The Sherman paradox was a term used to describe the anomalous pattern of

inheritance Inheritance is the practice of receiving private property, titles, debts, entitlements, privileges, rights, and obligations upon the death of an individual. The rules of inheritance differ among societies and have changed over time. Offi ...

found in

fragile X syndrome Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder. The average IQ in males with FXS is under 55, while affected females tend to be in the borderline to normal range, typically around 70–85. Physical features may include a lo ...

. The phenomenon is also referred to as

anticipation Anticipation is an emotion involving pleasure or anxiety in considering or awaiting an expected event. Anticipatory emotions include fear, anxiety, hope, and trust. When the anticipated event fails to occur, it results in disappointment (for ...

or dynamic mutation.

Background

The paradox was named in the late 1980s after American geneticist Stephanie Sherman, who studied the inheritance patterns of people with fragile X syndrome. Sherman observed that the effects of fragile X syndrome seemed to occur more frequently with each passing

generation A generation is all of the people born and living at about the same time, regarded collectively. It also is "the average period, generally considered to be about 20–⁠30 years, during which children are born and grow up, become adults, and b ...

. This observation became 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 In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

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. Fragile X syndrome is so named because of the appearance of the

X chromosome The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...

in individuals with fragile X. Under an

electron microscope An electron microscope is a microscope that uses a beam of electrons as a source of illumination. It uses electron optics that are analogous to the glass lenses of an optical light microscope to control the electron beam, for instance focusing it ...

, 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 () is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one c ...

. In normal individuals, an insertion of extra CGGs is unlikely. However, as the length of the repeat increases, the

probability Probability is a branch of mathematics and statistics concerning events and numerical descriptions of how likely they are to occur. The probability of an event is a number between 0 and 1; the larger the probability, the more likely an e ...

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 dystrophy Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of genetic disorders that cause progressive muscle loss and weakness. In DM, muscles are often myotonia, unable to relax after contraction. Other manifestations may include catarac ...

spinocerebellar ataxia Spinocerebellar ataxia (SCA) is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a neurological condition in its own right. An estimated 150,000 people in the United States have a diagnosis of ...

and

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

. In Huntington's disease, in contrast to fragile X, somatic as well as

germline mutation A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and Egg cell, ova). Mutations in these cells are the only mutations that can be passed on to offspring, when e ...

s occur.

Autopsies An autopsy (also referred to as post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of death; ...

of affected individuals reveal an accumulation of long repeats of CAG in DNA in the

striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...

. In both conditions, effects are less severe if the long repeat is interspersed with other triplets.

References

{{Reflist Mutation Paradoxes