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 Dominant
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.
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
Figure 15.4
General strategy for linkage mapping
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.
Table V
Identification of Human Disease Genes
Disease
Defective
Function
Diseases caused by previously known proteins:
Pelizaeus-Merzbacher
Proteolipoprotein
Component of CNS myelin
Gerstmann-Straussler (in some familial forms)
Prion protein
Unknown
Malignant hyperthermia
Ryanodine receptor
Calcium release channel in muscle
Retinitis pigmentosa (in some autosomal dominant forms)
Rhodopsin
Photoreceptor pigment
Hyperkalemic periodic paralysis
Muscle-specific sodium channel
Generation of action potential
Dutch cerebral amyloidosis
Beta amyloid
Unknown
Alzheimer disease (in some familial cases with early onset)
Beta amyloid
Unknown
Disease
Defective
Function
Diseases caused by previously unknown proteins:
Retinoblastoma
RB
Nuclear phosphoprotein, "tumor suppressor"
Duchenne muscular dystrophy
Dystrophin
Structural protein associated with plasma membrane
