Position Effect Variegation in Human Genetic Disease


Position effect variegation (PEV) is the mosaic pattern of expression shown by genes placed within or near heterochromatic environments. Research on several model organisms has identified molecular mechanisms that account for PEV. These studies suggest that some human genetic diseases might be attributed to PEV.

Keywords: chromatin; facioscapulohumeral disease; gene expression; genetic disease; position effect variegation

Figure 1.

(a) Flies containing a chromosomal rearrangement of the euchromatic white gene placed next to heterochromatin show a variegated red and white eye phenotype. The red eye phenotype indicates high levels of gene expression, whereas the white eye phenotype represents gene silencing. (b) Yeast colonies containing ADE2 in a euchromatic region of the genome are completely white, indicating full expression of the ADE2 gene. Colonies containing ADE2 within the telomeric region of the genome show red striations. The red phenotype indicates a buildup of nucleotide precursors due to gene silencing, whereas the white represents gene expression. (c) Fluorometric analysis of hCD2 expression on T cells from transgenic mice carrying hCD2. The top plot, obtained from transgenic lines with the hCD2 transgene inserted outside heterochromatin, shows a unimodal distribution of cells with high expression. The bottom plot, obtained from transgenic lines with the hCD2 transgene inserted near the centromeres, shows a mosaic distribution, with two populations of high and low expression.

Figure 2.

Models of facioscapulohumeral disease (FSHD) silencing. The telomere is represented by small black triangles and the D4Z4 repeats by rectangles with arrows. (a) Silencing model. A normal array of D4Z4 repeats provides a buffer from telomeric silencing (curved line), due either to an increase in distance or the presence of an insulator. In an FSHD chromosome, an array of less than 10 repeats allows telomeric silencing to reach the FSHD critical‐region gene (FCRG). (b) Activation model. The D4Z4 array is heterochromatic in nature and normally represses the expression of a nearby FCRG. In FSHD, the array is too small to support heterochromatin formation and FCRG is expressed. (c) Nuclear localization model. Chromosome 4q telomeres (black dots) do not normally associate in the nucleus with the 10q telomeres (white dots). In individuals with FSHD, the FSHD chromosome 4 telomere pairs with a 10q telomere.



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Further Reading

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Web Links

FRG1 (FSHD region gene 1); Locus ID: 2483. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2483

FRG1(FSHD region gene 1); MIM number: 601278. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?601278

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Parnell, Timothy J, Grade, Stephanie K, Geyer, Pamela K, and Wallrath, Lori L(Jan 2006) Position Effect Variegation in Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0006040]