Anticipation (genetics)
Encyclopedia
In genetics
, anticipation is a phenomenon whereby the symptoms of a genetic disorder
become apparent at an earlier age as it is passed on to the next generation
. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders
such as Huntington's disease
and myotonic dystrophy
where a dynamic mutation
in DNA occurs. All of these diseases have neurological symptoms. Prior to the understanding of the genetic mechanism for anticipation, it was debated whether anticipation was a true biological phenomenon or whether the earlier age of diagnosis was related to heightened awareness of disease symptoms within a family.
in the human genome
. They have been found in introns, exons and 5'
or 3' UTR's. They consist of a pattern of three nucleotides (e.g. CGG) which is repeated a number of times. During meiosis
, unstable repeats can undergo triplet expansion (see later section); in this case, the germ cells produced have a greater number of repeats than are found in the somatic tissues.
The mechanism behind the expansion of the triplet repeats is not well understood. One hypothesis is that the increasing number of repeats influence the overall shape of the DNA
, which can have an effect on its interaction with DNA polymerase
and thus the expression of the gene.
, where the trinucleotide repeat encodes a long stretch of glutamine residues. When the repeat is present in an untranslated region, it could affect the expression
of the gene
in which the repeat is found (ex. fragile X) or many genes through a dominant negative effect (ex. myotonic dystrophy
).
In order to have a deleterious effect, the number of repeats must cross a certain threshold. For example, normal individuals have between 5 and 30 CTG repeats within the 3' UTR of DMPK, the gene that is altered in myotonic dystrophy
. If the number of repeats becomes greater than 50, the person is only mildly affected - perhaps having only cataracts. However, meiotic instability could result in a dynamic mutation
that increases the number of repeats in offspring inheriting the mutant allele. Once the number of copies reaches over 100, the disease will manifest earlier in life (although the individual will still reach adulthood before the symptoms are evident) and the symptoms will be more severe - including electrical myotonia
. As the number progresses upwards past 400, the symptoms show themselves during childhood or infancy.
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
, anticipation is a phenomenon whereby the symptoms of a genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
become apparent at an earlier age as it is passed on to the next generation
Generation
Generation , also known as procreation in biological sciences, is the act of producing offspring....
. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders
Trinucleotide repeat disorders
Trinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide repeats in certain genes exceeding the normal, stable, threshold, which differs per gene...
such as Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
and myotonic dystrophy
Myotonic dystrophy
Myotonic dystrophy is a chronic, slowly progressing, highly variable inherited multisystemic disease. It is characterized by wasting of the muscles , cataracts, heart conduction defects, endocrine changes, and myotonia. Myotonic dystrophy can occur in patients of any age...
where a dynamic mutation
Dynamic mutation
In genetics, a dynamic mutation is an unstable heritable element where the probability of expression of a mutant phenotype is a function of the number of copies of the mutation. That is, the replication product of a dynamic mutation has a different likelihood of mutation than its predecessor...
in DNA occurs. All of these diseases have neurological symptoms. Prior to the understanding of the genetic mechanism for anticipation, it was debated whether anticipation was a true biological phenomenon or whether the earlier age of diagnosis was related to heightened awareness of disease symptoms within a family.
Trinucleotide Repeats and Expansion
Trinucleotide repeats are apparent in a number of lociLocus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
in the human genome
Human genome
The human genome is the genome of Homo sapiens, which is stored on 23 chromosome pairs plus the small mitochondrial DNA. 22 of the 23 chromosomes are autosomal chromosome pairs, while the remaining pair is sex-determining...
. They have been found in introns, exons and 5'
Five prime untranslated region
A messenger ribonucleic acid molecule codes for a protein through translation. The mRNA also contains regions that are not translated: in eukaryotes these include the 5' untranslated region, 3' untranslated region, 5' cap and poly-A tail....
or 3' UTR's. They consist of a pattern of three nucleotides (e.g. CGG) which is repeated a number of times. During meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
, unstable repeats can undergo triplet expansion (see later section); in this case, the germ cells produced have a greater number of repeats than are found in the somatic tissues.
The mechanism behind the expansion of the triplet repeats is not well understood. One hypothesis is that the increasing number of repeats influence the overall shape of the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, which can have an effect on its interaction with DNA polymerase
DNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....
and thus the expression of the gene.
Disease mechanisms
For many of the loci, trinucleotide expansion is harmless, but in some areas expansion has detrimental effects that cause symptoms. When the trinucleotide repeat is present within the protein-coding region, the repeat expansion leads to production of a mutant protein with gain of function. This is the case for Huntington's diseaseHuntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
, where the trinucleotide repeat encodes a long stretch of glutamine residues. When the repeat is present in an untranslated region, it could affect the expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
in which the repeat is found (ex. fragile X) or many genes through a dominant negative effect (ex. myotonic dystrophy
Myotonic dystrophy
Myotonic dystrophy is a chronic, slowly progressing, highly variable inherited multisystemic disease. It is characterized by wasting of the muscles , cataracts, heart conduction defects, endocrine changes, and myotonia. Myotonic dystrophy can occur in patients of any age...
).
In order to have a deleterious effect, the number of repeats must cross a certain threshold. For example, normal individuals have between 5 and 30 CTG repeats within the 3' UTR of DMPK, the gene that is altered in myotonic dystrophy
Myotonic dystrophy
Myotonic dystrophy is a chronic, slowly progressing, highly variable inherited multisystemic disease. It is characterized by wasting of the muscles , cataracts, heart conduction defects, endocrine changes, and myotonia. Myotonic dystrophy can occur in patients of any age...
. If the number of repeats becomes greater than 50, the person is only mildly affected - perhaps having only cataracts. However, meiotic instability could result in a dynamic mutation
Dynamic mutation
In genetics, a dynamic mutation is an unstable heritable element where the probability of expression of a mutant phenotype is a function of the number of copies of the mutation. That is, the replication product of a dynamic mutation has a different likelihood of mutation than its predecessor...
that increases the number of repeats in offspring inheriting the mutant allele. Once the number of copies reaches over 100, the disease will manifest earlier in life (although the individual will still reach adulthood before the symptoms are evident) and the symptoms will be more severe - including electrical myotonia
Myotonia
Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by the slow relaxation of the muscles after voluntary contraction or electrical stimulation. Generally, repeated effort is needed to relax the muscles, and the condition improves after the muscles have warmed...
. As the number progresses upwards past 400, the symptoms show themselves during childhood or infancy.
Examples of Diseases showing Anticipation
Some examples of diseases showing anticipation, and some of the corresponding repeat sequences. Click on section title for internal link to a thorough list.- Autosomal Dominant
- Several spinal cerebellar ataxias
- Huntington's DiseaseHuntington's diseaseHuntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
- CAG - Myotonic DystrophyMyotonic dystrophyMyotonic dystrophy is a chronic, slowly progressing, highly variable inherited multisystemic disease. It is characterized by wasting of the muscles , cataracts, heart conduction defects, endocrine changes, and myotonia. Myotonic dystrophy can occur in patients of any age...
- CTG - dyskeratosis congenitaDyskeratosis congenitaDyskeratosis congenita , also called Zinsser-Cole-Engman syndrome, is a rare progressive congenital disorder which results in what in some ways resembles premature aging...
- TTAGGG (telomere repeat sequence). (Armanios, M., J. L. Chen, Y. P. Chang, R. A. Brodsky, A. Hawkins, C. A. Griffin, J. R. Eshleman, A. R. Cohen, A. Chakravarti, A. Hamosh, and C. W. Greider. 2005.Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A 102(44):15960-4.)
- Autosomal Recessive
- Friedreich Ataxia - GAA
- X-Linked
- Fragile X syndromeFragile X syndromeFragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability...
- CGG
- Fragile X syndrome