑔𝑒𝑛𝑒𝑡𝑖𝑐 𝑎𝑛𝑑 𝑎𝑙𝑙 𝑜𝑡ℎ𝑒𝑟 𝑐𝑎𝑢𝑠𝑒𝑠
Figure 1: Correlation between parent trait value and offspring trait value
,Common diseases – heritability 0.08 – 0.90
Factors that determine heritability;
1. Mutations
2. Environmental factors
3. Epigenetics
4. Genetic risk
Genetics and environmental factors are often dependent of one another. Genetic disadvantage and social
disadvantage often go together. Like people with a rough childhood, they are more likely to commit suicide.
However, in this category of people, similarities are found within genes.
Determine heritability
1.Twin studies
Measuring the concordance (heritability) between MZ and DZ twins
Twin concordance for a dominant disease → MZ 100%, DZ 50%
Twin concordance for a recessive disease → MZ 100%, DZ 25%
Concordance is never 100%, not only genetic factors are involved but also environmental factors are involved.
Furthermore, the environmental factors are never similar, so even if the concordance is dependent only on
environmental factors, it can never be 100%.
Separating MZ twins from birth to study environmental effects. However, there are several drawbacks. First, there
are often small sample sizes. There is bias of ascertainment (less alike twins that are separated are not
‘newsworthy’), and twins are not always separated from each other for the total time of their lives or while
separated, they do still live in a similar environment.
2.Adoption studies
Does adoption save the child from getting certain diseases?
Determine whether a disease is caused by the biological parents or the adoptive parents, comparing matched
controls. Determine whether the child has the disease from the affected biological parent by comparison studies
with matched controls. So, adoption studies is a method to find out if a phenotypic character has a genetic basis.
Adoption studies are a golden standard for disentangling genetic and environmental factors.
Example → Schizophrenia is caused mostly by environmental factors because the concordance rate is 15.8%. A lot of
other factors, such as environmental factors, are involved in the progeny of the disease.
Drawbacks: small sample size, no information on biological family, adoptive family is often ‘similar’ to
biological family, twins may be treated alike, twins’ same sex or different sex
3.Family studies
Comparison of the risk of a family member to the total population risk
Family pedigrees are an overview of the total members of the family (male/female) and whom are infected by
disease. Through family pedigrees, the risk ratios (λR) per family member can be determined in comparison to the
total population risk.
Risk ratios = λR
‘The risk ratio determines the relative risk of disease in a relative of an affected person, compared to a member of the
general population.’
, Example – Calculating risk ratio;
Calculate the risk ratio of a sibling in a family that has a parent with an autosomal dominant disease. The penetrance is 90%,
the population risk is 1%.
Answer: Parent has the dominant disease, so the risk of offspring getting the disease is 50%. The penetrance, however, is
90% so 50%/100 x 90 = 45%. The risk ratio of the sibling is thus 45% to inherit the disease.
Inheritance
Mendelian one single gene (ex. Blood group ABO)
Non-Mendelian
Oligogenic small number of genes, <10
Polygenic many loci/genes each of individually small effect
Complex/Multifactorial many genes that cooperate + many non-genetic causes (ex. IQ,
Schizophrenia)
Mendelian inheritance
Mendelian characters are necessarily dichotomous. Dichotomous means that you either have it or you do not. Most
human characteristics are therefore not dichotomous.
Autosomal dominant (50% risk, full penetrance)
- At least one affected parent
- Affects either sex / Transmitted by either sex
- 50% chance of being infected
Autosomal recessive (25% risk, full penetrance)
- Born to unaffected parents (asymptomatic carriers)
- Affects either sex / Transmitted by either sex
- 25% chance of being infected
X-linked inheritance dominant
- Affects either sex, but more females than males
- Born to affected parents
- Females are often more mildly/variably affected than
males (X-inactivation)
- 50% chance of being infected
X-linked inheritance recessive
- Affects mainly males
- Born to unaffected parents
- Females are affected when father is affected and mother is carrier
X-linked diseases can be characterised by pedigrees that show a father that has the disease and only his daughters
inherit the disease
Mitochondrial diseases
- Affects both sexes
- Not transmitted by fathers
- Transmitted by mother + de novo mutations
Genes & Genomes – BMW20605
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Week 1
- Phenotypes in families S&R: 5.1, 5.2, 5.4, 11.3, 14.5, 15.1, 15.2, 15.3, 18.1
- Natural genomic variation
Week 2
- Organisation of the human genome S&R: 2.4, 7.1, 9.1, 9.2, 9.4
Week 3
- Sequencing technologies S&R: 6.3, 6.4, 6.5
Test
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Week 4
- Linkage S&R: 17
- De Novo gene mapping
Week 5
- Molecular pathology S&R: 16.1, 16.2, 16.3, 16.5
Week 6
- Comparative genetics S&R: 11.4, 13.1, 13.2, 13.5, 21.1, 21.2, 21.3
Week 7
- Functional studies S&R: 9.4, Alberts
Week 8
- Back to the patient S&R 21.1, 22.1 (intro)
- Cardiovascular genetics
Test
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Paper analysis
- Week 1 – ABCB6 gene (DUH disease)
Liu, Hong, et al. "Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic
gene of dyschromatosis universalis hereditaria." PLoS One 9.2 (2014).
- Week 2 – GRIN2A and GRIN2B mutations
Endele, Sabine, et al. "Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable
neurodevelopmental phenotypes." Nature genetics 42.11 (2010): 1021.
- Week 3 – Sequencing technologies – the next generation
Metzker, Michael L. "Sequencing technologies—the next generation." Nature reviews genetics 11.1 (2010): 31-46.
,Week 1
Phenotypes in families
A locus: unique chromosomal location, defining the position of a gene
Allele: alternative version of a gene
Genotype: a list of the alleles present at one or several loci
Phenotype: observable properties of an organism
Homozygous: two of the same alleles
Heterozygous: different alleles
Why do diseases/mutations exist?
- Novel variants are continuously created with every offspring
- De novo mutations
- Mutations occur at a relative constant rate across or through replications errors
- Mutations are essential for fitness of a species and the species ability to develop, evolve and adapt to
changing environment
Diseases and mutations
Rare diseases → caused by a single gene mutation
Common disease → caused by environmental factors and common genetic variants (hypertension, stroke, cancer,
diabetes, autoimmune diseases)
Susceptibility for infections can also be influenced by rare and common genetic factors
- See figure leprosy slide 7 (Example)
Sources of DNA
Peripheral blood
- T-lymphocytes culture for karyotyping
- Nuclear DNA isolation
Buccal swab
- Nuclear DNA isolation
Skin biopsy
- Fibroblast culture
- Karyotyping
- Nuclear DNA isolation
- Metabolic / Enzymological essays
Muscle biopsy
- Study mitochondrial genome
Heritability
‘The proportion of the causation of a character that Is due to genetic causes’ or ‘The proportion of the total variance
of a trait that is genetic’. Heritability is specific to a given population at a given time.
𝑣𝑎𝑟𝑖𝑎𝑛𝑐𝑒 𝑑𝑢𝑒 𝑡𝑜 𝑔𝑒𝑛𝑒𝑡𝑖𝑐 𝑐𝑎𝑢𝑠𝑒𝑠
𝐻2 =
𝑣𝑎𝑟𝑖𝑎𝑛𝑐𝑒 𝑑𝑢𝑒 𝑡𝑜 𝑔𝑒𝑛𝑒𝑡𝑖𝑐 𝑎𝑛𝑑 𝑎𝑙𝑙 𝑜𝑡ℎ𝑒𝑟 𝑐𝑎𝑢𝑠𝑒𝑠
Figure 1: Correlation between parent trait value and offspring trait value
,Common diseases – heritability 0.08 – 0.90
Factors that determine heritability;
1. Mutations
2. Environmental factors
3. Epigenetics
4. Genetic risk
Genetics and environmental factors are often dependent of one another. Genetic disadvantage and social
disadvantage often go together. Like people with a rough childhood, they are more likely to commit suicide.
However, in this category of people, similarities are found within genes.
Determine heritability
1.Twin studies
Measuring the concordance (heritability) between MZ and DZ twins
Twin concordance for a dominant disease → MZ 100%, DZ 50%
Twin concordance for a recessive disease → MZ 100%, DZ 25%
Concordance is never 100%, not only genetic factors are involved but also environmental factors are involved.
Furthermore, the environmental factors are never similar, so even if the concordance is dependent only on
environmental factors, it can never be 100%.
Separating MZ twins from birth to study environmental effects. However, there are several drawbacks. First, there
are often small sample sizes. There is bias of ascertainment (less alike twins that are separated are not
‘newsworthy’), and twins are not always separated from each other for the total time of their lives or while
separated, they do still live in a similar environment.
2.Adoption studies
Does adoption save the child from getting certain diseases?
Determine whether a disease is caused by the biological parents or the adoptive parents, comparing matched
controls. Determine whether the child has the disease from the affected biological parent by comparison studies
with matched controls. So, adoption studies is a method to find out if a phenotypic character has a genetic basis.
Adoption studies are a golden standard for disentangling genetic and environmental factors.
Example → Schizophrenia is caused mostly by environmental factors because the concordance rate is 15.8%. A lot of
other factors, such as environmental factors, are involved in the progeny of the disease.
Drawbacks: small sample size, no information on biological family, adoptive family is often ‘similar’ to
biological family, twins may be treated alike, twins’ same sex or different sex
3.Family studies
Comparison of the risk of a family member to the total population risk
Family pedigrees are an overview of the total members of the family (male/female) and whom are infected by
disease. Through family pedigrees, the risk ratios (λR) per family member can be determined in comparison to the
total population risk.
Risk ratios = λR
‘The risk ratio determines the relative risk of disease in a relative of an affected person, compared to a member of the
general population.’
, Example – Calculating risk ratio;
Calculate the risk ratio of a sibling in a family that has a parent with an autosomal dominant disease. The penetrance is 90%,
the population risk is 1%.
Answer: Parent has the dominant disease, so the risk of offspring getting the disease is 50%. The penetrance, however, is
90% so 50%/100 x 90 = 45%. The risk ratio of the sibling is thus 45% to inherit the disease.
Inheritance
Mendelian one single gene (ex. Blood group ABO)
Non-Mendelian
Oligogenic small number of genes, <10
Polygenic many loci/genes each of individually small effect
Complex/Multifactorial many genes that cooperate + many non-genetic causes (ex. IQ,
Schizophrenia)
Mendelian inheritance
Mendelian characters are necessarily dichotomous. Dichotomous means that you either have it or you do not. Most
human characteristics are therefore not dichotomous.
Autosomal dominant (50% risk, full penetrance)
- At least one affected parent
- Affects either sex / Transmitted by either sex
- 50% chance of being infected
Autosomal recessive (25% risk, full penetrance)
- Born to unaffected parents (asymptomatic carriers)
- Affects either sex / Transmitted by either sex
- 25% chance of being infected
X-linked inheritance dominant
- Affects either sex, but more females than males
- Born to affected parents
- Females are often more mildly/variably affected than
males (X-inactivation)
- 50% chance of being infected
X-linked inheritance recessive
- Affects mainly males
- Born to unaffected parents
- Females are affected when father is affected and mother is carrier
X-linked diseases can be characterised by pedigrees that show a father that has the disease and only his daughters
inherit the disease
Mitochondrial diseases
- Affects both sexes
- Not transmitted by fathers
- Transmitted by mother + de novo mutations
