A History of the Discovery of Random X Chromosome Inactivation in the Human Female and its Significance

Abstract

Genetic determinants of sex in placental mammals developed by the evolution of primordial autosomes into the male and female sex chromosomes. The Y chromosome determines maleness by the action of the gene SRY, which encodes a protein that initiates a sequence of events prompting the embryonic gonads to develop into testes. The X chromosome in the absence of a Y chromosome results in a female by permitting the conversion of the embryonic gonads into ovaries. We trace the historical progress that resulted in the discovery that one X chromosome in the female is randomly inactivated in early embryogenesis, accomplishing approximate equivalency of X chromosome gene dosage in both sexes. This event results in half of the somatic cells in a tissue containing proteins encoded by the genes of the maternal X chromosome and half having proteins encoded by the genes of the paternal X chromosome, on average, accounting for the phenotype of a female heterozygote with an X chromosome mutation. The hypothesis of X chromosome inactivation as a random event early in embryogenesis was first described as a result of studies of variegated coat color in female mice. Similar results were found in women using the X chromosome-linked gene, glucose-6-phosphate dehydrogenase, studied in red cells. The random inactivation of the X chromosome-bearing genes for isoenzyme types A and B of glucose-6-phosphate dehydrogenase was used to establish the clonal origin of neoplasms in informative women with leiomyomas. Behind these discoveries are the stories of the men and women scientists whose research enlightened these aspects of X chromosome function and their implication for medicine.

X chromosome escapee genes are involved in ischemic sexual dimorphism through epigenetic modification of inflammatory signals

“…Our previous studies using the Four Core Genotypes (FCG) mouse model have recapitulated this clinical epidemiology. Stroke sensitivity is mediated primarily by gonadal hormones in young animals, regardless of their chromosome complement, but as animals age, chromosomal sex drives ischemic outcomes [9]. Because the number of X chromosomes correlates with susceptibility to ischemic disease, we asked if specific X genes contribute to this phenotype.…”

“…It has been recognized for some time that genes on the X chromosome can escape XCI [9]. Some genes escape from XCI during 4-8 cell stage of embryonic development [10], and some others may escape during aging [11,12], leading to gene dosage imbalance between males and females.…”

Teaching Epigenetic Regulation of Gene Expression Is Critical in 21st-Century Science Education: Key Concepts & Teaching Strategies

“…Epigenetic marks rapidly accumulate on the X chromosome and convert it into inactive condensed chromatin. The condensed X chromosome is called the Barr body (Balderman & Lichtman, 2011).…”

“…It has been over 50 years since Mary Lyon first proposed her X-chromosome inactivation hypothesis (Balderman & Lichtman, 2011). Although X-chromosome inactivation is well accepted as an epigenetic phenomenon, a detailed mechanistic understanding is still lacking.…”

The Stem Cell Niche as the Key to Early Cancer Development

“…Today, most published X-chromosome inactivation studies make use of the human androgen receptor (HUMARA) gene. Tumors with identical allelic inactivation patterns are of monoclonal origin [51,52].…”