Genetics 25
HC 18
25.1
Personalized medicine is becoming more widespread, meaning we are more and more using
the genotype of individuals to provide medication and treatment suited to the person.
Genetic diseases are often due to one mutation but can also be a combination of mutated
alleles. A variety of observations can determine the basis of a genetic disease in humans:
- A person with a genetic disease has more likely relatives with the same genetic
disease than a random person in public.
- Identical twins (monozygotic) share the disease more often than nonidentical twins
(dizygotic). A disorder’s concordance – degree in which it is inherited – is not always
predictable, provided that not all disorders are equally penetrant and that new
mutations after fertilization can happen.
- The disease does not spread to individuals in the same environment.
- Different populations have different frequencies of the disease.
- The disease tends to develop at a characteristic age, it has an age of onset when
disease symptoms appear.
- The human disease resembles a known genetic disorder in animals.
- There is a correlation between the disease and a mutant gene or chromosomal
disorder.
The pattern of inheritance can be deduced using a human pedigree:
- Autosomal recessive: often loss-of-function genes encoding enzymes
o Affected offspring has two unaffected parents
o Two unaffected heterozygotes have 25% affected offspring
o Two affected have 100% affected offspring
o Trait occurs in same frequency between sexes
o Often skips a generation
- Autosomal dominant:
o Affected offspring has one or two affected parents
o Affected individual with one affected parent, produces 50% affected
offspring, so affects individuals in every generation.
o Two affected heterozygotes have 75% affected offspring
o Trait occurs in same frequency between sexes
o The homozygote is more severely affected, in some cases even lethal
Haplo-insufficiency: only one single copy of a gene and that copy does
not produce normal phenotype; 50% is not sufficient to produce
normal phenotype.
Gain-of-function mutations: gene product changed so it gains a new
or abnormal function, whereby one copy of the dominant allele may
be sufficient already.
Dominant-negative mutations: altered gene product works against
the regular gene product.
- X-linked recessive:
, o Males are much more likely to exhibit the trait, since they only have one X
chromosome
o Mothers of affected males often have brothers or fathers who are also
affected
o Daughters of affected males produce 50% affected sons
- X-linked dominant:
o Only females exhibit the trait when it is lethal to males, because they only
have one X chromosome, they do not have a second one to compensate
o Affected mothers have 50% chance to pass it on to their daughters
Locus heterogeneity describes that a disease is caused by mutations in two or more genes,
which thus might follow complex patterns of inheritance; usually, the more genes are
involved, the more complex the system functions/processes. Gene A might give disease X,
but gene B and gene C could also contribute to disease X.
25.2
Disease-causing alleles may be identified due to the known locations of genes and molecular
markers along the chromosome. So, the close proximity to such markers may indicate a
disease-causing allele.
In time, homologous chromosomes may exhibit allelic variations and a variance in markers.
Along a chromosome, there are distinct sites for specific locations; may called site 1, 2, etc.
Every site has a letter designation based on the base sequence, if this sequence is identical
in the homologous chromosome, it has the same letter, if not, a new one. The specific
linkage of alleles or markers along the chromosome is the haplotype. These might change
due to mutations, though rare, they more often change via crossing-over; more likely for
sites that are far apart. The same accounts for inheritance.
If a disease is near such a marker, there is a low chance due to crossing-over or other
recombinational events, the disease-causing allele and the marker separate. Therefore, the
marker may be an indication of the allele. Originally, a mutation must have occurred near a
marker, causing a disease in a single individual: founder. So, the allele must be located in a
region of the chromosome with a particular haplotype. An individual with that haplotype is
more likely to have the disease-causing allele than another without it; moreover, if an allele
and molecular marker are associated at a frequency higher than random chance, there is
linkage disequilibrium.
After a disease is narrowed down to a localized region, which allele or gene of that region is
responsible? Genome mapping is one option, another is to look at the biological function.
You could also sequence the DNA of candidate genes, to exactly look at and identify a
mutation.
25.3 & 25.4
Skip them!
25.5
Cancer is a genetic disease characterized by uncontrolled cell division. It originates in a
single cell, that divides and undergoes more genetic changes (clonal). So, first a pre-
cancerous genetic change, benign growth and then accumulation of additional changes
leading to cancerous growth, being malignant now. They invade other healthy cell tissues
(invasive) and they migrate to other body parts causing secondary tumors (metastatic).
HC 18
25.1
Personalized medicine is becoming more widespread, meaning we are more and more using
the genotype of individuals to provide medication and treatment suited to the person.
Genetic diseases are often due to one mutation but can also be a combination of mutated
alleles. A variety of observations can determine the basis of a genetic disease in humans:
- A person with a genetic disease has more likely relatives with the same genetic
disease than a random person in public.
- Identical twins (monozygotic) share the disease more often than nonidentical twins
(dizygotic). A disorder’s concordance – degree in which it is inherited – is not always
predictable, provided that not all disorders are equally penetrant and that new
mutations after fertilization can happen.
- The disease does not spread to individuals in the same environment.
- Different populations have different frequencies of the disease.
- The disease tends to develop at a characteristic age, it has an age of onset when
disease symptoms appear.
- The human disease resembles a known genetic disorder in animals.
- There is a correlation between the disease and a mutant gene or chromosomal
disorder.
The pattern of inheritance can be deduced using a human pedigree:
- Autosomal recessive: often loss-of-function genes encoding enzymes
o Affected offspring has two unaffected parents
o Two unaffected heterozygotes have 25% affected offspring
o Two affected have 100% affected offspring
o Trait occurs in same frequency between sexes
o Often skips a generation
- Autosomal dominant:
o Affected offspring has one or two affected parents
o Affected individual with one affected parent, produces 50% affected
offspring, so affects individuals in every generation.
o Two affected heterozygotes have 75% affected offspring
o Trait occurs in same frequency between sexes
o The homozygote is more severely affected, in some cases even lethal
Haplo-insufficiency: only one single copy of a gene and that copy does
not produce normal phenotype; 50% is not sufficient to produce
normal phenotype.
Gain-of-function mutations: gene product changed so it gains a new
or abnormal function, whereby one copy of the dominant allele may
be sufficient already.
Dominant-negative mutations: altered gene product works against
the regular gene product.
- X-linked recessive:
, o Males are much more likely to exhibit the trait, since they only have one X
chromosome
o Mothers of affected males often have brothers or fathers who are also
affected
o Daughters of affected males produce 50% affected sons
- X-linked dominant:
o Only females exhibit the trait when it is lethal to males, because they only
have one X chromosome, they do not have a second one to compensate
o Affected mothers have 50% chance to pass it on to their daughters
Locus heterogeneity describes that a disease is caused by mutations in two or more genes,
which thus might follow complex patterns of inheritance; usually, the more genes are
involved, the more complex the system functions/processes. Gene A might give disease X,
but gene B and gene C could also contribute to disease X.
25.2
Disease-causing alleles may be identified due to the known locations of genes and molecular
markers along the chromosome. So, the close proximity to such markers may indicate a
disease-causing allele.
In time, homologous chromosomes may exhibit allelic variations and a variance in markers.
Along a chromosome, there are distinct sites for specific locations; may called site 1, 2, etc.
Every site has a letter designation based on the base sequence, if this sequence is identical
in the homologous chromosome, it has the same letter, if not, a new one. The specific
linkage of alleles or markers along the chromosome is the haplotype. These might change
due to mutations, though rare, they more often change via crossing-over; more likely for
sites that are far apart. The same accounts for inheritance.
If a disease is near such a marker, there is a low chance due to crossing-over or other
recombinational events, the disease-causing allele and the marker separate. Therefore, the
marker may be an indication of the allele. Originally, a mutation must have occurred near a
marker, causing a disease in a single individual: founder. So, the allele must be located in a
region of the chromosome with a particular haplotype. An individual with that haplotype is
more likely to have the disease-causing allele than another without it; moreover, if an allele
and molecular marker are associated at a frequency higher than random chance, there is
linkage disequilibrium.
After a disease is narrowed down to a localized region, which allele or gene of that region is
responsible? Genome mapping is one option, another is to look at the biological function.
You could also sequence the DNA of candidate genes, to exactly look at and identify a
mutation.
25.3 & 25.4
Skip them!
25.5
Cancer is a genetic disease characterized by uncontrolled cell division. It originates in a
single cell, that divides and undergoes more genetic changes (clonal). So, first a pre-
cancerous genetic change, benign growth and then accumulation of additional changes
leading to cancerous growth, being malignant now. They invade other healthy cell tissues
(invasive) and they migrate to other body parts causing secondary tumors (metastatic).
