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A HUMAN POPULATION STUDY OF THE GENETIC CONTROL OF X-INACTIVATION

Amos-Landgraf, James
http://rave.ohiolink.edu/etdc/view?acc_num=case1089861669

Abstract Details

2005, Doctor of Philosophy, Case Western Reserve University, Genetics.
Many X-linked disorders have been reported to manifest to some degree in females. This is due to preferential inactivation of the X-chromosome carrying the normal allele and subsequent expression of the mutant allele in the majority of cells. The determination of which X-chromosome becomes inactivated is believed to be a random event, with each parental X-chromosome having an equal probability of becoming inactivated. However, alleles have been identified in inbred mouse strains that control X chromosome inactivation patterns resulting in varying degrees of skewed X-inactivation ratios. These alleles, termed X-inactivation controlling element (Xce) alleles map to the X-inactivation center (XIC), have only been identified in mice, and effect X-inactivation ratios when they are heterozygous in the mouse. To determine if similar Xce alleles exist in humans, we have identified markers in the X-inactivation center (XIC) and tested these variants with observed X-inactivation ratios. I have sequenced 30 kb of the XIC in 15 unrelated X-chromosomes, identifying 18 single nucleotide changes, and 5 insertion/deletion changes. Interestingly, 11 of the 23 variant sites were only found on two independent chromosomes identifying a distinct haplotype that extends more than 50 kb within the XIC. Further phylogenetic analysis has revealed that all of these variant sites are present in chimpanzee samples revealing an ancient ancestral haplotype. All but one these SNPs are in strong disequilibrium across the XIC.Eleven single nucleotide polymorphisms (SNPs), with calculated allele frequencies of between 5% -45%, were genotyped in 560 newborn females. To determine if any of these SNPs identify alleles within the XIC that control X-chromosome inactivation choice I applied the mouse Xce model. This model compares heterozygous genotypes to homozygous genotypes to determine if there is a heterozygous affect on the X-inactivation distribution. Each of the genotyped SNPs were tested and two of the SNPs revealed a significant difference between the XCI distribution variances (p< 0.05) with the heterozygous sample distribution exhibiting a greater degree of skewing.
Huntington Willard (Advisor)
X-INACTIVATION; SNP; XIST; X-inactivation ratios; XIC; X-chromosome; allele

Recommended Citations

Citations

  • Amos-Landgraf, J. (2005). A HUMAN POPULATION STUDY OF THE GENETIC CONTROL OF X-INACTIVATION [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1089861669

    APA Style (7th edition)

  • Amos-Landgraf, James. A HUMAN POPULATION STUDY OF THE GENETIC CONTROL OF X-INACTIVATION. 2005. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1089861669.

    MLA Style (8th edition)

  • Amos-Landgraf, James. "A HUMAN POPULATION STUDY OF THE GENETIC CONTROL OF X-INACTIVATION." Doctoral dissertation, Case Western Reserve University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=case1089861669

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.