Chapter 24
- Personalized medicine: the use of the information about a patient’s genotype and other clinical data in order to
select a medication, therapy, or preventative measures that is specifically suited to the patient.
When the occurrence of a disease correlates with several of the following observations, a geneticist is confident that the
disease has a genetic basis:
1. An individual who exhibits a disease is more likely to have genetic relatives with the disorder that is someone
in the general population. For example, someone with CF is more likely to have relatives with this disease.
2. Identical twins share the disease more often than non-identical twins. Identical twins (monozygotic twins) are
generically identical to each other, because there were formed from the same sperm and egg. A non-identical
twin/fraternal twins (dizygotic twins) are formed from separate pairs of sperm and egg cells. When a disorder has
a genetic component, both identical twins are more likely to exhibit the disorder. Geneticist evaluate the
disorder’s concordance – the degree to which it is inherited by calculating the percentage of twin pairs in which
both twins exhibit the disease relative to pairs where only one of the twins shows the disorder. Diseases caused
by one gene, the concordance in identical twins should be 100%, whereas with non-identical twins it should be
50%. For recessive diseases, the concordance in non-identical twins should be 25%. However, the actual
concordance is always lower due to reasons such as the not complete penetrance and one twin might have a
mutation that might have occurred after fertilization. It would be unlikely that the other twin would have the
same mutation.
3. The disease does not spread to individuals sharing similar environmental conditions.
4. Different populations tend to have different frequencies of the disease. Because mutations are rare events, they
may arise in one population, but not in the other, as well as the fact that each population has different
environmental conditions that may influence the prevalence of the allele.
5. The disease tends to develop at a characteristic age. The age of onset is the age where the first symptoms of a
disease appear.
6. The human disorder may resemble a disorder that is already known to have a genetic basis in an animal.
7. A correlation is observed between a disease and a mutant human gene or chromosomal alteration.
When a human disorder is causes by a mutation of a single gene simple Mendelian inheritance. It can be determined by
analysing human pedigrees. A geneticist must obtain data from large pedigrees with many affected individuals.
- Autosomal recessive inheritance: the Tay-Sachs disease is an example. Autosomal means that the gene is not on
the sex chromosome. 5 common features of an autosomal recessive inheritance are:
1. Frequently, an affected offspring has two unaffected parents.
2. When two unaffected heterozygotes have children, the percentage of affected children is on average 25%.
3. Two affected individuals have 100% affected children.
4. The trait occurs with the same frequency in both sexes.
5. Skip generations.
Disorders that involve defective enzymes typically have an autosomal recessive mode of inheritance. The heterozygote
carrier has 50% of the normal enzyme, which is sufficient for a normal phenotype, but not always: incomplete
penetrance/haplo-insufficiency. Human recessive alleles are often caused by mutations that result in the loss-of-function in
the encoded enzyme. Also, in a pedigree, it is often unknown whether or not someone is a carrier.
- Autosomal dominant inheritance: a single copy of the dominant allele cause the disease. Most affected
individuals hare heterozygotes . example: Huntington disease. The mutated gene encodes for a protein called
Huntingtin. The mutation, called triplet repeat expansion, adds a polyglutamine tract to the protein which causes
aggregation of the protein in the neurons, 5 common features of a dominant inheritance:
1. An effected offspring usually has two affected parents. However, due to incomplete penetrance and
mutations that might occur during gametogenesis, two unaffected parents may produce an affected
offspring.
2. An effected individual with only one affected parent is expected to produce 50% affected offspring (on
average).
3. Two affected heterozygous individuals have (on average) 25% unaffected offspring.
4. The trait occurs with the same frequency in both sexes.
5. For most dominant disease-causing alleles, the homozygote is more severely affected with the disorder,
and in some cases the dominant allele might be lethal.
3 common explanations for autosomal dominant disorders are:
1. Haploinsufficiency/incomplete dominance: the phenomenon in which a person has only one functional copy of
the gene and that the single functional gene does not produce a normal phenotype. 50% of the functional protein
is not sufficient to produce a normal phenotype. A heterozygote with one functional allele and with one inactive
allele has the disease example: aniridia.
- Personalized medicine: the use of the information about a patient’s genotype and other clinical data in order to
select a medication, therapy, or preventative measures that is specifically suited to the patient.
When the occurrence of a disease correlates with several of the following observations, a geneticist is confident that the
disease has a genetic basis:
1. An individual who exhibits a disease is more likely to have genetic relatives with the disorder that is someone
in the general population. For example, someone with CF is more likely to have relatives with this disease.
2. Identical twins share the disease more often than non-identical twins. Identical twins (monozygotic twins) are
generically identical to each other, because there were formed from the same sperm and egg. A non-identical
twin/fraternal twins (dizygotic twins) are formed from separate pairs of sperm and egg cells. When a disorder has
a genetic component, both identical twins are more likely to exhibit the disorder. Geneticist evaluate the
disorder’s concordance – the degree to which it is inherited by calculating the percentage of twin pairs in which
both twins exhibit the disease relative to pairs where only one of the twins shows the disorder. Diseases caused
by one gene, the concordance in identical twins should be 100%, whereas with non-identical twins it should be
50%. For recessive diseases, the concordance in non-identical twins should be 25%. However, the actual
concordance is always lower due to reasons such as the not complete penetrance and one twin might have a
mutation that might have occurred after fertilization. It would be unlikely that the other twin would have the
same mutation.
3. The disease does not spread to individuals sharing similar environmental conditions.
4. Different populations tend to have different frequencies of the disease. Because mutations are rare events, they
may arise in one population, but not in the other, as well as the fact that each population has different
environmental conditions that may influence the prevalence of the allele.
5. The disease tends to develop at a characteristic age. The age of onset is the age where the first symptoms of a
disease appear.
6. The human disorder may resemble a disorder that is already known to have a genetic basis in an animal.
7. A correlation is observed between a disease and a mutant human gene or chromosomal alteration.
When a human disorder is causes by a mutation of a single gene simple Mendelian inheritance. It can be determined by
analysing human pedigrees. A geneticist must obtain data from large pedigrees with many affected individuals.
- Autosomal recessive inheritance: the Tay-Sachs disease is an example. Autosomal means that the gene is not on
the sex chromosome. 5 common features of an autosomal recessive inheritance are:
1. Frequently, an affected offspring has two unaffected parents.
2. When two unaffected heterozygotes have children, the percentage of affected children is on average 25%.
3. Two affected individuals have 100% affected children.
4. The trait occurs with the same frequency in both sexes.
5. Skip generations.
Disorders that involve defective enzymes typically have an autosomal recessive mode of inheritance. The heterozygote
carrier has 50% of the normal enzyme, which is sufficient for a normal phenotype, but not always: incomplete
penetrance/haplo-insufficiency. Human recessive alleles are often caused by mutations that result in the loss-of-function in
the encoded enzyme. Also, in a pedigree, it is often unknown whether or not someone is a carrier.
- Autosomal dominant inheritance: a single copy of the dominant allele cause the disease. Most affected
individuals hare heterozygotes . example: Huntington disease. The mutated gene encodes for a protein called
Huntingtin. The mutation, called triplet repeat expansion, adds a polyglutamine tract to the protein which causes
aggregation of the protein in the neurons, 5 common features of a dominant inheritance:
1. An effected offspring usually has two affected parents. However, due to incomplete penetrance and
mutations that might occur during gametogenesis, two unaffected parents may produce an affected
offspring.
2. An effected individual with only one affected parent is expected to produce 50% affected offspring (on
average).
3. Two affected heterozygous individuals have (on average) 25% unaffected offspring.
4. The trait occurs with the same frequency in both sexes.
5. For most dominant disease-causing alleles, the homozygote is more severely affected with the disorder,
and in some cases the dominant allele might be lethal.
3 common explanations for autosomal dominant disorders are:
1. Haploinsufficiency/incomplete dominance: the phenomenon in which a person has only one functional copy of
the gene and that the single functional gene does not produce a normal phenotype. 50% of the functional protein
is not sufficient to produce a normal phenotype. A heterozygote with one functional allele and with one inactive
allele has the disease example: aniridia.
