Medical genomics – Lecture 9 – Mendelian Genetics
Introduction
Causes of individual differences;
• Non-inherited (environment)
• Inherited variation
Variants; (any change to DNA is variant)
• Neutral; harmless (no change in phenotype)
• Functional; beneficial, harmful (mutation is a variant that cause a disease)
Mendelian diseases are monogenic; caused by defects in single genes/activity of 1
gen determines if the disease is present or not.
Germ line vs somatic variant;
Germ line; cells that go from mother to daughter etc.
Somatic; cells that divide normally, increasing cells (all other
cells apart from germ line cells)
Mutation germ line cell; mutation present in the full daughter
Mutation in somatic cell; mutation only present in cells mother.
Genetic Variation
Genetic variation is the result of;
1. Mutations; level of base pairs --> generates new variation
Differences in the DNA.
Causes are fails is DNA replication, effects of extern factors like
UV, non-homologous recombination and insertion of exogenic
DNA like viral DNA or transposons.
It is the basis for evolutionary processes
Variation types;
• Single nucleotide variant (SNV); single base change in
DNA sequence. Origin by starting cell which can undergo
as well mitosis as meiosis.
o Synonymous; do not affect the sequence of
protein
o Nonsynonymous; do affect the sequence of the
protein
o Nonsense; protein is changed in stop protein.
o readthrough; stop protein is changed in coding
protein
, • Structural variants (SV); Origin by the beginning of
meiosis
o Deletion
o Insertion
o Tandem duplication
o Interspersed duplication
o Inversion
o Translocation
2. Segregation; level of combination of full chromosome
--> re-distribution of new variation
Separate chromosomes by sperm and egg cells.
Down Syndrome, segregation don’t go well (mental retardation, early-onset
Alzheimer’s disease and cardiovascular problems)
3. Recombination; level parts of the chromosome --> re-distribution of new
variation
2 parts of chromosomes close together, information transfer
between these 2.
Other form of transfer is cross-over.
Increase cross-over is increasing the distance between the 2
loci.
With each generation portion of original chromosome decrease.
Total amount of recombination correlate with the length of the
chromosome.
Mapping human disease genes
First step in identify genes responsible for genetic diseases is found the
chromosomal location. Done by markers.
Genetic markers (polymorphic genetic markers = positions in the genome that occur
in multiple forms)
Variant; any change in the DNA sequence
Polymorphism; variants present at significant frequencies in the population (>1%)
Using these markers, we can determine recombination rates and use this to
construct ordered genome wide marker maps.
All variations can be used as markers, some more suitable;
• Single nucleotide substitutions (SNP)
o RFLP = restriction fragment length polymorphism; studied by restriction
enzyme digestions followed by electrophoreses --> informative meiosis
▪ Advantage; equally distributed throughout the genome
▪ Disadvantage; labor intensive since it often required to perform
Southern and only 2 possible forms (alleles) the enzyme cut or
not
Could only detect a fraction of all base substitutions because of the
limited number of restriction enzymes available.
o SNP = single nucleotide polymorphism --> bi-allelic
Introduction
Causes of individual differences;
• Non-inherited (environment)
• Inherited variation
Variants; (any change to DNA is variant)
• Neutral; harmless (no change in phenotype)
• Functional; beneficial, harmful (mutation is a variant that cause a disease)
Mendelian diseases are monogenic; caused by defects in single genes/activity of 1
gen determines if the disease is present or not.
Germ line vs somatic variant;
Germ line; cells that go from mother to daughter etc.
Somatic; cells that divide normally, increasing cells (all other
cells apart from germ line cells)
Mutation germ line cell; mutation present in the full daughter
Mutation in somatic cell; mutation only present in cells mother.
Genetic Variation
Genetic variation is the result of;
1. Mutations; level of base pairs --> generates new variation
Differences in the DNA.
Causes are fails is DNA replication, effects of extern factors like
UV, non-homologous recombination and insertion of exogenic
DNA like viral DNA or transposons.
It is the basis for evolutionary processes
Variation types;
• Single nucleotide variant (SNV); single base change in
DNA sequence. Origin by starting cell which can undergo
as well mitosis as meiosis.
o Synonymous; do not affect the sequence of
protein
o Nonsynonymous; do affect the sequence of the
protein
o Nonsense; protein is changed in stop protein.
o readthrough; stop protein is changed in coding
protein
, • Structural variants (SV); Origin by the beginning of
meiosis
o Deletion
o Insertion
o Tandem duplication
o Interspersed duplication
o Inversion
o Translocation
2. Segregation; level of combination of full chromosome
--> re-distribution of new variation
Separate chromosomes by sperm and egg cells.
Down Syndrome, segregation don’t go well (mental retardation, early-onset
Alzheimer’s disease and cardiovascular problems)
3. Recombination; level parts of the chromosome --> re-distribution of new
variation
2 parts of chromosomes close together, information transfer
between these 2.
Other form of transfer is cross-over.
Increase cross-over is increasing the distance between the 2
loci.
With each generation portion of original chromosome decrease.
Total amount of recombination correlate with the length of the
chromosome.
Mapping human disease genes
First step in identify genes responsible for genetic diseases is found the
chromosomal location. Done by markers.
Genetic markers (polymorphic genetic markers = positions in the genome that occur
in multiple forms)
Variant; any change in the DNA sequence
Polymorphism; variants present at significant frequencies in the population (>1%)
Using these markers, we can determine recombination rates and use this to
construct ordered genome wide marker maps.
All variations can be used as markers, some more suitable;
• Single nucleotide substitutions (SNP)
o RFLP = restriction fragment length polymorphism; studied by restriction
enzyme digestions followed by electrophoreses --> informative meiosis
▪ Advantage; equally distributed throughout the genome
▪ Disadvantage; labor intensive since it often required to perform
Southern and only 2 possible forms (alleles) the enzyme cut or
not
Could only detect a fraction of all base substitutions because of the
limited number of restriction enzymes available.
o SNP = single nucleotide polymorphism --> bi-allelic
