– genetic composition at a given location of the genome ("locus)".
Phenotype
– observed trait of the organism being studied: physical, biochemical, or behavioral trait.
Autosomal Dominant Inheritance
Definition
: Autosomal Dominant (AD) inheritance is a condition in which one copy of a missing or abnormal gene causes the observed phenotype. AD mutations cause a trait to appear in the heterozygous genetic state because the abnormal, or "mutant" copy of the gene, "dominates" the normal copy.
AD characteristics:
(1) Vertical transmission – the trait appears in every generation.
(2) Any child of an affected parent has a 50% of inheriting the trait.
(3) Individuals who do not have the trait will not transmit it to their children.
(4) Males and females are equally likely to have the disorder and are equally likely to transmit it to their kids.
AD inheritance is characterized by vertical transmission of the disease phenotype, a lack of skipped generations, and roughly equal numbers of affected males and females. Father-son transmission may be observed.
Exceptions:
(1) New mutations – random mutations not inherited from an affected parent.
Achondroplasia
(dwarfism) – AD trait which 80% of the time results from a new mutation
Thanatophoric Dysplasia
(rib cage fails to grow properly thus inhibiting lung growth. Infant dies immediately after birth) –genetic lethal, i.e. 100% of cases are from new mutations because individuals with the mutations are not able to pass on their genes. This is either because the mutation is lethal to the infant or because adults are not able to reproduce.
(2) Reduced penetrance – penetrance is the percentage of people with a certain gene who have outward signs that they carry the gene. An individual carrying the gene with no phenotypic manifestations is incompletely penetrant. Unlike expressivity, penetranceis a "yes" or "no" outcome.
Colon Cancer
– phenotype is not readily apparent in an individual with the mutation. If an individual has an AD trait and their parents did not have it consider that parents may have died before developing the phenotype.
(3) Variable expressivity – expressivity refers to how severely is an individual affected. Individuals can express all or few symptoms of a disorder. An "unaffected" parent of a severely affected child might be so mildly affected that the disorder was not recognized at the time of initial evaluation.
(4) Germline mosaicism – refers to when only a percentage of an individual’s cells have a mutation. Occurs when only some cells in an embryo develop a mutation which is spread mitotically. The individual is generally unaffected because only a few cells are abnormal. However, if a germ cell happens to carry the mutation the individual’s offspring will present with the phenotype.
Types of AD mutations:
(1) Loss of function
Amorphic – the gene fails to work.
Hypomorphic – the gene works poorly, could result from deletions or mutations.
(2) Gain of function
Neomorphic – the gene functions in an inappropriate way.
Hypermorphic – the gene functions in an excess.
Achondroplasia
(dwarfism), gene which slows down bone growth works too well.
(3) "Protein Suicide"
Antimorphic – the mutated gene affects various systems in the body.
Collagen Diseases
affects multiple systems including eyes, connective tissue, etc.
Autosomal Recessive Inheritance
Definition
: Autosomal Recessive (AR) inheritance is a condition in which BOTH copes of a particular gene are missing or abnormal. AR mutations are homozygous at the genetic locus. AR conditions involve genes that produce no abnormalities when there is a single working copy.
AR characteristics:
(1) Horizontal transmission – disease phenotype seen in multiple siblings, but usually no earlier generations affected.
(2) 25% recurrence rate with each pregnancy.
(3) Consanguinity – mating of related individuals. Should be suspected, especially in rare AR diseases.
(4) Males and females are affected equally.
Note: If two carriers (Aa) have a "healthy" child, that child might be a carrier (Aa) or normal (AA). Therefore, the chance that a "healthy" child of two carriers is a carrier is 2/3. Regardless, when considering all outcomes of a pregnancy (including the affected (aa) child) the chance that a child is a carrier is ˝
AR inheritance is characterized by clustering of the disease phenotype among siblings, but the disease is not usually seen among parents or other ancestors. Equal numbers of affected males and females are usually seen, and consanguinity may be present. (Jorde)
X-Linked Inheritance
Traditionally, X-linked (XL) inheritance is divided into XL recessive, and XL dominant.
Lyon hypothesis of X inactivation
- (lyonization) - Genes on the X chromosome are present in 2 copies in women (homozygous or heterozygous), 1 in men (hemizygous). In the female embryo one X chromosome is randomly inactivated in each somatic cell. As a result men and women are functionally equal in the number of active X chromosome genes. This ensures that females will produce X-linked gene products in quantities roughly similar to those in males (dosage compensation). As a result, the phenotype caused by a genetic mutation on the X chromosome depends on the function of the locus, and stochastic events (i.e. 50% of inactivation).
(1) XL Recessive
Characteristics:
(1) Incidence of the trait is much higher in males than in females.
(2) All the daughters of an affected man are carriers.
(3) Son of a carrier female has 50% chance of inheriting the disorder.
(4) No father to son transmission.
(5)
Disorder may be transmitted via series of carrier females with affected males being related through these carrier females.Heterozygous females are
(6) generally healthy, but may show variable expression of the trait.
How can females show signs of XL recessive disorders???
(a)
Structurally abnormal X chromosome.
(b) Homozygous – i.e. offspring of affected male and a carrier female.
(c) Unfavorable lyonization – having most cells with the "healthy" X being inactivated.
(d) 46 XY female.
(2) XL Dominant
Characteristics:
(1) Affected males have no affected sons and all daughters are affected.
(2) A child of a heterozygous female has a 50% chance of inheriting the trait.
(3) Males are generally more severely affected than females.