Abstract

Dominance and recessivity are not intrinsic properties of genes or alleles but describe, in diploid
organisms, the pattern of occurrence of a phenotypic trait with respect to the possible
combinations of two alleles. If the trait is present in the heterozygote, it is said to be dominant or
semidominant, and if it is present only in one of the homozygotes, it is recessive.

Introduction

Different combinations of alleles of a gene (genotypes) may give rise to different manifestations
(phenotypes). The foundations of this observation were laid down by Gregor Mendel in his
hybridization experiments on peas, published in 1866. When Mendel crossed two pure-bred lines
of peas grown from round or wrinkled seeds, the seeds on these plants were all round. However,
when the plants grown from these progeny seeds were intercrossed, wrinkled seeds reappeared in
a ratio of about one wrinkled seed to three round seeds.

To explain the 1:3 ratio, Mendel hypothesized that the round-seeded trait was ‘dominating’ over
the wrinkled-seeded one and introduced an alphabetic notation that is still in wide use. He
showed that the segregation of round and wrinkled seeds could be explained by the transmission
of binary factors, later called alleles (derived from Bateson's term ‘allelomorph’). If seeds of RR
and Rr types were round and only the rr seeds wrinkled, the 1:3 ratio observed in the
hybridization experiment was neatly explained (Figure 1). Mendel went on to show that the
segregation of six other dichotomous traits of pea plants could be accounted for in a similar
fashion. These fundamental experiments underpin the science of genetics. See also Mendel,
Gregor Johann

Figure 1

Mendel's experiment demonstrating the properties of dominance and recessivity. Cross-

pollination between pure-bred lines of peas grown from round and wrinkled seeds gave rise only
to round seeds (F1 generation). However, these F1 plants produced wrinkled seeds as well as
round seeds when intercrossed, in a ratio of about three round to one wrinkled (F2 generation).
Mendel explained this pattern by postulating that the phenotype was determined by the
combination of factors R and r. The round is dominant over the wrinkled trait because the round
trait is manifested in the heterozygote Rr. Conversely, wrinkled is recessive to round.

The question to be addressed here is: what features of the two alleles determined that the round
trait was dominant over the wrinkled trait? More generally, what biological features determine
the dominance relationship of traits determined by a pair of alleles? To avoid confusion in the
ensuing discussion, it must first be noted that there are several operational uses of the word
dominance, which must be clearly distinguished.
Different Definitions of Dominance and Recessivity
Semidominance and codominance
Many allele pairs do not exhibit the phenotypic relationship observed in Mendel's original
experiments. Rather, the phenotype of the heterozygote is intermediate between the two
homozygotes and, strictly speaking, the two alleles do not have a dominant/recessive relationship
for the trait in question. Usually the heterozygous phenotype represents a blend of the
characteristics of the two homozygotes, in which case the alleles are referred to as semidominant
(Figure 2a). Occasionally, as in the case of some blood groups, the distinct characters of the two
homozygotes are independently expressed in the heterozygote: this is termed codominance
(Figure 2b). Note that dominance and recessivity are not intrinsic properties of genes or alleles:
rather, the terms describe the relationship between different combinations of alleles and observed
characters (see next subsection). In human genetics, there is an additional complication. Often
the disease allele is very rare and the homozygote for this allele has never been observed. It is
therefore unknown whether the disease allele is dominant or semidominant, with respect to wild
type (Figure 2c). In this context, a different operational definition of dominance, based on
inheritance pattern, tends to be used.

Figure 2

Dominance relationships between a pair of alleles A and B. (a, b) Phenotypes corresponding to

the different genotypes AA, AB and BB are indicated by filled rectangles of different tones. (c)
In many dominantly inherited diseases, the phenotype associated with the homozygous mutant
BB has not been observed; hence it is not known whether allele B is a true dominant or
semidominant, with respect to A.

Some common misconceptions about dominance and recessivity

Dominance and recessivity are intrinsic properties of genes or alleles
Although reference is commonly made to ‘dominant genes’ or ‘dominant alleles’, dominance
and recessivity are not intrinsic properties of either genes or alleles. Strictly speaking, the
terminology is only appropriate when comparing a pair of alleles for a particular trait that makes
up a phenotype. For example, in mice an allelic series of mutations at the agouti (a) gene give
rise to variation in coat color from yellow (dominant) through to black (recessive). The wild-type
allele is intermediate in the dominance hierarchy: it appears recessive in combination with a
yellow allele, but dominant in combination with a black allele. In other words, the
dominance/recessivity of the wild-type allele is dependent on context.

The major variation in the function of agouti alleles occurs at the transcriptional level: dominant
alleles show increased transcription and recessive alleles decreased transcription, compared with
the wild type. The lethal yellow allele (Ay) illustrates another important point: although the
yellow coat is (semi)dominant with respect to wild type, lethality only occurs in homozygotes.
Hence the trait of lethality is recessive with respect to wild type.

Dominantly inherited diseases are rarer than recessive diseases

The observation that most mutations are recessive to wild type does not imply that dominantly
inherited diseases must be rare compared with recessively inherited ones. On the contrary, it has
been estimated that autosomal dominant single-gene disorders constitute 0.7% of live births
compared to only 0.25% with an autosomal recessive basis. The phenotypic variation tends to be
greater for dominant than for recessive disorders, both because different dominant mutant alleles
differ in the strength of their pathogenic effect and because the ameliorating influence of the
wild-type allele may vary with genetic background. This often enables at least some individuals
affected with dominant disorders to reproduce, which contributes to maintaining the number of
affected individuals in the population. Many dominant diseases are also characterized by a high
rate of new mutations. Although the overall number of recessive mutant alleles is far greater (it is
estimated that every healthy person is heterozygous for approximately three mutations that
would be associated with severe or lethal phenotypes in the homozygous state), the great
majority of these are latent because they are masked by being in combination with a wild-type
allele.

Dominant inheritance
Pedigrees showing vertical transmission of a phenotypic character are said to exhibit dominant
inheritance (Figure 3a); the allele segregating with the phenotypic character is assumed to be
dominant to its partner. However, this is not necessarily equivalent to the previous definition of
dominance. First, the occurrence of a rare homozygote will often reveal that the alleles are
semidominant, because the homozygote is more seriously affected than the heterozygote.
Second, dominant inheritance does not necessarily imply dominance of one allele over the other
at a cellular level. For example, mutations of tumor suppressor genes are recessive at a cellular
level but segregate in a dominant pattern because of the high cumulative risk of a somatic
mutation occurring in the wild-type allele of a target cell. A similar process may underlie the
dominant inheritance of some nonneoplastic diseases, for example autosomal dominant
polycystic kidney disease. Sex-limited vertical transmission may occur in disorders caused either
by mutations of imprinted genes, which are functionally hemizygous (acting in the haploid state),
or by mutations in the mitochondrial genome, in which enteroplasty (the occurrence of multiple
copies of distinct alleles) is an additional complicating factor. In X-linked disorders, the
definition of dominance is made ambiguous by the occurrence of X inactivation, the
consequence of which, for the majority of X-encoded genes, is to render only one or other allele
active in an individual cell. A disorder conventionally regarded as recessive (no manifesting in
carrier females) may be clinically manifest in rare females owing either to preferential
inactivation of the wild-type allele or to incomplete selection against cells in which the mutant
allele is active. Finally, very common recessive traits may also show vertical transmission

Figure 3
Typical pedigrees showing autosomal dominant and autosomal recessive inheritance. Affected
and unaffected individuals are denoted by filled and open symbols (square, male; circle, female)
respectively. (a) Autosomal dominant inheritance of mutant allele B. Transmission of the
phenotype occurs vertically between generations. On average, 50% of the offspring of an
affected individual are themselves affected, irrespective of sex. (b) Autosomal recessive
inheritance of mutant allele B. Consanguinity is frequent, as shown here (closely spaced parallel
lines). Usually only a single sibship is affected, with previous and succeeding generations free of
the disease. (c) If there is extensive inbreeding or the recessive mutant allele B is very common,
pseudodominant inheritance may occur.

Recessive inheritance
Recessive traits are typically recognized by the occurrence of multiple affected siblings within a
single sibship, the previous and subsequent generations being free of the disease (Figure 3b). The
rarer the trait, the higher the proportion of affected individuals who are born to consanguineous
unions, in which the mutant allele in each parent segregated from a shared ancestor. This is
referred to as auto zygosity.

The classical patterns of dominant and recessive inheritance can be confused in certain
situations. In the case of very common recessive disorders, there is a significant chance of union
between a homozygous affected individual and an unaffected individual who is, by chance, a
heterozygous carrier of the same recessive allele. In that case, half their children will be affected,
giving rise to vertical or ‘pseudodominant’ transmission (Figure 3c). Conversely, the birth of two
or more affected siblings to unaffected parents does not necessarily imply recessive inheritance.
Germinal mosaicism for a dominant mutation, recurrent transmission of an unbalanced karyotype
from a parent with a balanced translocation and segregation of an imprinted locus are all
alternative possibilities

Most Mutant Alleles are Recessive to Wild Type and Cause Loss of Function

Saturation mutagenesis of Drosophila melanogaster by Hermann Muller and others in the late
1920s and 1930s first showed that most mutant alleles (over 90%) are recessive to wild type.
Similar conclusions have more recently been reached for other species including yeast, zebra fish
and mouse. (It is incorrect to conclude that dominantly inherited diseases must be rarer in
humans than recessively inherited diseases, for reasons given above.) The explanation for why
mutant alleles are usually recessive sparked a great debate between Ronald Fisher, who
developed a complex mathematical theorem based on selection of modifier alleles, and Sewall
Wright, who believed that it was inherent in the pathophysiology of gene action. Although
Fisher's ideas were influential, Wright's view has been vindicated by decades of accumulated
knowledge. An especially persuasive demonstration of this was provided by an analysis of
mutations in the alga Chlamydomonas reinhardtii. This alga reproduces vegetatively in the
haploid state over many generations, so that mutations arise as hemizygotes rather than
heterozygotes. However, the effect of the mutation in association with a wild-type allele (as a
temporary heterozygote) can be examined either by artificially fusing two haploid gametes, or by
screening for rare diploid vegetative cells that arise because diploid zygotes occasionally divide
mitotically instead of meiotically. Of 59 mutations examined, 52 were recessive, seven were
semidominant and none was dominant to wild type.

A combination of two arguments explains the recessive nature of most mutations. The first, and
more straightforward, is that most mutations cause loss of function. This follows directly from
the particular mutation in many cases. For example, complete gene deletions, also nonsense
mutations or frameshifts leading to instability of the transcribed messenger ribonucleic acid
(mRNA), are loss of function by definition. Less predictably, this may also be the case with
simple amino acid substitutions that often lead to misfolding of the protein and premature
degradation. The consequence in the heterozygote of such a loss-of-function mutation will be
that all synthesized protein is normal, but it is only present at 50% of the wild-type level. See
The second argument, more subtle and in some aspects still controversial, is that a 50% reduction
in the level of a protein will usually not affect the phenotype. The reason why this might be the
case is most easily understood in terms of the theory of metabolic fluxes developed in 1973 by
Henrik Kacser and James Burns. As shown in Figure 4, the relationship between the level of a
protein and the activity of the pathway in which it acts is hyperbolic: the activity reaches a
maximum value asymptotically as further protein is added. This nonlinear relationship
determines that a 50% reduction in protein level will in most cases have little detectable effect on
activity. Although this may be true, it begs the question as to why surplus protein is made in the
first place. If it is assumed that the costs of gene expression are relatively low, it can be shown
that it is selectively advantageous for a pathway to have high activity rates and the recessively of
mutations then follows.

Figure 4

Relationship between protein level and metabolic activity. Most proteins act at the asymptotic
end of the activity curve. A 50% reduction in protein compared with the wild-type level, caused
by a heterozygous loss-of-function mutation, results in a reduction in activity of less than 10%
(assumed to reflect the phenotype); complete loss of the protein abolishes activity. Hence the
phenotype of the heterozygote resembles wild type and the mutation is recessive.

Dominance at the Cellular Level: Gain and Loss of Function

As should be apparent from the above discussion, recessivity of mutations with respect to wild
type represents the default state. Mutations that, by contrast, have a dominant or semidominant
action at the cellular level in relation to wild type always require a specific explanation. Broadly
speaking, the mutations fall into two groups, depending on which of the two assumptions about
recessive mutations is contravened. First, a minority of proteins are dosage sensitive. In other
words, the 50% reduction in level caused by a loss-of-function mutation significantly impedes
normal function, implying that the Kacser–Burns reasoning is not applicable. This dosage
sensitivity is termed haploinsufficiency. Second, some mutations alter, rather than abolish, the
function of the mutant protein: these are gain-of-function mutations. Gain-of-function mutations
may be further divided into two types: dominant negative and dominant positive. Dominant
negative mutations are so called because they abrogate the function of the wild-type allele. This
requires that the mutant protein is able to compete with normal protein synthesized by the wild-
type allele, but is itself nonfunctional (Figure 5). The consequence of this is that the phenotype
associated with a dominant negative mutation of one allele may resemble that caused by
recessive mutations of both alleles. Dominant positive mutations impart increased, constitutive,
novel or toxic activities to the mutant protein. Their molecular mechanisms tend to be diverse
and idiosyncratic, requiring elucidation, on a case-by-case basis, by experimental analysis. Many
distinct mechanisms of gain of function have been identified, which can broadly be categorized
as acting at the level of the gene, the transcript or the protein (Table 1). The effects on phenotype
are correspondingly unpredictable: a corollary of this is that dominant mutations tend to provide
fewer clues to the essential functions of the affected protein than do recessive mutations

Figure 5

Common mechanism of dominant negative mutation. (a) Dimerization mediated by the left half
of the normal monomeric protein activates the function of the right half (shown as a change to
shaded fill). (b) Heterozygous mutation that abolishes the activation domain but does not affect
dimerization will cause half of the normal protein to become sequestered into nonproductive
signaling complexes.

Table 1. Classification of cellular mechanisms of dominance in human disorders (where

possible, the examples are selected from the text or Tables 2 and 3)
Category of mutation Mechanism Affected Selected disorder
gene/protein

Loss of function

Haploinsufficiency Metabolic LDL Familial

rate receptor hypercholesterole
determining mia
step

Developme Transcripti Waardenburg

ntal on factors syndrome
regulator (PAX3), many
developmental
disorders

Gain of function:
dominant negative

Substrate Binding by Ligands, Short stature

sequestration inactive transcriptio (GH1, POU1F1)
monomer n factors

Dimer sequestration Formation Receptors Piebaldism (KIT),

of inactive insulin resistance
dimers (INSR)
Category of mutation Mechanism Affected Selected disorder
gene/protein

Disruption of Missense Collagens Osteogenesis

structure substitution imperfecta,
Stickler
syndrome

Gain of function:
dominant positive

Increased gene Duplication PMP22 Charcot–Marie–

dosage Tooth disease

Amplificati Oncogene Many tumors

on products (MYC, RAS)

Altered mRNA expre Increased γ Hereditary

ssion gene Hemoglobi persistence of
expression n fetal hemoglobin

Alternative WT1 Frasier syndrome

splicing

Toxic RNA DMPK Myotonic

inclusions dystrophy

Altered protein Constitutive Ion Myotonia

activity activity channels, congenita
receptors (CLCN1),
McCune–
Albright
syndrome
(GNAS)

Increased Hemoglobi Methemoglobine

binding n mia
affinity

Formation Diverse Amyloidosis

of toxic (TTR, FGA),
proteins polyglutamine
disorders (HD)

Novel protein Altered α1 Pittsburgh

activity substrate Antitrypsi mutation
specificity n (antithrombin
activity)

Chimeric Transcripti Alveolar

Category of mutation Mechanism Affected Selected disorder
gene/protein

protein on factors rhabdomyosarco

(translocati ma
on) (PAX3/FOXO1A)

A special class of mutations is those caused by expansion of triplet repeats. With the exception
of the gene associated with Friedreich ataxia, these are dominantly inherited but the cellular
mechanisms of this dominance are diverse. The proposed mechanisms include reduction of
transcription associated with haploinsufficiency, production of abnormal RNA aggregates or
spliceforms and synthesis of proteins containing expanded stretches of polyglutamine that are
toxic to the cell.

Semidominant mutations are much more common than true dominant mutations
It is a rare event for two clinically affected individuals with heterozygous mutations of the same
disease gene to reproduce. Only one-quarter of their children are expected to be homozygous for
the mutant allele, so it is even rarer to observe the consequences of homozygosity. However,
these cases are very instructive and tend to be reported in the medical literature. Table 2 provides
a listing of genes for which homozygosity of dominantly inherited mutations has been reported.
At present only six genes have been identified for which mutations exhibit completely dominant
behavior. In three cases (huntingtin (Huntington disease) (HD), prion protein (p27-30)
(Creutzfeldt–Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia)
(PRNP) and transthyretin (prealbumin, amyloidosis type I) (TTR)) the mutant protein forms
abnormal aggregates, and a heterozygous quantity of these aggregates is presumably sufficient to
trigger the disease irrespective of the presence of the wild-type allele. A different mechanism
applies to the keratin 5 (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber-
Cockayne types) (KRT5) gene, which encodes a structural protein of skin. In heterozygotes, the
mutant protein forms polymers with the wild-type protein, completely abrogating its normal
function in a classical dominant negative fashion. The two other cases involve tumor suppressor
genes (breast cancer 1, early onset (BRCA1), multiple endocrine neoplasia I (MEN1)); the
reasons for the completely dominant behavior have not been elucidated. In a much larger number
of cases (Table 2) the homozygous phenotype is more severe than the heterozygous phenotype;
the mutation is semidominant and the phenotypic effects are mitigated by the wild-type allele.

Table 2. Cases of molecularly proven homozygosity for mutations showing dominant

inheritance
Genea OMIM Disorder Homozygous
Nob mutant
phenotype
more severe
than
heterozygote?

BRCA1 120160 Familial breast cancer No

HD 143100 Huntington disease No

KRT5 148040 Epidermolysis bullosa simplex No

MEN1 131100 Multiple endocrine neoplasia, No

Genea OMIM Disorder Homozygous
Nob mutant
phenotype
more severe
than
heterozygote?

type 1

PRNP 123400 Familial Creutzfeldt–Jakob No

disease

TTR 176300 Familial amyloidotic No

polyneuropathy

CACNA1 601011 Spinocerebellar ataxia type 6 Yes

A

CASR 601199 Hypocalciuric hypercalcemia Yes

COL1A2 120160 Osteogenesis imperfecta Yes

CRX 602225 Leber congenital amaurosis, Yes

cone rod dystrophy 2

DRPLA 125370 Dentatorubralpallidoluysian Yes

atrophy

DMPK 605377 Myotonic dystrophy Yes

EFEMP1 601548 Honeycomb retinal dystrophy Yes

FBN1 134797 Marfan syndrome Yes

FGFR3 100800 Achondroplasia Yes

GDF5 601146 Brachydactyly type C (AD), Yes

Grebe syndrome (AR)

HOXD13 186000 Synpolydactyly Yes

KRT14 148066 Epidermolysis bullosa simplex Yes

LDLR 143890 Familial hypercholesterolemia Yes

MJD 109150 Machado–Joseph disease Yes

Genea OMIM Disorder Homozygous
Nob mutant
phenotype
more severe
than
heterozygote?

PABPN1 602279 Oculopharyngeal muscular Yes

dystrophy

PAX3 193500 Waardenburg syndrome Yes

PAX6 106210 Aniridia Yes

PMP22 601097 Charcot–Marie–Tooth disease Yes

ROR2 602337 Brachydactyly type B (AD), Yes

Robinow syndrome (AR)

TRPS1 604386 Trichorhinophalangeal Yes

syndrome I

 a
 Full names of gene and links to further information can be found on the Genew: Human
Gene Nomenclature Database Search Engine (see Web links).
 b
 See Online Mendelian Inheritance in Man (Web links).

More commonly in human genetic diseases it is not known whether a mutation behaves in a true
dominant or semidominant fashion (Figure 2c): in the following sections, these are simply
referred to as ‘dominant mutations’, reflecting their inheritance pattern.

Both dominant and recessive disease-causing mutations may occur in the same gene
The identification of both dominant and recessive mutations in the same disease-causing gene
can be very instructive for understanding structure–function relationships of the encoded protein.
Examples are listed in Table 3. In the majority of cases, the dominant and recessive mutations
are responsible for the same disease phenotype. One of two mechanisms is usually responsible.
The recessive mutations can cause loss of function, whereas the dominant mutations act in a
dominant negative fashion; the net effect of both mutations is a marked reduction of function.
Examples include aquaporin 2 (collecting duct) (AQP2), growth hormone 1 (GH1), hemoglobin,
beta (HBB), insulin receptor (INSR), POU domain, class 1, transcription factor 1 (Pit1, growth
hormone factor 1) (POU1F1) and thyroid hormone receptor, beta (erythroblastic leukemia
viral (v-erb-a) oncogene homolog 2, avian) (THRB). Alternatively, the dominant mutations cause
loss or gain of function; the recessive mutations have a qualitatively similar, but quantitatively
lesser effect, so that the phenotypic effects are approximately comparable. Examples include
mutations of ankyrin 1, erythrocytic (ANK1) and serine (or cysteine) proteinase inhibitor, clade
G (C1 inhibitor), member 1, (angioedema, hereditary) (SERPING1), in which the recessive
mutations occur in the promoter or splice sites and probably reduce rather than abolish the
normal transcript, whereas the dominant mutations cause haploinsufficiency; and potassium
voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1), protein C (inactivator of
coagulation factors Va and VIIIa) (PROC) and uroporphyrinogen decarboxylase (UROD) in
which the recessive mutations are relatively mild missense substitutions that are phenotypically
silent in heterozygotes.
Table 3. Genes additional to those in Table 2 for which both heterozygous and homozygous
mutations have been identified
Genea OMIM Disease
Nob

ABCC6 603234 AD and AR pseudoxanthoma elasticum

ACTA1 102610 AD and AR nemaline myopathy

ALPL 171760 AD and AR hypophosphatasia

ANK1 182900 AD and AR hereditary spherocytosis

APOE 107741 AD and AR hyperlipoproteinemia

AQP2 107777 AD and AR diabetes insipidus

AVP 192340 AD and AR familial central diabetes insipidus

CLCN1 118425 AD and AR myotonia congenita

CHRNE 100725 AD and AR myasthenic syndromes

COL4A4 120131 Benign familial hematuria (AD), Alport

syndrome (AR)

COL7A1 120120 AD and AR epidermolysis bullosa

COL11A2 601868 Stickler syndrome type III (AD), deafness

(AD), otospondylomegaepimetaphyseal
dysplasia (AR)

DES 125660 AD and AR desmin-related myopathy

EDAR 604095 AD and AR hypohidrotic ectodermal dysplasia

EVC 604831 Ellis–van Creveld syndrome (AR), Weyers

acrodental dysostosis (AD)

FECH 177000 AD and AR erythropoietic protoporphyria

FGA 134820 Amyloidosis (AD), congenital

afibrinogenemia (AR)

GCH1 600225 Progressive dystonia (AD),

hyperphenylalaninemia (AR)
Genea OMIM Disease
Nob

GH1 139250 AD and AR growth hormone deficiency

GJB2 121011 AD and AR deafness, Vohwinkel syndrome

GJB3 603224 AD and AR deafness, erythrokeratoderma

variabilis

GLRA1 138491 AD and AR familial hyperekplexia

HBB 141900 AD and AR beta thalassemia

HF1 134370 AD and AR hemolytic uremic syndrome

INSR 147670 AD and AR insulin resistance, leprechaunism

(AR)

KCNQ1 192500 Long QT syndrome (AD), Jervell and Lange–

Nielsen syndrome (AR)

LHCGR 152790 Leydig cell hypoplasia with male

pseudohermaphroditism (AD), male limited
precocious puberty (AR)

LMNA 150330 AD and AR Emery–Dreifuss muscular

dystrophy, dilated cardiomyopathy, familial
partial lipodystrophy

MAT1A 250850 AD and AR methionine adenosyltransferase

deficiency

MC4R 155541 AD and AR obesity

MYO7A 276903 AD nonsyndromic deafness, Usher syndrome

type 1B (AR)

PMP22 601097 AD and AR Charcot–Marie–Tooth disease

POU1F1 173110 AD and AR combined pituitary hormone

deficiency

PROC 176860 AD and AR thrombophilia

PTH 168450 AD and AR hypoparathyroidism

Genea OMIM Disease
Nob

RGR 600342 AD and AR retinitis pigmentosa

RHO 180380 AD and AR retinitis pigmentosa

SERPING 106100 AD and AR hereditary angioneurotic edema

1

SLC4A1 109270 Hereditary spherocytosis, renal tubular

acidosis

SOD1 147450 AD and AR amyotrophic lateral sclerosis

TECTA 602574 AD and AR deafness

TG 188450 AD and AR congenital goiter

THRB 190160 AD and AR thyroid hormone resistance

TNFRSF6 134637 AD and AR lymphoproliferative syndrome

UROD 176100 AD porphyria cutanea tarda, AR

hepatoerythropoietic, porphyria

VWF 193400 AD and AR von Willebrand disease

 a
 Full names of gene and links to further information can be found on the Genew: Human
Gene Nomenclature Database Search Engine (see Web links).
 b
 See Online Mendelian Inheritance in Man (Web links).

AD: autosomal dominant; AR: autosomal recessive.

In a smaller number of cases, the dominant and recessive mutations act by different mechanisms
and give rise to entirely distinct phenotypes. Recessive (and some dominant) mutations
of fibrinogen, A alpha polypeptide (FGA), encoding the clotting factor fibrinogen, cause
thrombosis and bleeding. By contrast, other dominant mutations do not affect clotting but create
structurally abnormal fibrinogen proteins that accumulate as amyloid deposits in various tissues,
leading, for example, to kidney failure. Loss-of-function mutations of the gene luteinizing
hormone/choriogonadotropin receptor (LHCGR) lead to phenotypically female external genitalia
in genetically male individuals; gain-of-function mutations of the same receptor are
constitutively activated in the absence of luteinizing hormone, causing the phenotypically male
children to enter puberty by the age of 4 years. Two classes of proteins that are notable for the
frequency with which both dominantly and recessively inherited phenotypes occur are ion
channels and the receptor tyrosine kinases (RTKs). In the case of ion channels, recessively
inherited mutations abolish channel function whereas dominantly inherited mutations tend to
prolong channel opening. Receptor tyrosine kinase proteins are usually activated by
dimerization: dominantly inherited mutations either enhance or bypass this requirement, whereas
recessive mutations cause loss of function. Mutations occurring in distinct domains of the protein
may uncover distinct functions. For example, mutations in the gap junction proteins connexin 26
and 31, encoded by gap junction protein, beta 2, 26 kDa (connexin 26) (GJB2) and gap junction
protein, beta 3, 31 kDa (connexin 31) (GJB3) respectively, cause either deafness (dominantly or
recessively inherited) or specific skin disorders, depending on their location

Dominant mutations often occur sporadically

In some cases, the consequences of the mutation for the cell or the organism may be too severe
for the mutation ever to be transmitted to offspring. Certain constitutively activating
heterozygous mutations of fibroblast growth factor receptor 3 (achondroplasia, thanatophoric
dwarfism) (FGFR3) cause thanatophoric dysplasia, a serious bone disorder. Affected infants die
at birth because they are unable to breathe, hence the frequency of the disorder is maintained by
new mutations occurring in the germ line. Even more serious are specific activating mutations in
the G protein-coupled receptor encoded by GNAS complex locus (GNAS). Germ-line mutations
would be incompatible with fetal development; all mutations arise postzygotically and so exist as
somatic mosaics. Here, the wild-type cells may be viewed as rescuing the mutant cells from
lethality. Affected individuals manifest McCune–Albright syndrome, which is associated with
abnormalities of the bone, skin and endocrine systems. These abnormalities depend on the
distribution of mutant cells in the body and so are extremely variable between patients.

Postzygotic mutations occurring later in development contribute to the abnormalities in the

control of cellular growth that lead to cancer. Frequently, the genes involved are also mutated in
inherited disorders. For example, inherited loss-of-function mutations in the receptor tyrosine
kinase gene v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) cause the
pigmentary disorder piebaldism by haploinsufficiency or dominant negative mechanisms,
whereas distinct somatic constitutively activating mutations cause tumors of the gastrointestinal
stroma and mast cells. Haploinsufficiency of the paired box transcription factor paired box gene
3 (Waardenburg syndrome 1) (PAX3) located on chromosome 2q, causes Waardenburg
syndrome; somatically acquired (2q;13q) translocations create a fusion protein
between PAX3 and the forkhead transcription factor encoded by forkhead box
O1A (rhabdomyosarcoma) (FOXO1A) located on chromosome 13q, leading to alveolar
rhabdomyosarcoma.

Atypical Heterozygous Phenotypes

In the majority of cases, the phenotype of the heterozygote falls within the range depicted in
Figure 2, that is, somewhere between the extremes represented by the two homozygotes.
Occasionally, however, the heterozygous phenotype may be either more severe or less severe
than either homozygote.

The best documented example of a more severe phenotype in the heterozygote concerns the
gene myocilin, trabecular meshwork inducible glucocorticoid response (MYOC) (encoding
myocilin), mutations of which cause the dominantly inherited eye disorder primary open angle
glaucoma. A consanguineous family segregating a missense mutation in myocilin included
several individuals homozygous for the mutation: surprisingly, these individuals were clinically
normal. This phenomenon has been referred to as metabolic interference or homoallelic
complementation. The molecular basis has not been fully elucidated, but as myocilin function
requires dimerization, it is speculated that homodimers of the mutant allele are able to form in a
manner similar to the wild-type allele, but heterodimer formation is reduced or abnormal. A
similar mechanism may explain several instances of X-linked diseases that are more severe in
females than males, for example, Juberg–Heilman syndrome and craniofrontonasal syndrome.

The converse situation occurs when there is heterozygous advantage. If selection is relatively
strong, this will maintain a high carrier rate in the population even if the homozygous recessive
phenotype has low genetic fitness. The classical examples are provided by mutations of the α-
and β-globin genes causing thalassemia and sickle cell disease, which occur commonly in
tropical countries because heterozygotes for these mutations are protected against malaria. A
somewhat different example is the valine/methionine polymorphism at position 129 of the prion
protein (encoded by PRNP). Neither of these amino acids is disease causing, but heterozygosity
at this site seems to protect against development of both classical and variant Creutzfeldt–Jakob
disease by inhibiting protein aggregation. See also 

Conclusion: Molecular Basis of the Wrinkled Pea Phenotype

This article started with a description of Mendel's observations of the segregation of plants
bearing round and wrinkled pea seeds that led directly to the concepts of dominance and
recessivity. In 1990, the molecular basis of the recessive wrinkled allele originally studied by
Mendel was discovered. A mobile genetic element (transposon) had inserted into the gene
encoding starch-branching enzyme I, leading to a high sugar content in the fleshy seedling leaves
(cotyledons) and osmotically-induced wrinkling. This insertion inactivates the gene so that no
functional enzyme is produced in the homozygote. In accordance with the Kacser–Burns
principle (Figure 4), sufficient enzyme activity remains in the heterozygote for normal starch
metabolism, hence no wrinkling occurs. The wrinkled phenotype therefore segregates, as Mendel
observed, as a classical recessive trait.