Genetics Ch. 4 Autosomal Dominant and Recessive Inheritance
Many genetic diseases are the result of a mutation of a single gene (monogenic traits)
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More than 18,000 located on autosomes
Basic Concepts of Formal Genetics

Gregor Mendel’s contribution
o 2 central principles:
 Principle of segregation – sexually reproducing organisms
possess genes that occur in pairs and that only one member of this
pair is transmitted to the offspring
 Genes remain intact and distinct
 Principle of independent assortment – genes at different loci are
transmitted independently
 Transmission of a specific allele at one locus has no effect
on what is transmitted at the other locus

Concept of phenotype
o Genotype – an individuals genetic constitution at a locus
 Individuals with 2 different genotypes can have the same
phenotype (dominant homozygote and heterozygote)
 Cystic fibrosis – disease in which only recessive
homozygote is affected
o Most common in European American newborns
o Pancreas – one of the principle organs affected
(pancreas is unable to secrete digestive enzymes,
contributing to chronic malabsorption of nutrients)
o Intestinal tract – thickened, obstructive intestinal
matter
o Sweat glands – high levels of chloride in sweat
o Pulmonary disease – major cause of
morbidity/mortality in CF patients
o Caused by mutations in CFTR gene (encodes cystic
fibrosis transmembrane conductance regulator)
 Encodes cyclic AMP regulated chloride ion
channels that span membranes of specialized
epithelial cells
 Regulates transport of sodium ions across
epithelial cell membranes
o Identification of the specific mutations that are
responsible for CF in a patient can help predict the
severity of the disease
o Phenotype – what is actually observed physically
 Results from interaction of genotype and environment


The same genotype can produce different phenotypes in different
environments
 Phenylketonuria (PKU)
o Mutations in locus encoding metabolic enzyme
phenylalanine hydroxylase; render the homozygote
unable to metabolize the amino acid phenylalanine
o There is a build up of phenylalanine and its toxic
metabolites – toxic to the CNS, producing severe
mental retardation
Basic pedigree structure
o Illustrates relationships among family members; shows which family
members are affected and which are unaffected with a genetic disease
o Proband – first person in whom the disease is diagnosed in a pedigree
(also referred to as propositus); usually denoted with an arrow
Autosomal Dominant Inheritance
- Ex: Postaxial polydactyly – presence of an extra digit next to the 5th digit
 Characteristics of autosomal dominant inheritance
o Vertical transmission of disease phenotype (lack of skipped generations)
 if neither parent has the trait, none of the children will have it
o Roughly equal numbers of affected males and females
o Father-to-son transmission may be observed
o An affected heterozygote transmits the trait to approximately half of his
children

Recurrence risk – probability that an individual offspring will be affected by the
disease in question
o Each birth is an independent event
o Recurrence risk = 50% for autosomal dominant disorder
 Because of independence, this risk remains constant no matter how
many affected or unaffected children are born
Autosomal Recessive Inheritance
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Ex: Albinism – mutations in gene tyrosinase, a tyrosine metabolizing enzyme;
tyrosinase deficiency creates a block in the metabolic pathway that normally leads
to the synthesis of melanin pigment
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Usually both parents are heterozygous carriers

Characteristics of autosomal recessive inheritance
o Clustering of the disease phenotype among siblings
o Disease not seen among parents or other ancestors
o Equal numbers of males and females typically seen
o Consanguinity may be present (mating of related persons)

Recurrence risks
o Usually 25% for autosomal recessive diseases
o Quasidominant inheritance has a recurrence risk of 50%, seen when an
affected homozygote mates with a heterozygote

“Dominant” vs. “recessive” – some cautions
o A dominant disease allele will produce disease in a heterozygote, where as
a recessive disease allele will not
o Many dominant diseases are more severe in affected homozygotes than
heterozygotes
 Achondroplasia – autosomal dominant disorder in which
heterozygotes have reduced stature, enjoy a nearly normal life span
(10 years shorter than average), while homozygotes usually die in
infancy due to respiratory failure
o In some cases, a disease may be inherited in either autosomal dominant or
autosomal recessive fashion, depending on the nature of the mutation that
alters the gene product
 Familial isolated growth hormone deficiency (IGHD) – another
disorder that causes reduced stature
 Recessive IGHD can be caused by frameshift, nonsense, or
splice-site mutations that have a loss of function effect
(mature protein product not synthesized)
o Heterozygotes – have one normal copy of GH1, will
produce half of the normal amount of growth
hormone [sufficient for normal stature]
o Homozygotes – produce no GH1 product and have
reduced stature
 Dominant inheritance IGHD – splice site mutation deletes
3rd exon of GH1 gene, producing a protein that proceeds to
the secretory granules
o Abnormal GH1 product encoded by the mutated
chromosome interacts with the normal product
encoded by the normal chromosome
 Acting as dominant negative, abnormal
molecules disable the normal growth
hormone molecules; greatly reduced
production of GH1 and short stature
 -Thalassemia – majority occur as result of autosomal recessive
mutations, small fraction inherited in autosomal dominant fashion
 Sickle cell mutation – homozygotes develop sickle cell disease,
heterozygotes are usually clinically normal (but increased risk for
splenic infarctions at high altitudes)
 Sickle cell disease – recessive
 Sickle cell trait – dominant
Factors that Affect Expression of Disease-causing Genes

New mutation – common cause of appearance of a genetic disease in a person
with no previous family history of the disorder
o The recurrence risk for the person’s siblings is very low, but the
recurrence risk for the person’s offspring may be substantially increased
o Estimated that 7/8 of all cases of achondroplasia are caused by new
mutations, and only 1/8 of are inherited from an infected parent (disease
limits potential for reproduction)

Germline mosaicism – occurs when all or part of a parents germline is affected
by a disease mutation but the somatic cells are not; thus the parent carries the
mutation in his or her germline but does not actually express the disease because
the mutation is absent in other cells of the body
 Elevates the recurrence risk for offspring of the mosaic parent)
o Osteogenesis imperfecta (OI, type II) – caused by mutations in the type 1
procollagen genes
o Achondroplasia
o Neurofibromatosis type 1
o Duchenne muscular dystrophy – 15% germline mosaicism
o Hemophilia A – 20% germline mosaicism

Reduced penetrance – a person who has a disease causing genotype might not
exhibit the disease phenotype at all, even though he or she can transmit the
disease causing mutation to the next generation
o Obligate carriers – those who have an affected parent and affected
children, therefore must themselves carry the mutation
o Retinoblastoma – malignant eye tumor (example of reduced penetrance)
 60% cases caused by somatic mutations that occur in early
development and therefore not transmitted to the affected
individuals offspring
 Disease causing gene: RB1; an individual who has inherited a
disease causing RB1 mutation carries the mutation in every cell of
his/her body
 However, this is not sufficient to cause tumor formation
 In any cell, presence of RB1 allele is sufficient to prevent tumor
formation
 To initiate a tumor in a developing retinal cell, a second somatic
event must occur that disables the other, normal RB1 allele
 2nd event = somatic mutation, low probability of occurring
 RB1 encodes a protein product, pRb
 When hypophosphorylated pRb binds and inactivates members of
the E2F family of nuclear transcription factors
 Cell requires active E2F to proceed from the G1 to the S phase of
mitosis
 By inactivating E2F, pRb applies a brake to the cell cycle
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When cell division is required, pRb is phosphorylated by cyclindependent kinase complexes; E2F is released by pRb and activated
A loss-of-function mutation in pRb can cause a permanent loss of
E2F-binding capacity
The cell, having lost its brake, will undergo repeated, uncontrolled
mitosis, potentially leading to a tumor.
Rb gene belongs to a class of genes known as tumor suppressors

Age-dependent penetrance – delay in onset of a genetic disease
o Huntington’s disease – autosomal dominant neurological disorder whose
main features are progressive dementia and increasingly uncontrollable
movements of the limbs
 Symptoms not usually seen until age 30 or later
 Decreased glucose uptake in the brain, damage to corpus striatum,
loss of brain weight
 Mutation is a CAG expanded repeat located in exon 1
 90-95% of cases are inherited age of onset tends to be earlier when
the affected parent is the father
 Homozygotes display similar course to heterozygotes
o Hemochromatosis – recessive disorder of iron storage
o Familial Alzheimer disease
o Many inherited cancers – autosomal dominant breast cancer

Variable expression – genetic disease may be caused by environmental effects,
modifier loci, or allelic heterogeneity (different types of mutations at the same
disease locus)
o Penetrance – all r none phenomenon; either one has the disease phenotype
or one does not
o Variable expression – refers to degree of severity of the disease
phenotypes
o Neurofibromatosis type 1 (NF1) – autosomal dominant disorder
 Some patients have café-au-lait spots; can see Lisch nodules,
neurofibromas, learning disabilities, hypertension, scoliosis,
malignancies
 A mildly affected parent can produce severely affected offspring

Locus heterogeneity – a disease that can be caused by mutations at different loci
in different families is said to exhibit locus heterogeneity
o Adult polycystic kidney disease – autosomal dominant disorder,
progressive accumulation of renal cysts is seen; caused by mutations in
genes on either chromosomes 16 or 4
o Osteogenesis imperfecta – encoded by 2 genes, one on chromosome 17
and the other on chromosome 7

Pleiotropy – genes that exert effects of multiple aspects of physiology or anatomy
are pleiotropic (common feature of human genes)
o Marfan syndrome – autosomal dominant disorder, affects the eye,
skeleton, cardiovascular system
 Unusually stretchable connective tissue
 Mutations in gene FBN1 (encodes fibrillin)  altered structure of
connective tissue
o Other diseases in which pleiotropy is seen: cystic fibrosis, osteogenesis
imperfecta, albinism
Consanguinity in Human Populations

Consanguinity and the frequency of recessive diseases
o Consanguinity increases the chance that a mating couple will both carry
the same disease causing mutation
o Seen more often in pedigrees involving rare recessive diseases than in
those involving common recessive diseases

Health consequences of consanguinity
o At the population level, consanguinity increases the frequency of genetic
disease and mortality
o The closer the degree of consanguinity, the greater the increase