Patterns of Mendelian Inheritance
- Autosomal dominant-phenotype with one mutant gene copy
- Autosomal recessive-phenotype with two mutant gene copies
- X-linked-e.g., disease affects males and is not passed from father to son
| Table IV Patterns of Mendelian Inheritance |
||
| Autosomal Dominance | ||
| Autosomal Recessive | ||
| both parents are carriers |
one parent recessive |
related parents |
| X-linked | ||
Genetic (linkage) Mapping
A procedure by which any genetic trait is localized in the genome based on its segregation pattern with another marker or set of markers.
Recombination of homologous chromosomal segments
- Frequency of recombination events depends on length of segments, the specific nucleotide sequence and its genomic location, and whether the event takes place in the male or female.
- The consequence of recombination is that different offspring receive equal, but not identical, genetic information from each parent.
The genetic mapping of an unknown locus is established by examining the frequency with which it cosegregates with other previously mapped genetic markers. Mapping of anonymous markers and genes has allowed the construction of a fairly complete human genetic map. A number of disease genes with Mendelian phenotypes have been localized on the human linkage map to allow positional cloning. This has been helpful for linkage studies with traits that do not obey simple Mendelian patterns of inheritance.
Linkage analysis is a sequential procedure where data is collected until linkage is detected or refuted. Linkage is based on a lod score-a statistical evaluation of a set of data that examines the probability of joint segregation of two markers with a given recombination distance under the assumption of linkage or no linkage.
Figure 15.4 |
Applications of a Linkage Map
- establish the genetic basis of traits
- predict risk for disease
- localize hereditary disorders to specific regions of the genome
- clone genes by positional cloning
- study gene conservation across species and chromosomal evolution
Factors Affecting Linkage Mapping of a Disease Trait
- penetrance-probability that a carrier will have the phenotype
- frequency of the disease gene in the population (Mendelian < 0.1%)
- age of onset variability
The large majority of human diseases are NOT Mendelian (multigenic).
Familial aggregation of some genes (e.g., twins studies in schizophrenia) suggests both genetic and environmental factors contribute.
Proving a Candidate Gene is Causally Mutated
- DNA sequence comparisons of affected and unaffected individuals
- Gene expression patterns
- Multiple mutant alleles
- Phylogenetic (cross-species) comparisons
- Using a transgenic or knockout approach in the mouse
These are functional approaches but do not give much molecular insight into the mechanisms by which the mutated gene produces the aberrant phenotype. Dissection of the role of the candidate gene product and alterations in cellular function due to a given mutation must rely on examination of the function of the deduced protein using molecular and cell biological techniques.
