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Dominance and Recessivity

  1. Andrew OM Wilkie

Published Online: 27 JAN 2006

DOI: 10.1038/npg.els.0005475

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Wilkie, A. O. 2006. Dominance and Recessivity. eLS. .

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  1. University of Oxford, Oxford, UK

Publication History

  1. Published Online: 27 JAN 2006

Introduction

  1. Top of page
  2. Introduction
  3. Different Definitions of Dominance and Recessivity
  4. Most Mutant Alleles are Recessive to Wild Type and Cause Loss of Function
  5. Dominance at the Cellular Level: Gain and Loss of Function
  6. Atypical Heterozygous Phenotypes
  7. Conclusion: Molecular Basis of the Wrinkled Pea Phenotype
  8. See also
  9. Further Reading
  10. Web Links

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

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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

  1. Top of page
  2. Introduction
  3. Different Definitions of Dominance and Recessivity
  4. Most Mutant Alleles are Recessive to Wild Type and Cause Loss of Function
  5. Dominance at the Cellular Level: Gain and Loss of Function
  6. Atypical Heterozygous Phenotypes
  7. Conclusion: Molecular Basis of the Wrinkled Pea Phenotype
  8. See also
  9. Further Reading
  10. Web Links

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.

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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 actually 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 heteroplasmy (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 (nonmanifesting 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 (see next section). See also Mitochondrial Heteroplasmy and Disease, Retinoblastoma, and X-chromosome Inactivation

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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 autozygosity.

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. See also Imprinting Disorders, and Mosaicism

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

  1. Top of page
  2. Introduction
  3. Different Definitions of Dominance and Recessivity
  4. Most Mutant Alleles are Recessive to Wild Type and Cause Loss of Function
  5. Dominance at the Cellular Level: Gain and Loss of Function
  6. Atypical Heterozygous Phenotypes
  7. Conclusion: Molecular Basis of the Wrinkled Pea Phenotype
  8. See also
  9. Further Reading
  10. Web Links

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. See also Fisher, Ronald Aylmer, and Muller, Herman Joseph

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 also Nonsense-mediated mRNA Decay, and Protein Misfolding and Degradation in Genetic Disease

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 recessivity of mutations then follows.

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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

  1. Top of page
  2. Introduction
  3. Different Definitions of Dominance and Recessivity
  4. Most Mutant Alleles are Recessive to Wild Type and Cause Loss of Function
  5. Dominance at the Cellular Level: Gain and Loss of Function
  6. Atypical Heterozygous Phenotypes
  7. Conclusion: Molecular Basis of the Wrinkled Pea Phenotype
  8. See also
  9. Further Reading
  10. Web Links

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. See also Gain-of-function Mutations in Human Genetic Disorders, and Haploinsufficiency

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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 mutationMechanismAffected gene/proteinSelected disorder
Full names of gene and links to further information can be found on the Genew: Human Gene Nomenclature Database Search Engine (see Web links).
Loss of function   
HaploinsufficiencyMetabolic rate determining stepLDL receptorFamilial hypercholesterolemia
 Developmental regulatorTranscription factorsWaardenburg syndrome (PAX3), many developmental disorders
Gain of function: dominant negative   
Substrate sequestrationBinding by inactive monomerLigands, transcription factorsShort stature (GH1, POU1F1)
Dimer sequestrationFormation of inactive dimersReceptorsPiebaldism (KIT), insulin resistance (INSR)
Disruption of structureMissense substitutionCollagensOsteogenesis imperfecta, Stickler syndrome
Gain of function: dominant positive   
Increased gene dosageDuplicationPMP22Charcot–Marie–Tooth disease
 AmplificationOncogene productsMany tumors (MYC, RAS)
Altered mRNA expressionIncreased gene expressionγ HemoglobinHereditary persistence of fetal hemoglobin
 Alternative splicingWT1Frasier syndrome
 Toxic RNA inclusionsDMPKMyotonic dystrophy
Altered protein activityConstitutive activityIon channels, receptorsMyotonia congenita (CLCN1), McCune–Albright syndrome (GNAS)
 Increased binding affinityHemoglobinMethemoglobinemia
 Formation of toxic proteinsDiverseAmyloidosis (TTR, FGA), polyglutamine disorders (HD)
Novel protein activityAltered substrate specificityα1 AntitrypsinPittsburgh mutation (antithrombin activity)
 Chimeric protein (translocation)Transcription factorsAlveolar rhabdomyosarcoma (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. See also Trinucleotide Repeat Expansions: Disorders, and Trinucleotide Repeat Expansions: Mechanisms and Disease Associations

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. See also Huntington Disease, Keratins and Keratin Diseases, Prion Disorders, and Protein Aggregation and Human Disorders

Table 2. Cases of molecularly proven homozygosity for mutations showing dominant inheritance
GeneaOMIM NobDisorderHomozygous mutant phenotype more severe than heterozygote?
  1. 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).

  2. b

    See Online Mendelian Inheritance in Man (Web links).

BRCA1120160Familial breast cancerNo
HD143100Huntington diseaseNo
KRT5148040Epidermolysis bullosa simplexNo
MEN1131100Multiple endocrine neoplasia, type 1No
PRNP123400Familial Creutzfeldt–Jakob diseaseNo
TTR176300Familial amyloidotic polyneuropathyNo
CACNA1A601011Spinocerebellar ataxia type 6Yes
CASR601199Hypocalciuric hypercalcemiaYes
COL1A2120160Osteogenesis imperfectaYes
CRX602225Leber congenital amaurosis, cone rod dystrophy 2Yes
DRPLA125370Dentatorubralpallidoluysian atrophyYes
DMPK605377Myotonic dystrophyYes
EFEMP1601548Honeycomb retinal dystrophyYes
FBN1134797Marfan syndromeYes
FGFR3100800AchondroplasiaYes
GDF5601146Brachydactyly type C (AD), Grebe syndrome (AR)Yes
HOXD13186000SynpolydactylyYes
KRT14148066Epidermolysis bullosa simplexYes
LDLR143890Familial hypercholesterolemiaYes
MJD109150Machado–Joseph diseaseYes
PABPN1602279Oculopharyngeal muscular dystrophyYes
PAX3193500Waardenburg syndromeYes
PAX6106210AniridiaYes
PMP22601097Charcot–Marie–Tooth diseaseYes
ROR2602337Brachydactyly type B (AD), Robinow syndrome (AR)Yes
TRPS1604386Trichorhinophalangeal syndrome IYes

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
GeneaOMIM NobDisease
  1. 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).

  2. b

    See Online Mendelian Inheritance in Man (Web links).

AD: autosomal dominant; AR: autosomal recessive.
ABCC6603234AD and AR pseudoxanthoma elasticum
ACTA1102610AD and AR nemaline myopathy
ALPL171760AD and AR hypophosphatasia
ANK1182900AD and AR hereditary spherocytosis
APOE107741AD and AR hyperlipoproteinemia
AQP2107777AD and AR diabetes insipidus
AVP192340AD and AR familial central diabetes insipidus
CLCN1118425AD and AR myotonia congenita
CHRNE100725AD and AR myasthenic syndromes
COL4A4120131Benign familial hematuria (AD), Alport syndrome (AR)
COL7A1120120AD and AR epidermolysis bullosa
COL11A2601868Stickler syndrome type III (AD), deafness (AD), otospondylomegaepimetaphyseal dysplasia (AR)
DES125660AD and AR desmin-related myopathy
EDAR604095AD and AR hypohidrotic ectodermal dysplasia
EVC604831Ellis–van Creveld syndrome (AR), Weyers acrodental dysostosis (AD)
FECH177000AD and AR erythropoietic protoporphyria
FGA134820Amyloidosis (AD), congenital afibrinogenemia (AR)
GCH1600225Progressive dystonia (AD), hyperphenylalaninemia (AR)
GH1139250AD and AR growth hormone deficiency
GJB2121011AD and AR deafness, Vohwinkel syndrome
GJB3603224AD and AR deafness, erythrokeratoderma variabilis
GLRA1138491AD and AR familial hyperekplexia
HBB141900AD and AR beta thalassemia
HF1134370AD and AR hemolytic uremic syndrome
INSR147670AD and AR insulin resistance, leprechaunism (AR)
KCNQ1192500Long QT syndrome (AD), Jervell and Lange–Nielsen syndrome (AR)
LHCGR152790Leydig cell hypoplasia with male pseudohermaphroditism (AD), male limited precocious puberty (AR)
LMNA150330AD and AR Emery–Dreifuss muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy
MAT1A250850AD and AR methionine adenosyltransferase deficiency
MC4R155541AD and AR obesity
MYO7A276903AD nonsyndromic deafness, Usher syndrome type 1B (AR)
PMP22601097AD and AR Charcot–Marie–Tooth disease
POU1F1173110AD and AR combined pituitary hormone deficiency
PROC176860AD and AR thrombophilia
PTH168450AD and AR hypoparathyroidism
RGR600342AD and AR retinitis pigmentosa
RHO180380AD and AR retinitis pigmentosa
SERPING1106100AD and AR hereditary angioneurotic edema
SLC4A1109270Hereditary spherocytosis, renal tubular acidosis
SOD1147450AD and AR amyotrophic lateral sclerosis
TECTA602574AD and AR deafness
TG188450AD and AR congenital goiter
THRB190160AD and AR thyroid hormone resistance
TNFRSF6134637AD and AR lymphoproliferative syndrome
UROD176100AD porphyria cutanea tarda, AR hepatoerythropoietic, porphyria
VWF193400AD and AR von Willebrand disease

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. See also Ion Channels and Human Disorders, and Receptors and Human Nervous System Disorders

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. See also Activating and Inactivating Mutations in the GNAS1 Gene, and Mosaicism

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

  1. Top of page
  2. Introduction
  3. Different Definitions of Dominance and Recessivity
  4. Most Mutant Alleles are Recessive to Wild Type and Cause Loss of Function
  5. Dominance at the Cellular Level: Gain and Loss of Function
  6. Atypical Heterozygous Phenotypes
  7. Conclusion: Molecular Basis of the Wrinkled Pea Phenotype
  8. See also
  9. Further Reading
  10. Web Links

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 Genotype–Phenotype Relationships: Fatal Familial Insomnia and Creutzfeldt–Jakob Disease, and Thalassemias

Conclusion: Molecular Basis of the Wrinkled Pea Phenotype

  1. Top of page
  2. Introduction
  3. Different Definitions of Dominance and Recessivity
  4. Most Mutant Alleles are Recessive to Wild Type and Cause Loss of Function
  5. Dominance at the Cellular Level: Gain and Loss of Function
  6. Atypical Heterozygous Phenotypes
  7. Conclusion: Molecular Basis of the Wrinkled Pea Phenotype
  8. See also
  9. Further Reading
  10. Web Links

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.

Further Reading

  1. Top of page
  2. Introduction
  3. Different Definitions of Dominance and Recessivity
  4. Most Mutant Alleles are Recessive to Wild Type and Cause Loss of Function
  5. Dominance at the Cellular Level: Gain and Loss of Function
  6. Atypical Heterozygous Phenotypes
  7. Conclusion: Molecular Basis of the Wrinkled Pea Phenotype
  8. See also
  9. Further Reading
  10. Web Links

Web Links

  1. Top of page
  2. Introduction
  3. Different Definitions of Dominance and Recessivity
  4. Most Mutant Alleles are Recessive to Wild Type and Cause Loss of Function
  5. Dominance at the Cellular Level: Gain and Loss of Function
  6. Atypical Heterozygous Phenotypes
  7. Conclusion: Molecular Basis of the Wrinkled Pea Phenotype
  8. See also
  9. Further Reading
  10. Web Links