PS02. X-chromosome inactivation and evolution: A statistical study of skewed X-chromosome inactivation in autoimmune diseases
TAYFUN ÖZÇELİK Bilkent University, Department of Molecular Biology and Genetics, Bilkent – Ankara 06800, Turkeye e-mail: tozcelik@fen.bilkent.edu.tr
*Corresponding Author:
page: 15

Abstract

2006 marks the 45th anniversary of the discovery of X-chromosome inactivation in placental mammals.  Following the establishment of the human chromosome number as 46, renowned geneticist Susumu Ohno made the great discovery that the Barr body of mammalian female nuclei was in fact a condensed X-chromosome.  The important idea was that the condensed X-chromosome was not transcriptionally active.  This could account for the fact that females could have two X chromosomes and males one X chromosome, but the activity of an enzyme coded by a gene on the X chromosome was the same in the two sexes.  As early as 1959, Ohno also gave consideration to the origin of the putatively inactive X-chromosome. In 1961, Mary Lyon proposed that in a female cell one of the two X-chromosomes is selected for silencing, thus rendering a mosaic state of cells expressing either the paternally or the maternally inherited X-chromosome. Research conducted since then elucidated the basic molecular mechanisms involved in XCI such as the counting, choice, silencing, and maintenance stages. 

During the course of the past three years our group provided the first experimental proff that an association between female predisposition to autoimmunity and X-chromosome inactivation may exist. Paths to understanding the genetic bases of autoimmune disease have shown that simple Mendelian traits arising from single gene mutations, and complex traits resulting from interactions between multiple genotypes and the environment contribute to the breakdown of self-tolerance.  Important environmental factors include patogen exposure, pregnancy and life style.  Risk of autoimmunity could be increased by a lack of exposure to self-antigens in the thymus and the presence of autoreactive T cells.  It was hypothesized that lack of exposure to self-antigens could occur in women as a result of disturbances in the X-chromosome inactivation process.  Subsequently, the X-chromosome inactivation patterns of 200 scleroderma, 126 autoimmune thyroiditis, 43 premature ovarian failure, 55 sporadic preeclampsia, 82 juvenile rheumatoid arthritis patients, 200 control subjects, all female, were studied.  These findings suggest that the clinical consequence of skewed X-chromosome inactivation could be induction of autoimmunity in females. The causes of skewed X-chromosome inactivation are classified as primary and secondary.  Bias in the choice of which X-chromosome to be inactivated, due to germline X inactive specific transcript mutations is an example of a primary cause.  Secondary causes include deleterious X-linked mutations or X-chromosome rearrangements, aging, twining, or monoclonal expansion of cells.  I propose that existence of deleterious X-linked mutations or X-chromosome rearrangements and their differential expression patterns could provide a disadvantage to affected cells such as the critical components of the blood involved in immune recognition, and result in “loss of mosaicism”; thereby triggering autoimmunity.  Alternatively, “failure to achieve mosaicism” as a result of X-inactivation center mutations could lead to autoimmunity. 

It is a well-established fact that sexually dimorphic organisms cope with differences in sex-linked gene content arising from two X chromosomes in females and one X and one Y chromosome in males by employing different “dosage compensation” mechanisms.  For example, in the fruit fly, the male X is hypertranscribed.  In the round worm (Caenorhabditis elegans), expression from the two X’s is reduced in the female.  Although we know that dosage compensation mechanisms evolved differently in mammals in the form of transcriptional silencing, we do not know why such a divergence occured in placental mammals.  In fact, X-chromosome inactivation is an epigenetic paradigm affecting more than 600-1000 genes and it is one of the most striking examples of long-range monoallelic gene silencing in mammals.  Based on the data that establishes an association between female predisposition to autoimmunity and skewed X-chromosome inactivation, I will discuss why dosage compensation for X-chromosomal genes evolved in the form of transcriptional silencing in placental mammals.



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