Females: Genetic Mosaics

By Alice Barocco

Have you ever wondered what makes mosaics such a breath-taking piece of art? Perhaps, for some people, the answer lies in their beautiful colours ranging from vibrant shades to more subtle hues, whilst for others it may be the random scattering of small irregular pieces of cobblestone coming together to form a single cohesive image.

Regardless of what exactly makes mosaics special to each art lover, we often find ourselves looking at abstract art, regarding it as something distant, as something that is there to admire but that we often find difficult to understand or to connect with. If you are a female, you may be surprised to learn that you have more things in common with mosaics than you think; the secret lies within genetics.

 Humans’ genetic information is stored in 23 pairs of chromosomes [BK1] in the nucleus of each of the diploid somatic cells that make up our body.1 Each of our parents contributes one chromosome to each pair, meaning that we all receive half our genetic material from our mother and half from our father. These 23 pairs of chromosomes are comprised of 22 pairs of autosomal chromosomes and one special pair of sex chromosomes: either XX for females or XY for males.1

In early mammalian female embryonic development, one of the two X chromosomes is permanently inactivated in all somatic cells. This phenomenon is known as X-inactivation and can be thought of as a form of gene dosage compensation, making sure females have only one functional copy of the genes expressed on the X chromosome rather than two.2 This mirrors the gene expression pattern in males and, thus, provides dosage equivalence between males and females.

When analysing the process from a molecular point of view, X-inactivation is mediated by several factors including a region of the chromosome X: the X inactivation centre (XIC)The XIC comprises both non-coding and protein-coding genes.3 The non-coding X-inactive specific transcript (XIST) gene, located in this region, is fundamentally important for the process of X-inactivation. This gene is expressed exclusively from the XIC of the inactive X chromosome and results in the expression of a long non-coding RNA (lncRNA) known as X-ist

X-ist acts in cis and promotes hetero- chromatinization of the X-chromosome it is being transcribed from, by coating it.3 This causes the X-chromosome to be silenced.

What is truly fascinating about this phenomenon is the fact that it is completely random. As a result, in healthy females the maternal X-chromosome is active in some cells, whilst the paternal one is active in others.2 As a result, each female can be thought of as a mosaic of cells in which either the paternally inherited or the maternally inherited X-chromosome is inactivated. Once either the maternal X-chromosome or the paternal one has been inactivated in any one somatic cell, this epigenetic mark is mitotically inheritable, meaning that all the progeny of that somatic cell will have the same X-chromosome inactivated as well.4

You may be wondering what exactly happens to the silenced X-chromosome following X-inactivation? A microscope is all you need to get to the bottom of this question. When observing mammalian female somatic cells down a microscope, a clear dark-staining spot at the periphery of the nucleus of each cell can be seen; scientists call this the Barr body, i.e. the inactivated X chromosome.5

The way males and females express their X-linked genes play a fundamental role in determining how susceptible each sex is to X-linked diseases. [BK2] Diseases such as colour blindness or haemophilia A6  affect males at a much higher incidence than females precisely because healthy females are never going to be homozygous for a X-linked pathogenic variant as a result of X-inactivation. In other words, females almost always have less severe manifestations of X-linked diseases as the variant gene is not being expressed in all of the somatic cells of their body but is merely expressed in half of them in a heterozygous fashion.7 This renders female carriers of such diseases, but not phenotypically affected patients.

Despite X-inactivation being a protection mechanism, that females intrinsically have against X-linked diseases, this process is not always 100% efficient. When this is the case skewed X-inactivation takes place. Ørstavik et al. define skewed X-inactivation as a ‘pattern where 80% or more of the cells show a preferential inactivation of one X chromosome’ (p.1).8 Approximately 35% of adult females are subject to skewed X-inactivation, making this relatively common among the female population.9 Depending on whether the X-chromosome carrying the aberrant mutant allele is predominantly active or not, ‘unfavourable’ or ‘favourable’ skewed X-inactivation is manifested respectively. If a female carrier is subject to unfavourable skewed X-inactivation, she will also be affected by X-linked disorders to such an extent that is proportional to her degree of unfavourable skewed X-inactivation.8

On a more positive note, the truly beautiful nature of X-inactivation can be more easily observed, for example, in female calico cats. In cats, the fur pigmentation gene is X-linked and, depending on whether each cell randomly chooses to leave the material X chromosome or the paternal one active, either a black or orange coat colour results.10 The patchy distribution of the cats’ fur clearly resembles a mosaic!

Despite X-inactivation having been studied for over half a century, several unresolved questions persist. Many scientists still ask themselves exactly how each somatic cell is able to correctly count its number of X-chromosomes and consequently inhibit one, while others wonder about the link between X-inactivation and cancer biology following the discovery of two active X-chromosomes in many human breasts and ovarian tumours.10,11

However, what is certainly known is that such an amazing process, that renders half of the earth’s human population genetic mosaics, is a great model system for future perspectives in research fields ranging from developmental biology to epigenetics.10

References:

  • Ørstavik KH. Skewed X Inactivation in Healthy Individuals and in Different Diseases. Acta Paediatrica. 2006;95(451): 24-29. Available from: https://pubmed.ncbi.nlm.nih.gov/16720461/ [Accessed 21st February 2022]
  • Liao DJ, Du QQ, Yu BW, Grignon D, Sarkar FH. Novel perspective: focusing on the X chromosome in reproductive cancers. Cancer Invest. 2003;21(4):641-58. Available from: doi: 10.1081/cnv-120022385. PMID: 14533452.

 [BK1]The references should be as superscript.  [BK1]

 [BK2]Rephrase this section.

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