Pathology 3500 Lecture 21: Molecular Genetics
1 May 2018
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Lecture 006: Molecular Genetics
The central dogma of molecular biology
● Flow of genetic information
○ DNA -> RNA -> protein
● Function is mainly in protein (+ some RNA)
● Can also go backwards
○ RNA -> DNA
● Genetic information can be inherited in the protein conformation
The human genome
● First complete sequence in 2000 (rough draft), 2003 (essentially complete).
● 2 x 22 autosomes + 2 gonosomes (X or Y) + mitochondrial DNA (mtDNA)
○ 3 billion base pairs
○ 20,000 protein encoding genes (only)
■ 2% coding DNA
Mutation
● Permanent changes in DNA
● In germ cells
○ Can be transmitted to progeny
○ Give rise to inherited disease or predisposition to familial cancers
● In somatic cells
○ Not transmitted to progeny
○ E.g. caner, some congenital malformations
Types of mutations:
● Point mutation
○ Single nucleotide change
○ Missense
■ Replacement of one nucleotide base by another resulting in a different
amino acid
○ Nonsense
■ Replacement of one nucleotide base by another resulting in a stop codon,
truncates the protein (TGG or TGA)
○ Synonymous (silent)
■ Replacement of one nucleotide base by another resulting in the same
amino acid
■ benign
■ Used as markers in genetic studies
● Frameshift mutations
○ Deletion or insertion of nucleotides that changes the reading frame (and
therefore the entire amino acid sequence)
○ General insertion or deletion of 1 or 2 nucleotide (not 3 or multiples of 3)
● Trinucleotide or triplet repeat (TNR)
○ Amplification of a 3 nucleotide sequence (e.g. CAG)
■ Highly dynamic can change in size (expansion and contraction) during
gametogenesis
■ Unstable
● Splicing mutation
○ Do not directly affect the coding sequence since it occurs in the noncoding
sequence
■ Affects the processing of the RNA
○ In accurate splicing of introns
○ Alters coding sequence (e.g. adding amino acids, frameshift mutation)
Major categories of genetic disorders
Mendelian disorders
● Autosomal recessive (AR)
○ Need both copies of the chromosome to be affected
○ As a sum, fairly common in the population
○ Cystic fibrosis, Tay-Sachs disease, sickle cell anemia, phenylketonuria,
galactosemia
● Autosomal dominant (AD)
○ Only needs to be present in one copy of the chromosome
○ Familial Hypercholesterolemia, Marfan Syndrome, Ehler-Danlos Syndrome
● X-linked recessive (XLR)
○ Recessive in girls
○ Hemophilia A, duchenne nuclear dystrophy
● X-linked dominant (XLD)
○ Affected males (with normal mates) have no affected sons and no unaffected
daughters
○ Affected heterozygous females have 50% risk of passing the mutant gene to both
sons and daughters
○ Rett syndrome
● Y-linked
○ Very rare
○ Dominate
○ Effect male germ developmental phenotypes (leads to infertility)
Gain of function and loss of function mutations
● Gain of function
○ Mutation give protein new, toxic phenotype
■ Toxic can be completely unrelated to the original function of the protein
■ Can also be a combined phenotype
● Protein is also not doing what is suppose to do either
○ Mostly dominant inheritance
Document Summary
Function is mainly in protein (+ some rna) Genetic information can be inherited in the protein conformation. First complete sequence in 2000 (rough draft), 2003 (essentially complete). 2 x 22 autosomes + 2 gonosomes (x or y) + mitochondrial dna (mtdna) Give rise to inherited disease or predisposition to familial cancers. Replacement of one nucleotide base by another resulting in a different amino acid. Replacement of one nucleotide base by another resulting in a stop codon, truncates the protein (tgg or tga) Replacement of one nucleotide base by another resulting in the same amino acid. Deletion or insertion of nucleotides that changes the reading frame (and therefore the entire amino acid sequence) General insertion or deletion of 1 or 2 nucleotide (not 3 or multiples of 3) Amplification of a 3 nucleotide sequence (e. g. cag) Highly dynamic can change in size (expansion and contraction) during gametogenesis. Do not directly affect the coding sequence since it occurs in the noncoding sequence.
