Patterns of Single Gene Inheritance Flashcards
Genotype
genetic constitution of an individual or locus
phenotype
outward characteristics of an individual or gene product
Allele
One of both versions of a gene or DNA sequence at a given locus
Locus
Position occupied by a gene on a chromosome
Homozygote
Genotype will identical alleles at a given locus
Hemizygous
Genotype with a single allele for a given chromosome segment. Males are hemizygous for X.
Heterozygote
Genotype with different alleles at a given locus
Compound Heterozygote
genotype with 2 different mutant alleles at one locus
Polymorphism
alternate genotypes present in population greater than 1%
Penetrance
The proportion of mutant individuals manifesting disease. It is an All or None effect.
Expressivity
The extent to which a mutation exhibits a phenotype. The extent to which the disease manifests itself.
Carriers
Have a single mutant allele that is obscured by the normal copy
Genetic Heterogeneity
Can result from different mutations at 1 locus (allelic), or from mutations at different loci. It is where different genes contribute to the same disease or phenotype such as height.
Phenotypic Heterogeneity
Occurs when the same mutations manifests itself differently among individuals.
Sex-Linked
encoded on the X-chromosome (or Y-chromosome) thus conferred together with gender.
Autosomal
encoded on the autosomes or the numerical chromosomes, all chromosomes but X and Y
Recessive
Both alleles must be affected for the trait to be displayed
Dominant
A single mutant allele confers a phenotype
Recessive Inheritance Patterns
For single gene disorders, a phenotype is considered recessive if it manifests itself in the homozygotes. Needs two copies of the recessive allele to manifest disease. Individuals carry 1-5 recessive alleles that are lethal in homozygotes. Recessive disorders often display a clustering of disease among siblings and is absent among ancestors, although consanguinity may be present. Both parents are carriers and the recurrence risk for siblings is 1 in 4. Unaffected siblings of the proband have a 2/3 chance of being a carrier. Males and females are equally affected and parents are asymptomatic carriers. These seem to come out of no where!
Dominance Inheritance Patterns
A characteristic is dominant if it manifests itself in the heterozygote. If the disease is not lethal, the disease phenotype is usually seen in every generation. A child of an affected parent has a 1/2 chance of being affected. Males and females are usually equally affected.
Codominance
Both alleles, the dominant and recessive allele, are expressed equally in the heterozygote. This is seen with A and B blood type to get type AB
Incomplete Dominance
Get an in-between in the heterozygote. It is not red, not white, but pink. Each cell expresses half, not one or the other. The dominant allele is not quite as dominant as we think.
Haploinsufficiency
The single normal copy produces an insufficient quantity of the normal gene product for the requirements of the organism. An example is Familial Hypercholesterolemia in which now only 50% of the normal LDL receptor is present and this level is not enough to maintain blood cholesterol levels in the normal range.
4 things determine that a mutant allele is dominant
1) The single normal copy produces an insufficient quantity of the normal gene product for the requirements of the organism (haploinsufficiency)
2) The product of the inactive mutant gene interferes with the function of the normal gene product (dominant negative effect)
3) The product of the mutant gene acquires a new or enhanced function (simple gain of function)
4) The affected gene is a tumor suppressor resulting in predisposition to cancer that is inherited as a dominant trait because even a single cell losing the function of the other allele by mutation is enough to cause cancer.
Identify the percent of alleles related individuals have in common or the coefficient of relationship =
(1/2)^n where n is the degree of relationship
Calculate the probability of inherited disease in a child from consanguineous parents
When two related individuals mate, there is a probability that a child will receive both alleles for a particular gene from the same ancestor, one descending through the mother and one through the father. This probability is called the Coefficient of Inbreeding (F). It is also the proportion of loci at which a person is identical by decent.
F (coefficient of inbreeding) = 1/2 * Coefficient of relationship
Consanguinity
It is the relationship that results from common ancestry. It increases the chance that both parents are carriers of the same mutant allele from a common ancestor.
X-linked Recessive Inheritance Patterns
The incidence of the trait is much higher in males than females because they only have one X. Heterozygous females are usually unaffected but males do not have an extra X chromosome to compensate for the mutation. The trait is usually transmitted from an affected male to 50% of his grandsons through his daughters. Males never transmit the disease directly to their sons because they pass on a Y to their sons.
Reduced Penetrance
An individual may not have the disease although they have the bad allele. When they have a kid, they can pass this gene on.
X-linked Dominant Inheritance Patterns
This is very rare. Affected females have a 50% chance of passing it on to sons and daughters if they are heterozygous. It is more frequent among females. Affected fathers ALWAYS pass the trait on to their daughter but not their sons. Affected females usually have a milder phenotype because they can be heterozygous.
Somatic Mosaicism
When a mutation occurs in the course of development only that part of the body derived from the mutant cell may ultimately be affected
Germline Mosaicism
When a mutation affects germ cells, the parents may be negligibly affected but multiple offspring will exhibit a severe form of the disease. X-inactivation can lead to Duchenne’s Muscular Dystrophy
Describe genomic imprinting and inheritance of Prader-Willi and Angelman Syndromes
Genomic imprinting is when a certain sex silences genes while another keeps it active. Thus, if the parent passes on the disease in the chromosome that is affected and not silenced, then we can get disease because there is not a second allele to make up for it. These two result from a micro-deletion in the q-arm of chromosome 15 (15q11-q13). In a pedigree for these, for a defective genes imprinted active in the female during oogenesis, affected and carrier females should always produce children in which 1/2 are affected. Males, affected and carriers, should always produce children in which 1/2 are carriers. For defective genes imprinted active in males, the opposite results would be expected.
Understand how triplet repeat disorders, dynamic mutations and anticipation are related
In diseases such as huntington’s disease the parents have less repeats than the offspring will because when the DNA is replicated, the polymerase will skip and create even more repeats. Once a certain threshold of triple repeats is met, the disease will start to manifest itself. It is dynamic mutation because it is not a mutation of one gene, rather it is the changing number of triple repeats in the next generation. This thus leads to anticipation because the next generation will have even more repeats and thus more severe expression of the disease and earlier onset.
Explain replicative segregation, heteroplasty and maternal inheritance of mitochondria
Cells contain about 1,000 mitochondrial DNA molecules at several copies per mitochondrion. Every mitochondrial DNA molecule contains 37 genes of which 22 are tRNA genes. Nuclear and mitochondrial DNA are NOT interchangeable; several triplets translate into different amino acids or stop codons. The mature oocyte contains 100-fold more copies of mitochondrial DNA than the sperm and thus mitochondrial DNA is maternally inherited, as are mitochondrial diseases. Replicative segregation is the distribution of the mitochondrial DNA among daughter cells. It is a random event and disease is only passed on if the proportion of diseased mitochondrial DNA reach a certain threshold. THREE factors define the inheritance of mitochondrial diseases:
1) Mitochondrial DNA can be heteroplamic meaning that more than one type of mitochondrial DNA may be present in cells from a single individual. Mom can pass on many types of DNA and it has to reach a mutant threshold to manifest disease.
2) Mitochondrial DNA is inherited maternally. A small random sample of mitochondrial DNA is selected for inclusion in the oocyte during oogenesis
3) Mitochondrial DNA undergoes random segregation through multiple rounds of mitosis during embryogenesis. The mutant DNA may or may not be present is offspring depending on how much mutant DNA the offspring received.
Different offspring may inherit a a different, random sample of mutant mitochondrial DNA from there mom and thus could manifest the disease differently. If a male is affected, the disease turns into a dead end because he does not pass it on. On the pedigree an affected female passes it on significantly to her offspring where a male doesn’t pass it on at all.
Some Complications to pedigree patterns that may affect counseling and/or diagnosis
1) New mutations- especially for autosomal dominant disorders.
2) Genomic imprinting- different phenotypes depending on the parental source of the mutation
3) Reduced penetrance- not all patients with the disease genotype express symptoms
4) Variable expressivity- The severity of the disease differs in patients with the same genotype
5) Phenotypic variability- disorders that affect multiple organs can produce different symptoms in related family members (pleiotropy) due to effects of environment or other genes
6) Delayed onset- e.g. triple repeat expansion disorders such as huntingtons disease, myotonic dystrophy, etc.
7) Small family size- limited pedigree information on which to base counseling recommendations
