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

inheritance Inheritance is the practice of receiving private property, Title (property), titles, debts, entitlements, Privilege (law), privileges, rights, and Law of obligations, obligations upon the death of an individual. The rules of inheritance differ ...

found in

fragile X syndrome Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may ...

. The phenomenon is also referred to as anticipation or

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 Reproduction, replication product (offspring, progeny) of ...

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. 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 (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

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-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...

in individuals with fragile X. Under an

electron microscope An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...

, 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 (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...

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

probability Probability is the branch of mathematics concerning numerical descriptions of how likely an Event (probability theory), event is to occur, or how likely it is that a proposition is true. The probability of an event is a number between 0 and ...

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 unable to relax after contraction. Other manifestations may include cataracts, intel ...

, spinocerebellar ataxia and

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...

. 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 The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...

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

References

{{Reflist Mutation Paradoxes