In 1991 an international team of scientists identified the gene and mutation that causes fragile X syndrome. They found that in families with fragile X syndrome, there is a piece of the FMR1 gene, called a CGG repeat, which is abnormally expanded.
In the general population, the repeat length can range from about six to fifty-four copies of the CGG, and the repeat is stable, or is passed from parent to child without change. In fragile X families, the premutation form of the repeat contains between fifty and two hundred copies of the CGG repeat, and the repeat is unstable.
Premutation alleles can expand to full mutation alleles (with more than two hundred copies of the CGG repeat) by transmission of the premutation from a mother to her child. A woman's risk of having a child with the
The fragile X chromosome is stained with purple dye. The affected chromosome is described as "fragile" because of the extra constriction near the end of the long arm of the X chromosome. Mental disability presents in 80 percent of carrier males, and 50 percent of carrier females.
alleles particular forms of genes oooc ,oc full mutation correlates to her own repeat size. The larger her premutation, the more she risks having a child who carries the full mutation.
The CGG repeat is usually interrupted by a single AGG trinucleotide every ten CGG repeats, but this can vary from individual to individual. Because premutation alleles have fewer AGG interruptions compared with normal-size FMR1 alleles, it is believed that the AGG interruptions are important for stability of the CGG repeat.
Individuals with a premutation do not express the clinical symptoms associated with fragile X syndrome, although it has been reported that pre-mutation carrier females can experience premature ovarian failure. Individuals who carry the full mutation can express symptoms of fragile X syndrome because they are missing the protein produced by the FMR1 gene. Males with a full mutation always exhibit some symptoms of the disorder. Due to X inactivation, females with a full mutation may or may not express symptoms.
Although there is currently no cure for fragile X syndrome, scientists are making great progress in understanding the biology of the disorder. In the mid- to late 1990s, Stephen Warren and colleagues determined that the FMR1 gene product, named FMRP, is an RNA-binding protein that shuttles in and out of the nucleus and is involved in binding various messenger RNAs. Moreover, scientists successfully developed mice that lack the FMR1 gene, which will greatly aid research. Symptoms of fragile X mice include learning disabilities, hyperactivity, and, in males, enlarged testicles. Prevailing hypotheses about FMRP suggest that this protein is involved in forming neural connections in the developing brain.
The identification of FMR1 and the expanded CGG repeats was a landmark discovery in human genetics because it established a novel class of human genetic mutations, trinucleotide (or triplet) repeat expansions. Since the discovery of FMR1 and the expanding CGG repeats, scientists have identified more than ten other human genetic disorders that are caused by expansions of trinucleotide repeats, including disorders such as Huntington's disease and myotonic muscular dystrophy. see also Inheritance Patterns; Intelligence; Mosaicism; Triplet Repeat Disease; X Chromosome.
Hagerman, Randi Jenssen, and Amy Cronister, eds. Fragile X Syndrome: Diagnosis, Treatment, and Research, 2nd ed. Baltimore: Johns Hopkins University Press, 1996.
Online Mendelian Inheritance in Man: Fragile Site Mental Retardation 1; FMR1. Johns Hopkins University and National Center for Biotechnology Information. <http:// www.ncbi.nlm.nih.gov/htbin-post/0mim/dispmim?309550>.
Fruit Fly: Drosophila
Drosophila melanogaster, a common fruit fly, was one of the first model organisms used in genetic research, and continues to be one of the most important. Thomas Hunt Morgan (1866-1945) developed Drosophila as a model system in 1909. Morgan, along with his students, Calvin Bridges, Alfred
Sturtevant, and Hermann Muller, made some of the most important discoveries in genetics through their work with Drosophila. Among these were the genetic explanation of sex linkage (the location of a gene on a sex chromosome); proof that genes are contained on chromosomes; and the demonstration that genes are arranged on a chromosome in a linear order with fixed, measurable distances between them, the principle that underlies genetic mapping.
Like other good model organisms, Drosophila is easy to rear in the laboratory. It has a short life cycle, lasting about two weeks, and produces many offspring. Each female can lay hundreds of eggs. These traits make it ideal for isolating mutants and carrying out many genetic crosses rapidly.
Mutants are the cornerstone of genetic analysis. To find a mutation one must be able to recognize an observable physical trait, or phenotype, such as a change in anatomical structure or behavior. At first glance, watching a tiny fruit fly landing on a rotting banana, one may be hard pressed to imagine that anyone could spot an anatomical variant, much less begin to study such a complex subject as behavior. Observed through a low-powered microscope, however, Drosophila is a sculptural masterpiece of bristles, segments, colors, and mosaic patterns. By studying Drosophila mutants, scientists have devised ways to genetically dissect the cellular bases of these phenotypes, as well as such startlingly complex behaviors as learning, memory, and even sleep.
A feature of a model organism that aids geneticists is a small genome size and a small number of chromosomes, since the less DNA there is to sort through, the easier it is to find genes. Drosophila's genome, containing about 180 million base pairs, is approximately one-twentieth the size of the human genome. There are four pairs of chromosomes: the X and Y sex chromosomes, and autosomes 2, 3, and 4. The complete nucleotide sequence of the gene-rich portion of the genome was determined in 2000. The genome is estimated to encode approximately 13,000 genes.
Drosophila molecular geneticists make wide use of transposons. These are short segments of DNA that, when injected into a cell, can insert themselves into the chromosomal DNA at random positions. Using recombinant DNA methods, a researcher can splice any gene into a transposon, which can then serve as a vector for introducing the gene into a fly.
Alternatively, transposon insertion can be used to cause mutations in genes. While much of the chromosomal DNA consists of sequences that code for non-protein elements, such as introns and "spacer" sequences between genes, a transposon may become inserted directly into a protein-coding sequence. This usually alters the amino acid sequence of the protein encoded by a gene, rendering the gene product dysfunctional. Even without knowing which gene was mutated, or where in the genome it is located, a researcher can make use of the transposon insertion as a "molecular tag" to rapidly identify the gene. Since the sequence of the transposon is known, a DNA probe can be designed to detect it (and therefore find the gene which it has mutated) by molecular hybridization methods.
An unusual phenomenon of the chromosomes in certain of Drosophila's tissues provides a powerful tool for determining the positions of individual genes. The chromosomes in the fruit fly's salivary gland cells replicate
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