Complicating Factors in the Interpretation of Phenotypes and Pedigrees
The Genotype-Phenotype Relationship and the Interpretation of Pedigrees can be
complicated by the following factors:
 Epistasis -- *non-allelic gene-gene interactions that modify the expression of
a trait (i.e. the action of one locus modifies the effects of another locus).
Epistasis encompasses two different phenomena:
o Penetrance:
 Complete penetrance – all individuals that inherit the mutant
allele(s) responsible for a disease trait express the mutant
phenotype.
 Incomplete penetrance – individuals that inherit the mutant
allele(s) responsible for a disease trait may or may not
express the mutant phenotype (this is all or none).
 Difference in penetrance (incomplete penetrance) is
due to differences in genetic background (i.e. have
differences in other loci that modify the mutant allele).
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In the above pedigree, there is ample evidence for
autosomal dominant inheritance:
o The disease is passed from the father (II-3) to
the son (III-5), this never happens with X-linked
traits.
o The disease occurs in three consecutive
generations, this never happens with recessive
traits.
o Males and females are affected, with roughly the
same probability.
o However, II-1 does not express the disease. He
must have inherited the mutant allele because he
passed it on to two children, III-1 and III-3. II-1 is
a classical example of incomplete penetrance, he
has the allele for the disease but he does not
express it.
o Variable Expression – individuals inheriting a mutant allele are
affected, but show a large variation in expression of trait among
affected individuals.
 Can be variation in severity, type of manifestation, and/or age
of onset.
 Ex: Huntington Disease – defect in gene that encodes
the protein huntingtin (HTT).
o **Modifying genes affect age of onset in
Huntington Disease.
 In variable expressivity, penetrance is complete (all progeny
who carry the mutant allele express it in some way), it is the
severity of the phenotype that varies.
 Variable expression is more striking in dominant disorders
compared to recessive disorders (it is rarely associated with
recessive traits).
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Causes of Epistasis:
o Modifying Loci – genes that modify the expression of another gene.
 Ex: α-thalasemia modulates sickle cell disease expression,
resulting in a milder form of the trait.
 Hemoglobin chains in affected individuals (HbS)
aggregate when deoxygenated.
 Decreased globin synthesis in thalasemic patients limits
the hemoglobin concentration in red blood cells
(keeping them mostly oxygenated).
o Genetic Background – variations in modifying loci among individuals.
Other Complicating Factors:
 Genetic Heterogeneity:
o Allelic Heterogeneity – different alleles result in a similar, but
altered phenotype (i.e. different mutations occurring at the same
locus that cause a change in phenotype).
 Difference may be in severity of phenotype.
 NOT due to epistasis, but allelic differences.
Ex: Phenylketonuria – several alleles for phenylalanine
hydroxylase result in hyperphenylalanemia.
 One type results in the complete absence of
phenylalanine hydroxylase activity.
 Other alleles encode an enzyme having reduced activity
(less severe form of disease).
 In extreme cases, allelic heterogeneity can lead to phenotypic
heterogeneity, in which differing mutations in the same gene
can lead to dramatically different phenotypes.
 Ex: RET (ret proto-oncogene) a member of the cadherin
superfamily encodes a receptor tyrosine kinase.
Different mutations in RET can lead to:
o Failure to develop colonic ganglia, resulting in
loss of colonic motility and severe, chronic
constipation.
o Unregulated kinase function, resulting in
multiple endrocrine neoplasia (MEN).
o Both Hirschprung disease and MEN.
o Locus Heterogeneity – mutations at different loci (therefore having
different genetic causes) result in similar phenotypes.
 Ex: mutations in many different genes result in Nonsyndromic Deafness.
 Genes located on different chromosomes, and expressed
in different cell types/tissues result in a similar
phenotype.
 Many disease traits manifest in multiple modes of inheritance.
 To date, 48 different mutations responsible for hearing loss
have been identified.
Environmental Factors:
o Environment can affect phenotype.
o Ex: Pigment in hair of Himalayan rabbits and Siamese cats.
 Temperature-sensitive mutation in coat color gene results in
light/white fur, except in extremities where body temperature
is lower.
Sex:
o Sex-influenced traits – mode of trait’s expression modified by the
gender of the individual (e.g. male-pattern baldness).
 Ex: Hemochromatosis (autosomal recessive) – iron-overload
due to enhanced dietary iron absorption.
 More common in males (10x).
 Females are believed to have decreased dietary iron
intake and increased losses via menstruation.
o Sex-limited traits – appearance of certain features in only one sex.
 Ex: prostate cancer, milk production.
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Pleiotropy – mutation in one gene has multiple manifestations in different
tissues (one gene affecting multiple, distinct phenotypes).
o Ex: CT locus in mice affects development of tail (curly) and neural
tube.
o Pleiotropic effects of Phenylketonuria (PKU): (in untreated
individuals)
 Defective phenylalanine hydroxylase (PAH) enzyme,
autosomal recessive.
 High levels of Phe and metabolites in body fluids.
 Decreased head size and low IQ (inadequate myelin synthesis).
 Tendency toward fairer hair and skin than relatives, often have
blue eyes (deficient in tyrosine, a melanin precursor).
 Hyperactive and uncoordinated.
o PKU can also be thought of as a gene x environment interaction,
because restriction of dietary Phe in newborns homozygous for the
mutation prevents mental retardation.
Phenocopy – a condition in which environmental influences result in a
phenotype that mimics a genetic disease or disorder.
o Ex: Thalidomide – used to treat morning sickness in pregnant
women in the 1950s. Caused limb defects, which mimicked
Phocomelia, a rare mutation that causes limb shortening.
Mosaicism – presence of two or more genetically-distinct cell lines in an
individual.
o Somatic mosaicism – event triggering mosaic condition occurred
post-zygotically.
 Progeny of individuals with somatic mosaicism will be normal.
o Germline mosaicism – abnormal cell line present in the gonads
 Responsible for occurrence of a dominant phenotype when
neither parent was affected.
 Most commonly recognized in connective tissue diseases (e.g.
osteogenesis imperfecta).
 Ex: Duchenne Muscular Dystrophy (DMD) – an X-linked
recessive trait.
 Some mothers who are apparently non-carriers, but
produce affected sons, may be germline mosaics.
 While their somatic cells are homozygous for the
normal allele, their ovaries may contain a cluster of cells
carrying the mutant allele. If this is the case, the mother
has a recurrent risk for additional affected sons.
Inheritance of Multifactorial Traits
Multifactorial Inheritance – phenotypic traits resulting from the interaction of
multiple environmental factors with multiple genes.
 Characterized by risk conditioned by the number of mutant genes inherited.
 Risk should be increased for siblings of patients showing severe expression
of the trait.
 Examples: diabetes mellitus, epilepsy, hypertension, bipolar disorder etc.
Example—environmental interaction with a single gene: SERPINA1 serine
peptidase inhibitor clade A (α-1 antiproteinase antitrypsin) member 1 on HSA 14.
 Better known as α1-anti-trypsin (α1-AT).
 Inhibits trypsin and elastase (proteases) active in the lung.
 Cigarette smoke contains O2- (superoxide anion).
 Inactivates α1-AT in lung tissue.
 Inactivated α1-AT no longer inhibits protease in lung tissue, and lungs suffer
damage as structural proteins are degraded by proteases (emphysema).
SERPINA1 genotype
α1-AT Activity
++
100%
+z
55-60%
zz
10-15%
 zz homozygotes show decreased survival compared to general population,
and survival of zz individuals who smoke is further reduced.
Complex, Multifactorial Traits
 Do NOT demonstrate simple, Mendelian patterns of inheritance.
 Demonstrate familial aggregation –relatives of affected individuals are
more likely to share disease-predisposing alleles with the affected individual
compared to unrelated individuals.
 Can be measured by relative risk ratio (λ):
o Relative risk (λr) = Prevalence of disease in the relatives of affected
individual / Prevalence of disease in the general population
 *Subscript r refers to relatives. Normally calculated for a
specific class of relatives.
 Pairs of relatives who share disease-predisposing alleles may be
discordant for phenotype (incomplete penetrance) because of non-genetic
factors.
 Disease-prevalence increased in close relatives of proband compared to
more distant relatives (who share fewer predisposing alleles).
 Greater concordance in monozygotic (identical) twins compared to
dizygotic (fraternal) twins.
Inheritance of Quantitative Traits – AKA polygenic traits (i.e. involving multiple
genes)
 Described by variance – a measure of the degree of spread of the values on
either side of the mean value.
o VE = environmental variance
o VG = genetic variance
o VT = total variance
o VT = VG + VE thus, VG = VT – VE
 Heritability describes the degree to which a trait is influenced by genetic
makeup (versus environmental).
o Heritability = VG / VT = VG / VG + VE
 Blood Pressure is an example of a polygenic trait:
o In twin studies, variance of blood pressure between dizygotic twins
was higher compared with that observed in monozygotic twins.
 These studies collectively support a genetic component for
blood pressure in humans.
 Concordance – describes the probability that a pair of individuals will both
have a certain characteristic, given that one of the pair has a characteristic.
Usually used in twin studies to describe inheritance of a trait (e.g. twins are
concordant when both have or both lack a given trait).
o For polygenic traits, the likelihood that MZ twins will show
concordance is significantly <100%, but is much higher than the
chance that both DZ twins will be affected.
o For polygenic traits, the frequency of concordance observed between
MZ twins is usually in the range of 20-40%.
 Correlation – used to describe relationship between two factors measured
on a continuous scale.
o Measured by correlation coefficient (R), which varies between
1(perfect correlation) and 0 (no correlation).
o Parent-Child correlation for blood pressure, r=0.3 (significant)
o Adopted Child-Adopted Child correlation, r = 0.1 (not significant)
Models for the Inheritance of Quantitative Traits
 These models examine multifactorial inheritance, so:
o Several, but not an unlimited number, loci are involved in the
expression of the trait.
o The loci act in concert in an additive fashion, each adding or
detracting a small amount from the phenotype.
o The environment interacts with the genotype to produce the final
phenotype.
 Additive Model – Continuous distribution of phenotypic values.
o Given a Locus A, with alleles:
 A1 = minus allele (decreases trait)
 A2 = plus allele (decreases trait)
o And a Locus B, with alleles:
 B1 = minus allele (decreases trait)
 B2 = plus allele (decreases trait)
o We make the following assumptions:
 Locus A and Locus B exert equal effects on trait expression.
 Each plus and minus allele exerts equal effects on the
magnitude of trait expression (but opposite direction).
 The effects of each allele are additive.
The figure approximates a
continuous distribution of
phenotypic values.
The F2 generation shows a
distribution of individuals
with a phenotypic range that
is dependent on the amount
of alleles each individual
inherits. Those with all
minus alleles would not
exhibit the phenotype
associated with positive A
and B loci. Those with all
plus alleles would exhibit a
severe phenotype, while
those in between would
show an intermediate
(milder) phenotype.

Threshold Model – examines quantitative traits that are discretely
expressed in a limited number of phenotypes (usually two), but are based on
an assumed continuous distribution of factors that contribute to the
trait (underlying liability).
o Unlike in the additive model, phenotypes are discontinuous—either
present or absent (rather than exhibiting a spectrum of mild to severe
phenotypes).
o In this model, individuals are affected when the genetic
predisposition is above a certain value.
 Genetically-determined liability – defined as a function of
the number of mutant alleles carried, and/or the severity of
the effects associated with the mutant alleles carried.
o Risk increases with the number of affected relatives in the family.
o Risk increases with the severity of the malformation or disease.
o Differential risk to relatives of an affected proband increases as the
frequency of the disease or malformation decreases in the general
population:
o Also, when the sex ratio of affected progeny is significantly skewed,
the offspring of affected probands of the less frequently affected sex
have a higher relative risk (e.g. if a trait tends to affect more females,
any male progeny of proband will be differentially more at risk than
other males of the general population due to probability).
o When using the threshold model, both genetic and environmental
factors must be taken into account.
For individuals with affected relatives, there is a curve shift relative to the general
population, while the threshold remains the same:
When there are differences observed in the environmental contribution to a disease
phenotype, there is a threshold shift, while the distribution remains the same: