Basic Intro To Genetics

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Autosomal Dominant Inheritance

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* Each child has 50% chance of inheriting the mutation
* No skipped generations
* Equally transmitted by men and women
* HETEROZYGOTES express the trait
* Vertical transmission from one gen to next
* Structural genes are often involved
* New mutations are common

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Incomplete Penetrance

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* A trait that is NOT expressed in the phenotype of a gene carrier
* IE: Breast Cancer occurs in about 70% of BRCA1 gene mutation carriers
* Other genes or environmental factors influence gene expression in these traits

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Complete Penetrance

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* A genetic trait that is expressed in the phenotype
* IE: (Achondroplasia, and neurofibromatosis)

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Variable Expression

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* Genetic mutation associated with more than one phenotype
* Intrafamilial variability may be due to interaction with other genes or environmental factors
* IE: Van der Woude
* Interfamilial variation may be due to the effect of different mutations within the same gene

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Autosomal Recessive Inheritance

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* 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
* IE: Sickle cell disease
* Consanguinity is more common

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X-linked Recessive Interitance

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* HEMIZYGOTES are affected, heterozygotes are carriers
* When lethal, transmitted by FEMALES only (ie: Duchenne Muscular Dystrophy
* When not lethal, transmitted by both sexes (IE: color blindness)
* Sons of carriers mothers at 50% RISK, sons of affected fathers at no risk

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Anticipation

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* The phenotype becomes more severe or evident at a younger age of onset with each successive gen.
* IE: Myotonic dystrophy
* IE: 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. (Expansion of X chromo because one X doesn't match up with the other and so during crossover, get expansion of X)

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Autosomal Dominant Inheritance

Back 8

* Each child has 50% chance of inheriting the mutation
* No skipped generations
* Equally transmitted by men and women
* HETEROZYGOTES express the trait
* Vertical transmission from one gen to next
* Structural genes are often involved
* New mutations are common

Front 9

Incomplete Penetrance

Back 9

* A trait that is NOT expressed in the phenotype of a gene carrier
* IE: Breast Cancer occurs in about 70% of BRCA1 gene mutation carriers
* Other genes or environmental factors influence gene expression in these traits

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Complete Penetrance

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* A genetic trait that is expressed in the phenotype
* IE: (Achondroplasia, and neurofibromatosis)

Front 11

Variable Expression

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* Genetic mutation associated with more than one phenotype
* Intrafamilial variability may be due to interaction with other genes or environmental factors
* IE: Van der Woude
* Interfamilial variation may be due to the effect of different mutations within the same gene

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Autosomal Recessive Inheritance

Back 12

* 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
* IE: Sickle cell disease
* Consanguinity is more common

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X-linked Recessive Interitance

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* HEMIZYGOTES are affected, heterozygotes are carriers
* When lethal, transmitted by FEMALES only (ie: Duchenne Muscular Dystrophy
* When not lethal, transmitted by both sexes (IE: color blindness)
* Sons of carriers mothers at 50% RISK, sons of affected fathers at no risk

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Anticipation

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* The phenotype becomes more severe or evident at a younger age of onset with each successive gen.
* IE: Myotonic dystrophy
* IE: 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. (Expansion of X chromo because one X doesn't match up with the other and so during crossover, get expansion of X)

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Parent of Origin Effect

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* Phenotype varies depnding on which parent transmits the abnormal allele
* METHYLATION patterns differ in male and female meiosis: some genes active only when inherited from one parent (IMPRINTING). IE: Angelman syndrome-maternal copy of gene is active, paternal gene is inactive.
* In utero factors can affect severity, IE: Congenital myotonic dystrophy. Methyl groups cloak DNA and make some genes active and some genes inactive.

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Polygenic Traits (Non Mendelian Inheritance)

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* Many genes each make a small contribution to the phenotype.
* IE: Intelligence, height.

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Multifactorial Traits (NonMendelian Inheritance)

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* Few genes make a major contribution to the phenotype in permissive env't
* IE: Spina Bifida, MTHFR, and Folate

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Mosaicism (Non Mendelian Inheritance)

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* A mutation affects only some cells in the body with a variable phenotype
* IE: Gonadal mosaicism in an unaffected parent causes more than one affected child with OSTEOGENESIS IMPERFECTA TYPE II, lethal autosomal dominant trait.

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Chromosomal translocations (NMI)

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* IE: Down syndrome

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Maternal Inheritance (NMI)

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* IE: MITOCHONDRIAL GENOME is cytoplasmic so mitochondrial defects are passed down in the egg cyto from mother to all of her children

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Genotype/Phenotype Correlations

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* Diff mutations in same gene can cause different syndromes

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Genetic Heterogeneity

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* Mutations in different genes can cause the same disease
* IE: Mutation in BRCA1 and BRCA2 can both cause hereditary breast and ovarian cancer

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Comparative Genomic Hybridization (CGH) to Metaphase Chromosomes

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* Test Genomic DNA of Patient and have Reference Genomic DNA hybridize on chromosome to search for duplications and deletions
* Increased ratio will show on the graph for position on chromosome

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Polymorphism

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* DNA sequence changes that do NOT alter protein function

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Disease-Associated Mutations

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* A mutation is a change in the normal base pair sequence
* Commonly used to define DNA seq changes that alter protein function

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Missense Mutations

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* Changes to a codon for another aa (can be harmful mutation or neutral polymorphism)

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Nonsense Mutations

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* Change from an amino acid codon to a stop codon, producing a shortened protein

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Frameshift Mutations

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* Insertion or deletion of base pairs, producing a stop codon downstream and (usually) shortened protein

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Splice-Site Mutations

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* A change that results in altered RNA sequence

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Preparing for DNA for Analysis

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* Blood sample
* Centrifuge and extract DNA from white blood cells
* DNA for analysis

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Electrophoresis of DNA

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* DNA fragments loaded into the wells
* DNA fragments separate by size and charge with constant voltage gradient running through gel

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Linkage Analysis

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* Looks for pattern of DNA markers near gene of interest that segregate with disease
* Requires DNA analysis of multiple family members

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Allele Specific Oligonucleotide (ASO) Hybridization

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* Amplify DNA and hybridize membranes
* Add radio-labeled normal DNA probes
* Add known mutant DNA probes

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Single Strand Conformational Polymorphism (SSCP)

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* DNA is denatured into single strands
* Single strands fold; shape is altered by mutations
* Mobility of mutant and normal strands differ in gel

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Heteroduplex Analysis (CSGE)

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* Amplify and denature DNA
* Single-strand DNA
* In the cold, reanneal DNA
* Get mutated bands vs. normal band

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Protein Truncation Assay

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* DNA transcribed to mRNA
* RNA translated to protein
* Protein run on gel
* Truncated protein has different mobility in gel.