Telomere position effect influences in human terminal deletions Open Access

Gerfen, Jennifer Bosse (2015)

Permanent URL: https://etd.library.emory.edu/concern/etds/kk91fk98z?locale=en
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Abstract

Copy number variation (CNV) such as deletions and duplications are a well-known cause of intellectual disability and congenital anomalies. In most cases altered expression of the genes that are gained or lost explain the phenotype. However, alternate mechanisms are necessary to further explain other pathogenic CNV. Telomere position effect (TPE) is the silencing of intact genes adjacent to telomeres as a result of heterochromatin spreading from the telomere, which is known in artificially generated truncated chromosomes from yeast to humans. Here eight cell lines with different terminal deletions were studied to understand how gene expression and chromatin environment is changed as a result of the deletion on naturally occurring chromosomes. In a cell line from a patient with a 5.5-megabase deletion of chromosome 4 there was a ~300-kilobase (kb) region extending from the breakpoint that was enriched for heterochromatic modifications associated with the telomere. Analysis of gene expression within and outside this region shows silencing and allele-skewing of a gene that is ~150-kb from the breakpoint in the region of increased heterochromatin, but normal biallelic expression from a gene ~650-kb from the breakpoint, beyond the region of altered chromatin environment. Analysis by ChiP-chip did not reveal this classical TPE near the breakpoint. This demonstrates that a new telomere can have a cis-effect on nearby genomic regions.

Table of Contents

CHAPTER 2: PROJECT

1. HYPOTHESIS...8

2. MATERIALS AND METHODS ...9

3. RESULT...13

FIGURE 1 ...20

FIGURE 2 ...21

FIGURE 3 ...22

FIGURE 4 ..23

FIGURE 5 ..24

FIGURE 6 ...25

TABLE 1 ...26

TABLE 2 ...27

TABLE 3 ...28

TABLE 4 ...29

CHAPTER 3: DISCUSSION ...30

FIGURE 7 ...37

FIGURE 8 ..38

REFERENCES ...39



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