II.Other chromosome abnormalities

Terms

Erratum Figure 6.21 does not match the caption.

I. Changes in chromosome structure (rearrangements) also may occur. Chromosome breaks usually are repaired, but on occasion the repair may unite the wrong elements.

A. Deletions involve loss of a chromosome segment. The individual is thus hemizygous for genes in that segment, and any recessive genes on the normal chromosome will be expressed. The number of different deletions that have been found in patients is very large. Example: cri-du-chat syndrome.

B. Duplications involve a repeat of a chromosome segment. Duplications presumably arise primarily by unequal crossovers. Cells generally are more tolerant of three copies of a gene than only one copy, and many small duplications cause no phenotypic effect.

C. Translocations involve transfer or exchange of segments between different chromosomes, usually nonhomologous chromosomes. If no genetic material is lost in the process, the result is a balanced translocation with normal phenotype. However, serious problems can arise in meiosis, and many children with congenital defects have a parent who has a balanced translocation. Some 5% of Down syndrome patients involve unbalanced translocations derived from such a parent.

D. Inversions occur when a chromosome breaks in two places and the middle segment becomes inverted before repair. Such a person would be genetically balanced, with normal phenotype. However, meiosis can be a problem. Pairing can only occur by means of an inversion loop, and if crossing over happens to occur within the loop, the gametes are very unbalanced.

A. Uniparental disomy is the term applied to the condition in which both homologs of a particular chromosome come from one parent. If both homologs are identical, it is described as isodisomy. If the two homologs are different, it is described as heterodisomy.
1. There are several ways in which uniparental disomy can arise (Figure 6.26), and all probably occur at least rarely. The mechanisms lead to different genetic consequences. For example, if a trisomic zygote loses one of the three chromosomes, thus restoring the euploid state, and if the lost chromosome is from the parent that contributed only one chromosome, then the remaining pair could be either isodisomic or heterodisomic. However, if a monosomic zygote generates an extra copy of the missing chromosome through an extra cycle of duplication of the single chromosome, then the two homologs will be completely isodisomic.

2. The genetic consequences follow from the fact that isodisomic segments are homozygous for every gene in the segment. If the chromosome is completely isodisomic, then it is homozygous for every gene. This generates pedigrees of the type Aa × AA —> aa. One can get a child homozygous for a trait when only one of the parents is heterozygous. Furthermore, the child will be homozygous for other loci on that chromosome, and some of these may also result in inherited disorders. It is common for such a child to have multiple recessive disorders that are related to each other only by their location on the same chromosome.

B. Fragile sites are positions on chromosomes that, under certain culture conditions in the laboratory, become very "thin" although they really do not break very often. They are stable genetic variants and follow strict Mendelian transmission.
1. The only two with phenotypic consequences are FRAXA and FRAXE at Xq27, near the tip of the long arm. Most males who have a fragile X are mentally retarded and have other characteristic features (fragile-X syndrome). This relatively common condition accounts for the excess of mentally retarded males as compared to females.

2. The FRAXA mutation is one of a small number of mutations that occur in an unstable premutation form. A person who inherits a premutation is phenotypically normal but is likely to transmit the full mutation to offspring. This phenomenon will be discussed further under mutation.

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