Introduction:
Genes are the basic unit of heredity, changes in the genes such as alteration, mutation, or variation, can cause the cells to grow or multiply. Anticipation is a genetic phenomenon, where there is increasing severity of the genetic disease as it gets passed down. The mechanism of anticipation involves trinucleotide repeat expansion and telomere shortening, which is discussed in detail below.
What Is Anticipation?
Anticipation is a genetic phenomenon where the symptoms of a genetic condition become more severe and affect at an early age as the disease is passed down from generation to generation. It is mostly seen in nervous system genetic disorders such as Huntington's disease (a condition that causes degeneration of nerve cells causing functional disabilities and difficulty in concentrating), myotonic dystrophy (a condition that causes a decrease in muscle size and weakness), and fragile X syndrome (a disorder that causes intellectual disability, learning disabilities and affects memory and thinking abilities). It occurs due to a mutation known as trinucleotide repeat expansion or is associated with telomere shortening. A trinucleotide repeat (triplet) is a sequence of nucleotides, which is repeated a number of times in the mutated gene and the number of triplets increases as it gets inherited. These repeats can cause errors in cell division.
What Is the Mechanism of Genetic Anticipation?
Anticipation occurs due to a mutation known as trinucleotide repeat expansion or is associated with telomere shortening. The two mechanisms are:
Trinucleotide Repeat Expansion: It is a type of unstable mutation in which there is an expansion of trinucleotide repeat sequences (three nucleotides are repeated consecutively) and form DNA (deoxyribonucleic acid) polymerase slippage. These cause neurological diseases. These mutations show the anticipation phenomenon. These mutations become severe as it gets passed down. The age of onset of these diseases is inversely proportional to the number of repeats. Diseases that occur due to trinucleotide repeat expansion are:
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Myotonic Dystrophy: It is an inherited disorder where there is a decrease in muscle size and weakness. This disease has CTG (cytosine, thymine, and guanine) nucleotide repetition in the 3′ untranslated region of the DMPK gene (DM1 protein kinase). In the space of three generations, it can go from mild and late-onset to severe and early onset and it is mainly associated with transmission from the mother.
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Huntington's Disease: It is a rare disease that causes degeneration of nerve cells which leads to functional disabilities and difficulty in concentrating. It is an autosomal dominant degenerative disorder caused by unstable trinucleotide repeat of CAG (cytosine, adenine, and guanine) in the IT15 gene (interesting transcript 15 gene). Normal people have 6 to 29 CAG triplets, and persons with Huntington’s disease have 36 to 100 CAG triplets, as the gene repeats a gene product called huntingtin is produced, which causes the death of brain cells that control movements. The clinical symptoms are different for adult-onset and juvenile-onset.
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Fragile X Syndrome: Males are severely affected by this disorder, it causes intellectual disability, and learning disabilities and affects memory and thinking abilities. This involves mutation of the FMR-1 gene (fragile X messenger ribonucleoprotein 1). Unaffected people have six to fifty copies of CGG (1 cytosine and 2 guanine) repeat, people with fifty to two hundred CGG repeats are known as pre-mutation. People with more than two hundred CGG repeats show symptoms of these diseases and have broken X chromosomes.
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Spinal and Bulbar Muscular Atrophy (Kennedy Disease): It is a disorder that affects the nerve cells which originate from the spinal cord and brainstem, that control muscle movement. This involves the repetition of the CAG nucleotide in the androgen receptor (AR) gene. Unaffected people have 12 to 33 CAG repeats but these patients have 40 to 62 repeats.
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Fragile X E Mild Mental Retardation: It affects intellectual ability and mostly affects males. it is due to CGG repetition on FRAXE chromosomes
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Friedreich Ataxia: It is a degenerative disorder that damages the peripheral nerves, spinal cord, and the cerebellum portion of the brain, due to nerve injury it causes uncontrolled movements and loss of sensation. This is due to the GAA (1 guanine and 2 adenine) trinucleotide repeat expansion of the X25 gene which is located on chromosome 9q13 and there are more than 1700 repeats.
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Spinocerebellar Ataxia Type 2: This causes problems in coordination, movements, and balance and causes difficulty in speech, and swallowing. This involves repetition of CAG, and polyglutamine, in a gene on chromosome 6 with 41 to 81 repeats.
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Bipolar Affective Disorder: It is a condition that causes extreme mood swings from mania (high energy level) to depression. This involves CAG repetition.
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Dentatorubral-Pallidoluysian Atrophy: It is a brain disorder that affects thinking ability, and causes involuntary movements, and mental and emotional problems. This shows CAG repeats in the DRPLA gene (Dentatorubral-pallidoluysian atrophy gene) of 49 to 75 repeats.
Telomere Shortening: Telomeres are specific nucleoprotein structures that are present at both chromosomes’ ends. These telomeres keep getting shorter as the cell keeps dividing. Therefore short telomeres and unstable genes can lead to malignant formation. Diseases that occur due to telomere shortening are:
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Dyskeratosis Congenita: It is called inherited bone marrow failure syndrome associated with oral leukoplakia, reticular skin pigmentation, and abnormal nails. These have mutations in telomerase or shelterin complex genes which causes the reduced activity of telomerase, which are the nucleoproteins that protect the chromosome’s ends.
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Li-Fraumeni Syndrome: An inherited disorder that causes an increased risk of developing cancer. This is associated with short telomere length and mutation TP53 (tumor protein 53).
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Hereditary Breast Cancer: It has an autosomal dominant pattern of inheritance, with early onset and affects both the breasts
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Familial Breast And Ovarian Cancer (FBOC): This cancer has early onset as the disease gets passed down. This occurs due to mutation in BRCA1 and BRCA2 genes (breast cancer gene 1 and 2), which are involved in the repair of DNA breaks. BRCA1 is located at telomeres which regulate its stability and length and BRCA2 has a role in telomere replication.
Conclusion:
Signs and symptoms of genetic disorders can differ from individual, it can be due to not only anticipation but also other factors such as environmental, genetic, and lifestyle factors. This anticipation phenomenon, where the progression of severity and early onset increases as the disease is passed down to successive generations, occurs due to a mutation called trinucleotide repeat expansion and also the shortening of telomere.
