Overview of Mendelian Genetics Flashcards
What is the distribution of causes of congenital malformations?
60% unknown 20% multifactorial 7.5% single gene defect 6% chromosomal abnormalities The rest is external maternal factors
What are single gene defect?
Often termed mendelian because they follow inheritance patterns predicted by his classic experiments
What are the four categories of single-gene disorders?
>50% Autosomal dominant ~36% Autosomal recessive <10% X-linked Mitochondrial Y-linked
Define locus.
The position of a gene on a chromosome
Define allele.
The alternative versions of a gene that may occupy a given locus
Define polymorphism.
The occurrence in a population of two or more alternative genotypes (may or may not be deleterious)
Define genotype.
The genetic constitution of an individual
Define phenotype.
The observable expression of a genotype as a morphological, biochemical or molecular trait
Define homozygote.
Individual with a pair of identical alleles at a given locus
Define heterozygote.
Individual with different alleles at a given locus
Define compound heterozygote.
Individual with 2 different mutant alleles at a given locus
Define double heterozygote.
Individual with 1 mutant allele at each of 2 different loci
Define autosomal dominant dominance.
Heterozygotes are phenotypically affected
What are the criteria of autosomal dominance?
1) phenotype appears in every generation
2) offspring have 50% chance of inheritance
3) phenotypically normal individuals do not transmit the phenotype
4) no difference in male/female transmission
Examples of autosomal dominant diseases.
Marfan's disease Huntington's disease Familial hypercholesterolemia Achondroplasia Neurofibromatosis Non-insulin dependent diabetes
3 exceptions to autosomal dominance.
1) New mutation in gamete of phenotypically normal parent
2) Variable pentrance
3) Variable expressivity
These phenomena may mask other things
Define penetrance.
The probability that a gene will have any detectable phenotypic expression at all
Conditions of penetrance.
An all or none concept
Failure accounts for skipping of generations
Reported as %age of individuals to carry mutant genotype which express the mutant phenotype
Example of reduced penetrance.
Split-Hand Deformity
70%penetrance * 50% dominant risk = 35% overall risk
Define Expressivity.
The degree of expression of the phenotype
Conditions of expressivity.
Severity of disease manifestation can very considerably
Environmental factors play a role
Unrelated genes may affect function of the mutant gene product
Define autosomal recessive dominance.
Only homozygotes are phenotypically affected
4 criteria of autosomal recessive dominance.
1) Affected phenotype is apparent only in sibs
2) Recurrent risk for each sib is 25%
3) Consanguineous parents increases likelihood of inheritance
4) Males and females equally likely to be affected
Examples of autosomal recessive diseases.
Cystic Fibrosis
Sickle cell anemia
Tay-Sachs disease
Phenylketonuria (PKU)
Conditions of autosomal recessive dominance.
Complete absence of phenotype except in sibs
Both parents are carriers of 1 copy of the defective gene
Define X-linked recessive dominance.
“mother to son” transmission
3 criteria of X-linked recessive dominance.
1) Incidence of phenotype is much higher in males than females
2) Mutant gene is transmitted from father to all daughters/no sons
3) Heterozygous females are usually unaffected but may show some variable expression of the trait (manifesting heterozygote)
What are some X-linked dominant diseases?
Females are affected but males affected more severly, often lethal
Examples include Ornithine Transcarbomoylase Deficiency and Hypophosphatemic Rickets
Since males have only one X chromosome they are _____ for X genes.
Hemizygous
Why do female carriers of X-linked recessive traits sometimes exhibit phenotypes?
Due to unfavorable lyonization
What are some examples of X-linked recessive diseases?
Hemophilia A
Duchenne Muscular Dystrophy
Glucose-6-Phosphate Dehydrogenase Deficiency
Red/Green Color Blindness
Why do women not experience twice the gene products in X-linked disorders?
They undergo “dosage compensation” at the morula stage of development.
This was described by Mary Lyons in 1961.
What is the Lyon Hypothesis?
All females are mosaics with respect to their X chromosomes. Inactivated X chromosomes are referred to as Barr Bodies.
What is Somatic Cell Mosaicism?
Mutation occurs in somatic cell and results in clone of mutant cells derived from original mutant.
What is the classic example of Somatic Cell Mosaicism?
Cancer
Is there such thing as Y-linked genes?
Yes, several X-linked genes have Y-linked counterparts.
Other Y-linked genes are required for production of testes and sperm.
What are the 3 criteria for Mitochondrial Disorders?
1) Purely maternal inheritance
2) Sons and daughters are equally affected
3) Wide variability of expression
Diseases linked to mitochondrial disorders.
Leber’s hereditary optic atrophy (LHON)
Mitochondrial encephalomyopathy lactic acidosis, and stroke like episodes (MELAS)
Myoclonus epilepsy with ragged red fibers (MERRF)
Define mitochondrial disorders.
Mother to everybody transmission
