The X Chromosome
One of the chromosomes involved in sex determination is the X chromosome. In 2020, the first telomere-to-telomere assembly of X was finished. There are ~900 genes, many of which are only found on the X. However, genes in pseudoautosomal regions are found on both the X and Y. Males are usually affected by X-linked diseases, e.g. Ornithine transcarbamylase deficiency (Fig. 1). Due to X-inactivation, X-linked traits, may appear differently in males and females.
Fig1. The X chromosome structure and disorders associated with the p arm. (Adapted from Morey C, Avner P: Genetics and epigenetics of the X chromosome, Ann NY Acad Sci 1214(1), E18–E33, 2010; review is available: Migeon BR: X-linked diseases: susceptible females, Genet Med 22:1156–1174, 2020.)
X Chromosome Inactivation
The principle of X inactivation is that in somatic cells in normal females (but not in normal males), one X chromosome is inactivated early in development, thus equalizing the expression of X-linked genes in the two sexes. In normal female development, because the choice of which X chromosome is to be inactivated is a random one that is then maintained clonally, females are mosaic with respect to X-linked gene expression.
There are many epigenetic features, including gene expression, chromatin state, noncoding RNA, DNA replication timing, histone variants, and histone modifications, that distinguish the active and inactive X chromosomes in somatic cells (Table 1). These features can be useful diagnostically for identifying the inactive X chromosome(s) in clinical material. In patients with extra X chromosomes (whether male or female), any X chromosome in excess of one is inactivated. Thus all diploid somatic cells in both males and females have a single active X chromosome, regardless of the total number of X or Y chromosomes present.
Table1. Epigenetic and Chromosomal Features of X Chromosome Inactivation in Somatic Cells
The X chromosome contains ~900 genes, but not all of these are subject to inactivation. Notably, the genes that continue to be expressed, at least to some degree, from the inactive X are not distributed randomly along the X chromosome; many more genes “escape” inactivation on distal Xp (as many as 50%) than on Xq (just a few percent). This finding has important implications for genetic counseling in cases of a partial X chromo some aneuploidy because imbalance for genes on Xp may have greater clinical significance than imbalance for genes on Xq, where the effect is largely mitigated by X inactivation.
Patterns of X Inactivation. X inactivation is normally random in female somatic cells and leads to mosaicism for two cell populations expressing alleles from one or the other X. Where examined, most females have approximately equal proportions of cells expressing alleles from the maternal or paternal X (i.e., ~50:50), and ~90% of phenotypically normal females fall within a distribution that extends from ~25:75 to ~75:25 (Fig. 2). Such a distribution presumably reflects the expected range of outcomes for a random event (i.e., the choice of which X will be the inactive X) involving a relatively small number of cells during early embryo genesis. For individuals who are carriers for X-linked single-gene disorders, this X inactivation ratio can influence the clinical phenotype, depending on what proportion of cells in relevant tissues or cell types express the deleterious allele on the active X.
Fig2. X chromosome inactivation in karyotypes with normal or abnormal X chromosomes or X;autosome translocations. (A) Normal female cells (46,XX) undergo random X inactivation, resulting in a mosaic of two cell populations (left) in which either the paternal or maternal X is the inactive X (Xi, indicated by shaded box). In phenotypically normal females, the ratio of the two cell populations has a mode at 50:50, but with variation observed in the population (right), some with an excess of cells expressing alleles from the paternal X and others with an excess of cells expressing alleles from the maternal X. (B) Individuals carrying a structurally abnormal X (abn X) or X;autosome translocation in a balanced or unbalanced state show nonrandom X inactivation in which virtually all cells have the same X inactive. The other cell population is inviable or at a growth disadvantage because of genetic imbalance and is thus underrepresented or absent. der(X) and der(A) represent the two derivatives of the X;autosome translocation. (B, Data from Amos Landfraf JM, Cottle A, Plenge RM, et al: X chromosome inactivation patterns of 1005 phenotypically unaffected females, Am J Hum Genet 79:493–499, 2006; review is available: Fang H, Disteche CM, Berletch JB: X inactivation and escape: epigenetic and structural features, Front Cell Dev Biol 219, 2019.)
However, there are exceptions to the distribution expected for random X inactivation when the karyotype involves a structurally abnormal X chromosome. For example, in nearly all patients with unbalanced structural abnormalities of an X chromosome (including deletions, duplications, and isochromosomes), the structurally abnormal chromosome is always the inactive X. Because the initial inactivation event early in embryonic development is likely random, the patterns observed after birth probably reflect secondary selection against genetically unbalanced cells that are invisible (see Fig. 2). Because of this preferential inactivation of the abnormal X, such X chromosome anomalies have less of an impact on phenotype than unbalanced abnormalities of similar size or gene content involving autosomes.
Nonrandom inactivation is also observed in most cases of X;autosome translocations (see Fig. 2). If such a translocation is balanced, the normal X chromosome is preferentially inactivated, and the two parts of the trans located chromosome remain active, again likely reflecting selection against cells in which critical autosomal genes have been inactivated. In the unbalanced offspring of a balanced carrier, however, only the translocation product carrying the X inactivation center is present, and this chromosome is invariably inactivated; the normal X is always active. These nonrandom patterns of inactivation have the general effect of minimizing, but not always eliminating, the clinical consequences of the particular chromosomal defect. Because patterns of X inactivation are strongly correlated with clinical outcome, determination of an individual’s X inactivation pattern by cytologic or molecular analysis (see Table 1) is indicated in all cases involving X;autosome translocations.
The X Inactivation Center. Inactivation of an X chromosome depends on the presence of the X inactivation center region (XIC) on that chromosome, whether it is a normal X chromosome or a structurally abnormal X (see Chapter 3). Detailed analysis of structurally abnormal, inactivated X chromosomes led to the identification of the XIC within an ~800-kb candidate region in proximal Xq, in band Xq13.2 (Fig. 3), which coordinates many, if not all, of the critical steps necessary to initiate and promulgate the silenced chromatin state along the near-entirety of the X chosen to become the inactive X. As introduced in Chapter 3, this complex series of events requires a noncoding RNA gene, XIST, that appears to be a key master regulatory locus for the onset of X inactivation. Two additional noncoding RNA genes, DXZ4 and FIRRE are in the interval and have been implicated in various aspects of the development and maintenance of XIC.
Fig3. X chromosome inactivation and dependence on X inactivation center (XIC). (A) On normal X chromosomes, XIC lies within an ~800-kb candidate region in Xq13.2 that contains a number of noncoding RNA (ncRNA) genes, including XIST, the master X inactivation control gene. In early development in XX embryos, the XIST RNA spreads along the length of one X, which will become the inactive X (Xi), with epigenetic silencing of most genes on that X chromosome, resulting in monoallelic expression of most, but not all X-linked genes. (B) On structurally abnormal X chromosomes that lack the XIC, X inactivation cannot occur and genes present on the abnormal X are expressed biallelically. Although a fairly large abnormal X is shown here for illustrative purposes, in fact only very small such fragments are observed in female patients, who invariably display significant congenital anomalies, suggesting that biallelic expression of larger numbers of X-linked genes is inconsistent with normal development and is likely inviable.
X-Linked Intellectual Disability
A long-appreciated aspect of intellectual disability is the excess of males in the affected population, and a large number of variants, microdeletions, or duplications causing X-linked intellectual disability have been documented. The collective incidence of such X-linked defects has been estimated to be as high as 1 in 500 to 1000 live births.
The most common cause of X-linked intellectual disability is a variant in the FMR1 gene in males with fragile X syndrome. However, nearly 100 other X-linked genes have been implicated in X-linked intellectual disability, mostly on the basis of large family studies. Chromosomal microarray analysis has identified presumptive causal copy number variants and insertion-deletions in a further 10% of such families. In addition, exome sequencing efforts summarized in the preceding section to identify de novo changes in patients with intellectual disability have revealed an excess of such variants on the X chromosome.
The Y Chromosome
The structure of the Y chromosome and its role in sex development has been determined at both the molecular and genomic levels (Fig. 4). In male meiosis, the X and Y chromosomes normally pair by segments at the ends of their short arms and undergo recombination in that region. The pairing segment includes the pseudoautosomal region of the X and Y chromosomes, so-called because the X- and Y-linked copies of this region are essentially identical to one another and undergo homologous recombination in meiosis I, like pairs of autosomes. (A second, smaller pseudoautoso mal segment is located at the distal ends of Xq and Yq [Fig. 5].) By comparison with autosomes and the X chromosome, the Y chromosome is relatively gene poor and contains fewer than 100 genes (some of which belong to multigene families), specifying only ~2 dozen distinct proteins. Notably, the functions of a high proportion of these genes are restricted to gonadal and genital development.
Fig4. The Y chromosome in sex determination and in disorders of sex development (DSDs). Individual genes and regions implicated in sex determination, DSDs, and defects of spermatogenesis are indicated, as discussed in the text.
Fig5. The human genome X and Y homology chart. (Adapted from Affara N, Bishop C, Brown W, et al: Report of the second international workshop on Y chromosome mapping 1995, Cytogenet Cell Genet 73:33–76, 1996.)
Near the pseudoautosomal boundary on the Y chromosome lies the SRY gene (sex-determining region on the Y). It is present in many males with an otherwise normal 46,XX karyotype and is deleted or mutated in a proportion of females with an otherwise normal 46,XY karyotype, thus strongly implicating SRY in normal male sex determination. SRY is expressed only briefly early in development in cells of the germinal ridge just before differentiation of the testis. SRY encodes a DNA binding protein that is likely to be a transcription fac tor, which up-regulates a key autosomal gene, SOX9, in the ambipotent gonad, leading ultimately to testes differentiation.
Although there is clear evidence demonstrating the critical role of SRY in normal male sexual development, the presence or absence of SRY does not explain all cases of abnormal sex determination. Other genes are involved in the sex determination pathway and are dis cussed later in this chapter.
One or more genes on the long arm of the Y chromo some appear to be important for spermatogenesis because deletions of these regions, AZFa, AZFb, and AZFc, termed azoospermia factors (AZF), lead to low sperm count, ranging from cases of nonobstructive azoospermia (no sperm detectable in semen) to severe oligospermia (< 5 million/mL; normal range, 20–40 million/mL). De novo deletions of AZFc arise in ~1 in 4000 males and account for ~12% of azoospermic males and ~6% of males with severe oligospermia.
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