The X chromosome was first described in 1890 and since its function was not known, it was called the X factor as it did not appear to be involved in meiosis. In 1901, the X Chromosome was found involved in sex determination and was considered a chromosome. However, it was not until 2020 that the complete DNA sequence of the X was reported (1). Depending on the particular classification approach used by a particular researcher, there are 900 to 1400 reported genes on this sex chromosome (2). Scientific articles list different numbers, which can be confusing. What is important to remember is that the X Chromosome contains many genes. Of these, 109 of the protein coding genes are related to sex determination. The sex genes are outnumbered by genes responsible for the embryonic development of bone, nerves, blood. liver, kidney, retina of the eye, ears, heart, skin and teeth. The X chromosome also has a role in aging. Just as in the Y chromosome, the X has pseudoautosomal regions. These regions are essential for normal development. Usually, an individual is either XY (male) or XX (female), although variations occur in human individuals. The phenomenon of XX and XY individuals among humans creates two biological scenarios. The first is that in an XX individual the two X chromosomes, one from the father and one from the mother, creates a situation where expression of a gene on both X chromosomes would increase the amount of a protein encoded by the gene. Thus, one of the X chromosomes is inactivated in the cells of an individual. Without this process, cells in a XX individual would produce two much of the specific protein encoded by the gene, to the detriment of that individual’s normal physiological responses. The inactivated chromosome produces a Barr Body which can be noted microscopically. A gene, called Xist, expressed by the inactive X, is involved with this inactivation and ensures the balanced gene expression in the cells (3). This process of inactivation of the X genes is not totally complete as some X genes of the inactivated X are not silenced. The genes that are not silenced are often in the pseudoautosomal regions What is interesting is that a study published in 2019 reveals that during the aging process some of the genes on this inactive gene are turned on and are expressed in older women (4). The second biological scenario is that in XY individuals the genes on the X chromosome inherited from the mother are expressed. Because there is only one X chromosome, an altered gene can be expressed and can lead to X-linked disease (5,6). Thus, the expression of the one altered gene leads to certain conditions, such as red-green color blindness, hemophilia, and Duchene Muscular Dystrophy. These are X-linked recessive traits where a gene is inherited from a mother who is a carrier of the altered gene. In this situation, the mother is not affected as she has two X chromosomes. If the father of her children is a normal XY individual, their male children have a 50-50 chance of being affected while their female children have a 50-50 chance of being a carrier of the gene. In situations of X-linked dominant inheritance, the father will give the gene to all his daughters, but not to his sons as the X in sons comes from the mother. The mother will give the gene allele to 50% of her sons and 50% of her daughters (6) One example of this inheritance is Vitamin D resistant Rickets. The are over 553 other X-lined conditions! In addition to these situations, there are times when the number of the X chromosome and thus gene expression is altered leading to a number of differing genotypes and phenotypes. They are listed here.45 X Turner’s Syndrome. These individuals are short in stature, and have extra folds in their necks, the so-called web neck. Some have 45X/46XX cells and are those mosaic individuals. They often do not have a normal puberty and have ovarian failure although some do have ovarian function in early adulthood. Their intelligence is normal. One third to one half of these individuals have coarctation of the aorta and aortic valve abnormalities. This condition occurs in 1:2000 female newborns (7). 46, XX Testicular Difference of Sex Development. In this situation the male sex determining gene, SRY is located in the X chromosome instead of the Y. This has occurred by a translocation of the gene in the individual’s father during spermatogenesis. An individual with this condition develops a testis and develops a male appearance (phenotype). About 1 in 20,000 persons with a male phenotype has this translocation of the SRY gene to the X chromosome (7).47 XXX These individuals have learning problems and intellectual disabilities. There are rare persons who have 48 XXXX or 49 XXXXX. The condition is more severe when there are more X chromosomes. The frequency is stated as 1 in 1000 newborn females. It is thought that many such individuals are never diagnosed (7).47 XXY Klinefelter’s Syndrome is expressed in rather subtle ways and often is not diagnosed until puberty. They are often taller than average and have low testosterone levels. Testes may be undescended. They may have a curved pinky finger and flat feet. They are able to father children with the assistance of reproductive medicine technologies. They are at risk for metabolic syndrome and high blood pressure as well as obesity. XXY is the most common sex chromosome disorder and occurs in 1 in 650 newborn males. Some individuals will have some cells which are XY/ XXY which is called mosaic Klinefelter’s. These individuals have very mild signs and symptoms (7).48 XXXY Individuals with this condition are infertile and have intellectual disabilities. Sexual development before birth and at puberty is affected. At puberty they often may have breast enlargement. Their testes are small and the penis is short. They usually have decreased muscle tone, as well as skeletal abnormalities and eyes that are wide apart. This condition is found in 1 in 17,000 to 1 in 50,000 newborn boys (7). 48 XXYY These individuals have small testes and low testosterone. They have intellectual disabilities as well as neurodevelopment disorders. 1 in 18,000 to 1 in 40,000 male newborns are affected (7).49 XXXXY These individuals have similar features to Klinefelter’s syndrome are more severe. They have developmental delays and intellectual disabilities. They exhibit muscle weakness and skeletal abnormalities as well as facial abnormalities. Because of low testosterone levels puberty is incomplete. It is a very rare condition and affect 1 in 85,000 to 1 in 100,000 infants born with a Y chromosome. (7)Other X Chromosome conditions exist as well and are detailed in reference (7).References:(1) Miga KH, Koren S, Rhie A, Vollger MR, Gershman A, Bzikadze A, Brooks S, Howe E, Porubsky D, Logsdon GA, Schneider VA, Potapova T, Wood J, Chow W, Armstrong J, Fredrickson J, Pak E, Tigyi K, Kremitzki M, Markovic C, Maduro V, Dutra A, Bouffard GG, Chang AM, Hansen NF, Wilfert AB, Thibaud-Nissen F, Schmitt AD, Belton JM, Selvaraj S, Dennis MY, Soto DC, Sahasrabudhe R, Kaya G, Quick J, Loman NJ, Holmes N, Loose M, Surti U, Risques RA, Graves Lindsay TA, Fulton R, Hall I, Paten B, Howe K, Timp W, Young A, Mullikin JC, Pevzner PA, Gerton JL, Sullivan BA, Eichler EE, Phillippy AM. Telomere-to-telomere assembly of a complete human X chromosome. Nature. 2020 Sep;585(7823):79-84. doi: 10.1038/s41586-020-2547-7. Epub 2020 Jul 14. PMID: 32663838; PMCID: PMC7484160.(2) https://medlineplus.gov/genetics/chromosome/x/#:~:text=Because%20researchers%20use%20different%20approaches,different%20roles%20in%20the%20body.(3) Loda A, Heard E. Xist RNA in action: Past, present, and future. PLoS Genet. 2019 Sep 19;15(9):e1008333. doi: 10.1371/journal.pgen.1008333. PMID: 31537017; PMCID: PMC6752956.(4) Wainer Katsir, K., Linial, M. Human genes escaping X-inactivation revealed by single cell expression data. BMC Genomics 20, 201 (2019). https://doi.org/10.1186/s12864-019-5507-6(5) https://www.genome.gov/genetics-glossary/X-Linked(6) https://www.ncbi.nlm.nih.gov/books/NBK557383/(7) https://medlineplus.gov/genetics/chromosome/x/#conditions
Campion Blog