genetics- Robin clark- intro
Terms
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- how many generation pedegree do you want
- 3
- Autosomal Dominant Inheritance
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Heterozygotes express the trait
Vertical pattern of transmission from one generation to the next
Transmitted by both sexes
Offspring are at 50% risk
Structural genes are often involved
New mutations are common - Phenotypic Variability
- Penetrance
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Incomplete penetrance (def.)
- give example -
a trait that is not expressed in the phenotype of a gene carrier
e.g.,Breast cancer occurs in about 70% of BRCA1 gene mutation carriers
-Other genes or environmental factors influence gene expression in these traits. -
Complete penetrance (def.)
- give example -
a genetic trait that is expressed in the phenotype
-Achondroplasia and neurofibromatosis are highly penetrant mutations - Variable expression
- a genetic mutation associated with more than one phenotype
- Autosomal Recessive Inheritance
-
Homozygotes express the trait
Horizontal pattern of transmission within a sibship.
Transmitted by both sexes
Offspring of carrier parents are at 25% risk
Functional genes are often involved
Ex. Sickle cell disease
Consanguinity is more common - X-linked Recessive Inheritance
-
Hemizygotes (46,XY) are affected; heterozygotes (46,XX) are carriers
When lethal, transmitted by females only - ex. Duchenne Muscular Dystrophy
When not lethal, transmitted by both sexes - ex. Color blindness
Sons of carrier mothers at 50% risk; sons of affected fathers at no risk -
Anticipation
e.g., -
The phenotype becomes more severe or evident at a younger age of onset with each successive generation
Ex. The triple repeat mutation can expand with each generation in Myotonic dystrophy.
Ex. The premutation for Fragile X in a normal transmitting male expands during female meiosis in his unaffected daughter to a full mutation in her affected son. - Parent of Origin effect
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The phenotype varies depending on which parent transmits the abnormal allele
Methylation patterns differ in male and female meiosis: some genes are active only when inherited from one parent (imprinting)
Ex. Only the maternal copy of the Angelman syndrome gene is active; the paternal gene is inactive.
In utero factors can affect severity
Ex. Congenital myotonic dystorphy - Polygenic traits
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many genes each make a small contribution to the phenotype
Ex. Intelligence, height - Multifactorial traits
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Few genes make a major contribution to the phenotype in a permissive environment
Ex. Spina Bifida, MTHFR and folate deficiency - Mosaicism
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A mutation affects only some cells in the body with a variable phenotype
Ex. Gonadal mosaicism in an unaffected parent causes more than one affected child with osteogenesis imperfecta type II, a lethal autosomal dominant trait - Chromosomal translocations
- Ex. Down syndrome due to a familial translocation
- Maternal inheritance
- Ex. Mitochondrial genome is cytoplasmic so mitochondrial defects are passed down in the egg cytoplasm from the mother to all of her children
- genetic heterogenity
- mutations in different genes can cause same disease
- genotype/phenotype correlations
- different mutations in same gene can cause different syndromes
- carrier frequency
- prevolence of an altered disease gene in a given population
- founder effect
- high frequency of a specific gene mutation in a population founded by a small ancestral group
- Comparative Genomic Hybridization (CGH) to Metaphase Chromosomes
-
Genome scanning technique use for scanning to search for chromosome aberrations
Generally been used to examine chromosome structure in cancer - Microarray CGH
- Whole genome hybridization
- polymorphism
- dna sequence changes that do not alter protein function
- mutation
- change in normal base pair sequence
- disease associated mutations
- DNA sequence changes that alter protein function
- wildtype
- non mutant gene
- point mutation
- change in single base pair
- missense mutation
- changes to a codon for another amino acid (can be harmful or neutral)
- nonsense mutation
- change from an amino acid mutation to a stop codon, producing a shortened protein
- frameshift mutations
- insertion or deletion of base pairs, producing a stop codon downstream and usually a shortened protein
- splice site mutation
- a change that results in alterned mRNA sequence
- DNA electrophoresis
- dna loaded into wells and fragments are separated by size and charge
- linkage analysis
- looks for pattern of DNA markers near gene of interest that segregate with disease. Requires DNA analysis of multiple family members
- alelle specific ogliotide (ASO) hybridization
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1)amplify dna
2)add radio labeled normal DNA probes
3)add known mutant dna probes
4) compare (heterozygous, homozygous) - PCR
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1) isolate & denature DNA
2)anneal and extend primers
3)repeat as necessary
4)amplify segmenta - single strand conformational polymorphism
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1)dna is denatured into single strands
2)single strands fold; shape is altered by mutations
3)mobility of mutant and normal strands differ in gel