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Western University
Pathology 3240A
Craig Hall

Molecular Genetics Objectives: ­ central dogma of molecular biology ­ types of mutations ­ medelian vs non­mendelian inheritance Central Dogma ­ DNA ▯ RNA  ▯Protein ­ Transcription then translation ­ Flow of genetic information Mutations ­ permanent changes in DNA ­ In germ cells o Can be transmitted to progeny giving rise to inherited disease or  predisposition to familial cancers ­ In somatic cells o Not transmitted to progeny ­ Types o Point mutations  Single nucleotide change  Missense mutation • Replacement of 1 nucleotide base by another resulting in a  different amino acid  Nonsense mutation • Replacement of 1 nucleotide base by another resulting in  amino acid stop codon that truncates the protein  Synonymous mutation • Silent • Doesn’t change amino acid o Frameshift mutation  Deletion or insertion of nucleotide that changes the reading frame  and therefor the entire amino acid sequence  Generally insertion or deletion of 1 or 2 nucleotides (not 3 or  multiple of 3)  Trinucleotide or triplet repeat (TNR) • Amplification of a 3 nucleotide sequence (ex. CAG) o Highly dynamic, can chage in size (expansion and  contraction) during gametogenesis, unstable o Splicing mutation  Inaccurate splicing of introns  Alters coding sequence (ex. Adding amino acids) o Repeat expansion or contractions  Trinucleotide expansions Major Categories of Genetic Disorders Mendelian Disorders o Autosomal recessive  Ie. Cystic fibrosis, Tay­sach’s disease, sickle cell anemia,  Niemann­Pick disease, spinal muscular atrophy, etc. o Autosomal dominant  Only need one mutated allele on autosome to have disease  Ex. Huntingtons, spinocerebellar ataxias, etc. o X­linked recessive (XLR)  Kind of rare  Hemophilia A, duchenes muscular dystrophy o X­linked dominant  Very rare  X­linked hypophosphatemic rickets, Rett syndrome o Y­linked   Very rare  Non­obstructive spermatogenic failure o **know some examples** ­ Gain of Function Mutations o Gives protein new, toxic properties; mostly dominant inheritance  Ie. Huntingtons disease ­ Loss of Function Mutations o Strongly impairs or completely eliminates protein function, mostly  recessive inheritance o Can be compensated by non­muated allele  Ie. Cystic fibrosis o Exception:  Haplo­insufficiency • Loss of function and dominant inheritance • 50% reduction of protein function buy mutation in one  allele causes disease • ex. Polydactyly, ehlers­danlose syndrome ­ Multifactorial (polygenic) diseases o Combination of mutations cause disease o Each mutation alone typically doesn’t cause disease o Genetics and environmental influences reach a penetrance threshold  Ie. Hypertension, diabetes, schizophrenia, autism, mood disorders,  heart disease, cancer… o Inherit a higher probability to develop disease!! ­ Chromosomal Disorders o Human karyotype  2x22 autosomes +2 genosomes (XX or XY) = 46 chromosomes o numerical disorders  aneuploidy: abnormal number or chromosomes • disomic (normal, two sister chromosomes) • trisomic (one extra chromosome) – down syndrome • monosomic (one chromosome missing) – tumer syndrome o structural abnormalities  deletion, duplication, translocation, inversion  ex. Wolf­hirschhorn syndrome, Jacobson syndrome (deletions),  certain cancers (translocation)  usually fatal because they destroy the chromosomes Non­Mendelian Inheritance ­ trinucleotide/triple repeat expansion  o ie. Huntingtons disease, fragile – X disease o sites of expansion can be in coding or non­coding regions of gene o expansions are associated with neurodegenerative disorders o can be a gain of function (huntingtons disease) or loss of function (fragile  X syndrome) o all have threshold for repeats  everyone has repeats  once you reach threshold, then you can develop disease  the penetrance not high unless you reach threshold  the longer the repeats, earlier the penetrance of the disease o all have CG nucleotides o can be on autosomes or X chromosomes o number of triplets in muant alleles differs for different diseases o when certain threshold is met for normal number of triplet repeats… ­ Mitochondria o Contain genes that encode enzymes involved in oxidative phosphorylation o Replicate, transcribe and translate their DNA independently of nuclear  DNA o Mitochondrial Genome  Small and compact, no introns, genes overlap in regions  13 protein coding genes • 3 subunits…  exclusively inherited through mother
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