Research Article: Embryonic loss of human females with partial trisomy 19 identifies region critical for the single active X

Date Published: April 12, 2017

Publisher: Public Library of Science

Author(s): Barbara R. Migeon, Michael A. Beer, Hans T. Bjornsson, Anton Wutz.


To compensate for the sex difference in the number of X chromosomes, human females, like human males have only one active X. The other X chromosomes in cells of both sexes are silenced in utero by XIST, the Inactive X Specific Transcript gene, that is present on all X chromosomes. To investigate the means by which the human active X is protected from silencing by XIST, we updated the search for a key dosage sensitive XIST repressor using new cytogenetic data with more precise resolution. Here, based on a previously unknown sex bias in copy number variations, we identify a unique region in our genome, and propose candidate genes that lie within, as they could inactivate XIST. Unlike males, the females who duplicate this region of chromosome 19 (partial 19 trisomy) do not survive embryogenesis; this preimplantation loss of females may be one reason that more human males are born than females.

Partial Text

The concept of a single active X was introduced by Mary Lyon in her 1962 paper [1], wherein she extended her hypothesis from mice to other mammals, especially humans. She pointed out that a single X is sufficient for survival (i.e., Turner syndrome) and that no matter the number of X chromosomes in both sexes, only one was active (i.e., human sex chromosome aneuploidies, 47,XXY, 49,XXXXY)). The developmental pathway leading to X dosage compensation is not limited to human females, nor is it inhibited by a Y-chromosome [2, 3]. In fact, no compelling evidence precludes the likelihood that it maintains the activity of the single X chromosome in normal males as well as females.

Our analysis of copy number variants on the human autosomes has identified an extensive region (~ 8 MB) on the short arm of chromosome 19, (19p13.3–13.2) that is intolerant of duplication in females, and has shown that there are no other comparable regions in our genome. Most of the genes within this region (approximately 237) show marked skewing from the expected 50: 50 sex ratio of duplications, reflecting paucity of females. The region includes ordinary protein coding genes as well as epigenetic factors–not unexpected because of the large size of some de novo amplifications. This also impedes the effort to precisely map the limits of the critical regions.

The URLs for data presented herein are as follows:




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