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

Abstract

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.

Fig 1. The XIST repressor model for the single active X.

Our model depicts the putative dosage sensitive repressor(s) (yellow), which inactivate XIST, thereby protecting one X chromosome from inactivation in diploid 46,XX, 46,XY and 47,XXX cells, thus -directly choosing the active X (green). The non- blocked X chromosomes are inactivated by XIST transcription, becoming Barr bodies (red). In triploid cells (69,XXX, 69,XXY), more than one X is active because of the extra amount of the putative XIST repressor, contributed by the extra set of autosomes. The Y chromosome is depicted (black).

Fig 2

Systematic skewing of posterior gain rate (M:F sex ratio) on chromosome 19 (A) but not chromosome 1 (B). Because the lack of gains in either males or females leads to a zero value in either the nominator or denominator of a male/female gain ratio we calculated a posterior rate, which accurately reflects any observed deviation from the expected equal amount of male/female gains (= 1). The grey box shows previous candidate regions, based on living females with partial trisomies. Note abnormal M:F posterior gain ratio in the candidate region of chromosome 19, but not on chromosome 1.

Fig 3

Posterior rate (M:F sex ratio) of duplications, deletions and total variants on chromosome 19, at 500 kb intervals throughout the p (A) and q (B) arms of the chromosome from pter to qter. Because the lack of gains in either males or females leads to a zero value in either the nominator or denominator of a male/female gain ratio we calculated a posterior rate, which accurately reflects any observed deviation from the expected equal amount of male/female gains (= 1). Note the excess of males for both total variants and duplications in the domain 4.5–12.5 MB on the short arm (A) as well as a smaller peak from 41.0–41.5 MB on the long arm (B) of chromosome 19.