Haploinsufficiency in
genetics
Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wor ...
describes a model of
dominant gene action in
diploid organisms, in which a single copy of the
wild-type
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
at a
locus
Locus (plural loci) is Latin for "place". It may refer to:
Entertainment
* Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front
* ''Locus'' (magazine), science fiction and fantasy magazine
** ''Locus Award' ...
in
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
combination with a variant allele is insufficient to produce the wild-type
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...
. Haploinsufficiency may arise from a ''de novo'' or inherited
loss-of-function mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitos ...
in the variant allele, such that it yields little or no gene product (often a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
). Although the other, standard allele still produces the standard amount of product, the total product is insufficient to produce the standard phenotype. This
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
genotype may result in a non- or sub-standard, deleterious, and (or) disease phenotype. Haploinsufficiency is the standard explanation for dominant deleterious alleles.
In the alternative case of haplosufficiency, the loss-of-function allele behaves as above, but the single standard allele in the
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
genotype produces sufficient gene product to produce the same, standard phenotype as seen in the
homozygote
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
. Haplosufficiency accounts for the typical dominance of the “standard” allele over variant alleles, where the phenotypic identity of genotypes heterozygous and homozygous for the allele defines it as dominant, ''versus'' a variant phenotype produced only by the genotype homozygous for the alternative allele, which defines it as recessive.
Mechanism
The alteration in the
gene dosage Gene dosage is the number of copies of a particular gene present in a genome. Gene dosage is related to the amount of gene product (proteins or functional RNAs) the cell is able to express. Since, a gene acts as a template, the number of templates ...
, which is caused by the loss of a functional allele, is also called allelic insufficiency. An example of this is seen in the case of
Williams syndrome
Williams syndrome (WS) is a genetic disorder that affects many parts of the body. Facial features frequently include a broad forehead, underdeveloped chin, short nose, and full cheeks. Mild to moderate intellectual disability is observed in people ...
, a neurodevelopmental disorder caused by the haploinsufficiency of genes at 7q11.23. The haploinsufficiency is caused by the
copy-number variation
Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of d ...
(CNV) of 28 genes led by the deletion of ~1.6 Mb. These dosage-sensitive genes are vital for human language and constructive cognition.
Another example is the haploinsufficiency of
telomerase reverse transcriptase
Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.
T ...
which leads to anticipation in autosomal dominant
dyskeratosis congenita
Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and ...
. It is a rare inherited disorder characterized by abnormal skin manifestations, which results in
bone marrow failure,
pulmonary fibrosis
Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory failu ...
and an increased predisposition to cancer. A
null mutation
A null allele is a nonfunctional allele (a variant of a gene) caused by a genetic mutation. Such mutations can cause a complete lack of production of the associated gene product or a product that does not function properly; in either case, the all ...
in motif D of the reverse transcriptase domain of the telomerase protein, hTERT, leads to this phenotype. Thus telomerase dosage is important for maintaining tissue proliferation.
A variation of haploinsufficiency exists for mutations in the gene ''
PRPF31
PRP31 pre-mRNA processing factor 31 homolog (S. cerevisiae), also known as PRPF31, is a protein which in humans is encoded by the ''PRPF31'' gene.
Function
PRPF31 is the gene coding for the splicing factor hPRP31. It is essential for the forma ...
'', a known cause of
autosomal dominant retinitis pigmentosa
Retinitis pigmentosa (RP) is a genetic disorder of the eyes that causes loss of vision. Symptoms include trouble seeing at night and decreasing peripheral vision (side and upper or lower visual field). As peripheral vision worsens, people may ...
. There are two wild-type alleles of this gene—a high-
expressivity allele and a low-expressivity allele. When the mutant gene is inherited with a high-expressivity allele, there is no disease phenotype. However, if a mutant allele and a low-expressivity allele are inherited, the residual protein levels falls below that required for normal function, and disease phenotype is present.
Copy number variation
Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of ...
(CNV) refers to the differences in the number of copies of a particular region of the genome. This leads to too many or too few of the dosage sensitive genes. The genomic rearrangements, that is, deletions or duplications, are caused by the mechanism of
non-allelic homologous recombination Non-allelic homologous recombination (NAHR) is a form of homologous recombination that occurs between two lengths of DNA that have high sequence similarity, but are not alleles.
It usually occurs between sequences of DNA that have been previously ...
(NAHR). In the case of the Williams Syndrome, the microdeletion includes the ''
ELN'' gene. The hemizygosity of the elastin is responsible for
supravalvular aortic stenosis, the obstruction in the left ventricular outflow of blood in the heart.
Methods of detection
The most direct method to detect haploinsufficiency is the
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
deletion of one
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
in a model organism. This can be done in
tissue culture cells or in single-celled organisms such as yeast (''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have b ...
'').
Haploinsufficiency in humans
About 3,000 human genes cannot tolerate loss of one of the two alleles.
Human diseases caused by haploinsufficiency
These include:
* Some
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s
*
1q21.1 deletion syndrome
* 5q- syndrome in
myelodysplastic syndrome (MDS)
*
22q11.2 deletion syndrome
*
CHARGE syndrome
*
Cleidocranial dysostosis
*
Ehlers–Danlos syndrome
*
Frontotemporal dementia caused by mutations in
progranulin
*
GLUT1 deficiency (DeVivo syndrome)
*
Haploinsufficiency of A20
*
Holoprosencephaly
Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed an ...
caused by haploinsufficiency in the
Sonic Hedgehog gene
*
Holt–Oram syndrome
Holt–Oram syndrome (also called atrio-digital syndrome, atriodigital dysplasia, cardiac-limb syndrome, heart-hand syndrome type 1, HOS, ventriculo-radial syndrome) is an autosomal dominant disorder that affects bones in the arms and hands (the u ...
*
Marfan syndrome
*
Phelan–McDermid syndrome
*
Polydactyly
Polydactyly or polydactylism (), also known as hyperdactyly, is an anomaly in humans and animals resulting in supernumerary fingers and/or toes. Polydactyly is the opposite of oligodactyly (fewer fingers or toes).
Signs and symptoms
In human ...
*
Dravet Syndrome
Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or feve ...
*
ZTTK
*
FOXP1 Syndrome
*
NR4A2-related syndrome
References
Further reading
*
*
{{Commons category, Haploinsufficiency
Genetics