Biochemistry 8 Flashcards
A central focus of medical genetics is the
identification of
mutations that cause disease.
Several types of maps are used in the field of genetics:
- Cytogenetic Map
- Physical Map
- Genetic or linkage map
Cytogenetic Map
representing
the visual appearance of a
chromosome when stained and
visualized under the microscope.
Physical Map
representing
actual physical distances, usually
measured in base pairs.
Genetic or Linkage map
which represents the linear order of genes in a chromosome, with their distance proportional to the frequency of recombination, based on the frequency of meiotic crossovers.
Principle of independent assortment (second
law of Mendel)
states that genes will be transmitted to the next generation independently of one another
Mendel’s second law contrasted with the
chromosome theory: presenting chromosomes as linear structures with genes located at specific sites
Morgan’s (and Sturtevant’s) work unified both ideas with his work on
crossing over
The second law of Mendel holds as long as
genes are in different chromosomes, or far apart on the same chromosome
If two loci occupy the same region of a chromosome they are said to be
lined
Morgan and Sturtevant proposed that crossovers are more likely to occur between
loci that are situated close together
The distance between two loci can then be estimated by the
recombination frequency in families
(If alleles A and B undergo recombination 5% of the times (in a large number of meiosis studied in families), their
recombination frequency is 5%.)
If two genes are unlinked: recombination frequency
50%
If two genes are linked: recombination frequency is
less than 50% (more likely to be inherited together)
Linkage disequilibrium
refers to the tendency for some alleles at two linked locations to occur together more often than
expected by chance.
genetic distance
between two loci is measured in centimorgans, where one centimorgan = 1 cM = 1% = 1 Mbp
If two genes are far apart in the same chromosome or in different chromosomes, they
are
unlinked, recombination frequency is 50%
During meiosis, there is 50% times when genes remain in the same chromosome (non-recombinant, AB and ab) and 50% times when genes are separated due to crossing over (recombinant, Ab and aB), i.e. 50% recombination frequency.
If two genes are close in the same chromosome, they are
linked: recombination
frequency is <50%. Crossing over sometimes, but not always, will separate them. The closer they are, the lower the recombination frequency. If A and B were the same gene, the recombination frequency would be 0%.
Crossing-over takes place in
prophase I of meiosis I
the average chromosome experiences
1-3 crossover events during meiosis
_______ chromosomes have a higher (1.5X) frequency of recombination
females
The combination of allels in each chromosome is
haplotype (from haploid genotype) ex: A1B1 and A2B2 haplotype
As a result of crossover, new combinations of alleles can be?
Formed, in a process called recombinaiton
What is needed for gene mapping
- DNA from members of families in which a certain trait is prevalent, and 2. DNA markers
DNA markers or genetic markers
typically, non-coding DNA polymorphisms used to follow a disease-causing allele through a family, i.e. they “mark” the chromosome on which a disease causing allele is located. The marker does not a cause a disease but is close to the gene that IS causing the disease.
DNA markers do not (by themselves) identify the gene
responsible for the trait, but can roughly
indicate where the responsible gene is in the genome
If a gene is close to a DNA marker, they will likely
stay together during recombination and be passed on together from parent to child
If each family member with a disease also inherits a
particular DNA marker, it is very likely that
the gene responsible for the disease lies near that marker
The more DNA markers, the more likely is to have at least
one marker near the diseased gene
The Human Genome Project provided information to develop
dense maps of markers evenly spaced across the entire genome.
Three steps determine linkage and recombination frequencies
- Establish the arrangement of genes in each chromosome (aka linkage phase)
- Determine a hypothesis if linkage is present
- Calculate recombination frequency
Each marker can have
several alleles
Track transmission of?
The marker provided and the transmission of the disease (form affected individuals in pedigree)
The marker is not the
cause of the disease, but helps to determine which chromosome is being transmitted by a parent
The actual cause of the genetic disease will be a?
nearby mutation which can be identified in subsquent DNA sequencing analysis
The closer two linked loci are (e.g. gene and marker), the lower the
recombination frequency between them. Useful markers are <1 cM from the gene. The recombination frequency can be used to estimate the proximity between a gene and a linked marker.
Genetic diagnosis will determine whether the individual at-risk has
inherited the disease causing gene
Direct diagnosis
looks for a known mutation, using molecular biology techniques (DNA sequencing, etc). No markers.
Indirect diagnosis
based on linked markers to infer whether the
individual has inherited the DNA segment containing the disease-causing mutation
Genetic testing reveals mutations, not the presence of a
disease (reduced penetrance, mosaicism, additional mutations).
No genetic test is
100% accurate
Pros for Direct Disease
Q3 Sibling 2 is
affected
Q4, individual III-1 is
affected, but has a more severe manifestation because the band has a larger size (more expansion of trinucleotide repeat)
Q5, individual 6 is
is not affected
Q6 X linked
-X chromosome from the mother
-Not diseased
-Will be a female because there are two bands
