The Sherman paradox
Encyclopedia
The Sherman Paradox refers to an anomalous pattern of inheritance
found in Fragile X syndrome
. The phenomenon is also referred to as anticipation or dynamic mutation
.
The paradox is named after Stephanie Sherman, who studied the inheritance patterns of people with Fragile X syndrome. Sherman observed that the effects of Fragile X syndrome seemed to worsen with each passing generation
. This observation is now known as the Sherman Paradox.
The paradox was ultimately explained by insights into the mutation process that gives rise to the syndrome. Sherman theorized that the gene
responsible for Fragile X syndrome becomes mutated through a two-step process. The first mutation, called the 'premutation', doesn't cause any clinical symptoms. A second mutation was required to convert the 'premutation' into a 'full mutation' capable of causing the clinical symptoms associated with Fragile X syndrome. Additionally, premutations must pass through females in order to transform into the full mutation.
The Fragile X syndrome is so named because of the appearance of the X chromosome
in individuals with Fragile X. Under an electron microscope
, a region on the long arm of the chromosome resembles a thin string. Investigation showed that this region consists of a CGG repeat triplet in both normal and diseased individuals. The difference between normal and diseased is the length of the repeat; the repeat is longer where Fragile X syndrome is present. When the length of the repeat surpasses a critical threshold, symptoms of the disorder appear and they increase in likelihood and severity with further length. Even below this threshold there is a range where the repeat becomes unstable during meiosis
.
In normal individuals, an insertion of extra CGGs is unlikely. However, as the length of the repeat increases, the probability
of additional triplet insertions increases. When the expansion reaches the danger range, the carrier is still unaffected, but the risk of further mutation becomes significant. This is called the premutation range. Once the Fragile X syndrome emerges, symptoms worsen from generation to generation because of the self promoting aspect of the mutation.
, spinocerebellar ataxia
and Huntington's disease
. In Huntington's disease, in contrast to Fragile X, somatic as well as germline mutations occur. Autopsies
of affected individuals reveal an accumulation of long repeats of CAG in DNA in the striatum
. In both conditions, effects are less severe if the long repeat is interspersed with other triplets.
Heredity
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...
found in Fragile X syndrome
Fragile X syndrome
Fragile 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...
. The phenomenon is also referred to as anticipation or 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...
.
The paradox is named after Stephanie Sherman, who studied the inheritance patterns of people with Fragile X syndrome. Sherman observed that the effects of Fragile X syndrome seemed to worsen with each passing generation
Generation
Generation , also known as procreation in biological sciences, is the act of producing offspring....
. This observation is now known as the Sherman Paradox.
The paradox was ultimately explained by insights into the mutation process that gives rise to the syndrome. Sherman theorized that 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...
responsible for Fragile X syndrome becomes mutated through a two-step process. The first mutation, called the 'premutation', doesn't cause any clinical symptoms. A second mutation was required to convert the 'premutation' into a 'full mutation' capable of causing the clinical symptoms associated with Fragile X syndrome. Additionally, premutations must pass through females in order to transform into the full mutation.
The Fragile X syndrome is so named because of the appearance of the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
in individuals with Fragile X. Under an electron microscope
Electron microscope
An electron microscope is a type of microscope that uses a beam of electrons to illuminate the specimen and produce a magnified image. Electron microscopes have a greater resolving power than a light-powered optical microscope, because electrons have wavelengths about 100,000 times shorter than...
, a region on the long arm of the chromosome resembles a thin string. Investigation showed that this region consists of a CGG repeat triplet in both normal and diseased individuals. The difference between normal and diseased is the length of the repeat; the repeat is longer where Fragile X syndrome is present. When the length of the repeat surpasses a critical threshold, symptoms of the disorder appear and they increase in likelihood and severity with further length. Even below this threshold there is a range where the repeat becomes unstable 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....
.
In normal individuals, an insertion of extra CGGs is unlikely. However, as the length of the repeat increases, the probability
Probability
Probability is ordinarily used to describe an attitude of mind towards some proposition of whose truth we arenot certain. The proposition of interest is usually of the form "Will a specific event occur?" The attitude of mind is of the form "How certain are we that the event will occur?" The...
of additional triplet insertions increases. When the expansion reaches the danger range, the carrier is still unaffected, but the risk of further mutation becomes significant. This is called the premutation range. Once the Fragile X syndrome emerges, symptoms worsen from generation to generation because of the self promoting aspect of the mutation.
Triplet repeats and disease
A similar mechanism, involving triplet repeats, underlies myotonic dystrophyMyotonic 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...
, spinocerebellar ataxia
Spinocerebellar ataxia
Spinocerebellar ataxia is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a disease in its own right.-Classification:...
and 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...
. In Huntington's disease, in contrast to Fragile X, somatic as well as germline mutations occur. Autopsies
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
of affected individuals reveal an accumulation of long repeats of CAG in DNA in the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
. In both conditions, effects are less severe if the long repeat is interspersed with other triplets.
External links
- Anticipation & the Sherman Paradox - jmu.edu
- Genetic Research in Other Neuropsychiatric Diseases - acnp.org