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Genetics summary chapters 24 + 25 VU Amsterdam
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This summary covers complete chapters 24 and 25 of genetics at the Vrije Universiteit Amsterdam.
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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.
, Chapter 24
2. Gain-of-function mutations: mutations that change the gene product so that it gains a new/abnormal function
example: achodroplasia.
3. Dominant-negative mutations: mutations that alter the gene product in a way that acts antagonistically to the
normal gene product example: Marfan syndrome.
- X-linked recessive inheritance: the gene affecting the disorders lays on the X-chromosome and especially affects
the males. Males are hemizygous – have a single copy of the X chromosome. therefore, a female heterozygous for
an X-linked recessive allele will not have the disorder, but will pass this to 50% of her sons. Example: Hemophilia
A. The pattern of X-linked recessive inheritance is revealed by the following observations:
1. Males are more likely to exhibit the trait.
2. Mothers of affected males often have brothers/fathers who are also affected.
3. Daughters of affected males produce (on average) 50% affected sons.
- X-linked dominant inheritance: males are more severely affected than females, because females carry an X
chromosome with a normal copy of the gene. Often, male embryo’s die so most individuals exhibiting this mode
of inheritance are females and the individuals do not reproduce. Examples: Rett syndrome and Aicardi syndrome
are not passed from parent to offspring. The following pattern is observed:
1. Only females exhibit the trait when it is lethal to males.
2. Affected mothers have 50% of passing the trait to the daughters and sons, but affected sons often die.
- Locus heterogeneity: phenomenon in which a particular type of disease may be caused by mutations in two/more
different genes, e.g. Hemophilia.
a. Hemophilia A is a defect in the clotting factor VIII.
b. Hemophilia B is a defect in the clotting factor IX X-linked recessive disorder
c. Hemophilia C is a defect in the clotting factor XI autosomal recessive disease (chr. 4).
Researchers often rely on the known locations of genes and markers along a chromosome. Homologous chromosomes
exhibit genetic differences:
- Allelic variations between genes,
- Sequence differences not affecting genes but still used as molecular markers.
Haplotype (haploid genotype) refers to the linkage of alleles/markers on a single chromosome. They are rarely changed by
mutation, but can change in a few generations due to crossing-over if markers are not close together on a chromosome.
Haplotypes can distinguish different homologous chromosomes. A new mutation to a disease-causing allele is closely linked
to a molecular marker that characterizes a haplotype. Researchers find a disease-causing gene based on two assumptions:
1. The disease-causing allele has its origin in a single individual known as the founder.
2. When the disease-causing allele originated in the founder, it occurred in a region of a chromosome with a
particular haplotype. The haplotype is not likely to have changed over the course of several generations if the
disease-causing allele and markers are close together.
For example, if a molecular marker is the closest to the disease-causing allele, then the individuals would inherited that
close linked marker due to the fact that a crossing-over would not occur since they are so close to each other, thereby not
separating the closest marker/allele and the disease-causing allele. When alleles and molecular markers are associated with
each other at a frequency that is significantly higher than expected by a random chance, they exhibit linkage
disequilibrium. So in this case it would be 2c + disease-causing allele / tightly linked.
Linkage to a molecular marker localizes a mutation to a chromosomal location. This can still be very large, typically 1 million
bp in length and it would contain about 5-10 genes. These genes could be identified by a chromosome walk. The human
genome project can identify genes in a region.
- International HapMap project: worldwide effort to identify SNPs – base differences (single-nucleotide
polymorphisms) and other types of human genetic variations.
- HapMap: catalog of common genetic variants that occur in human beings.
- Genomic-wide association study: examination of a genome-wide set of genetic variants among different
individuals to see if any variant is associated with a disease or other type of trait.
- Genetic testing: the use of testing methods to determine if an individual carries a genetic abnormality.
- Genetic screening: population-wide genetic testing.
Genetic testing is used to identify inherited human diseases and can be performed prior to birth:
1. Amniocentesis: a doctor removes amnionic fluid containing fetal cells using a needle that is passed through the
abdominal wall. The fetal cells are then grown in the laboratory and then karyotyped to determine the number of
chromosomes per cell and whether chromosome structure changes have occurred.
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