NMC Guidelines For Competency-Based Training Programme For DM Medical Genetics

X Y Chromosomes

In the imprinted brain theory, everyone's brain is configured somewhere on a spectrum between hypomentalism and hypermentalism. In hypomentalism, the mechanistic, paternal genes are over-expressed, creating a baby with a larger head who demands more from the mother; this child is more likely to have autism. In hypermentalism, the mentalistic, maternal genes are over-expressed; the baby is likely to have a smaller head, demand less from the mother, and develop psychosis. The normal brain falls somewhere between the two extremes, ensuring that the child exhibits neither autism nor psychosis.

X Chromosome: X Inactivation

Bacher, C. P., et al. Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation. Nature Cell Biology 8, 293-299 (2006) doi:10.1038/ncb1365 (link to article)

Borsani, G., et al. Characterization of a murine gene expressed from the inactive X chromosome. Nature 351, 325–329 (1991) doi:10.1038/351325a0 (link to article)

Boumil, R. M., & Lee, J. T. Forty years of decoding the silence in X-chromosome inactivation. Human Molecular Genetics 10, 2225–2232 (2001)

Brockdorff, N., et al. Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome. Nature 351, 329–331 (1991) doi:10.1038/351329a0 (link to article)

———. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71, 515–526 (1992)

Brown, C. J., et al. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349, 38–44 (1991) doi:10.1038/349038a0 (link to article)

———. The human XIST gene: Analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71, 527-542 (1992)

Carrel, L., & Willard, H. F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400–404 (2005) doi:10.1038/nature03479 (link to article)

Clemson, C. M., et al. XIST RNA paints the inactive X chromosome at interphase: Evidence for a novel RNA involved in nuclear/chromosome structure. Journal of Cell Biology 132, 259–275 (1996)

Costa, F. F. Non-coding RNAs, epigenetics, and complexity. Gene 410, 9–17 (2008)

Duret, L., et al. The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene. Science 312, 1653–1655 (2006)

Graves, J. A. Sex chromosome specialization and degeneration in mammals. Cell 124, 901–914 (2006)

Ham, A. L., et al. Does genotype predict phenotype in Rett syndrome? Journal of Child Neurology 20, 768–778 (2005)

Hornecker, J. L., et al. Meiotic sex chromosome inactivation in the marsupial Monodelphis domestica. Genesis 45, 696–708 (2007)

Huynh, K. D., & Lee, J. T. X-chromosome inactivation: a hypothesis linking ontogeny and phylogeny. Nature Reviews Genetics 6, 410–418 (2005) doi:0.1038/nrg1604 (link to article)

Johnston, C. M., et al. Large-scale population study of human cell lines indicates that dosage compensation is virtually complete. PLoS Genetics 4, e9 (2008)

Lee, J. T. Disruption of imprinted X inactivation by parent-of-origin effects at Tsix. Cell 103, 17–27 (2000)

Lee, J. T., & Lu, N. Targeted mutagenesis of Tsix leads to nonrandom X inactivation. Cell 99, 47–57 (1999)

Lee, J. T., et al. Tsix, a gene antisense to Xist at the X-inactivation centre. Nature Genetics 21, 400–404 (1999) (link to article)

Liao, D. J., et al. Novel perspective: Focusing on the X chromosome in reproductive cancers. Cancer Investigation 21, 641–658 (2003)

Lucchesi, J. C., et al. Chromatin remodeling in dosage compensation. Annual Review of Genetics 39, 615–651 (2005)

Luikenhuis, S., et al. Antisense transcription through the Xist locus mediates Tsix function in embryonic stem cells. Molecular and Cellular Biology 21, 8512–8520 (2001)

Lyon, M. F. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190, 372–373 (1961) doi:10.1038/190372a0 (link to article)

Marahrens, Y., et al. Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes & Development 11, 156–166 (1997)

Martin, G. R., et al. X-chromosome inactivation during differentiation of female teratocarcinoma stem cells in vitro. Nature 271, 329–333 (1978) (link to article)

Namekawa, S. H., et al. Sex chromosome silencing in the marsupial male germ line. Proceedings of the National Academy of Sciences 104, 9730–9735 (2007)

Ogawa, Y., et al. Intersection of the RNA interference and X-inactivation pathways. Science 320, 1336–1341 (2008)

Okamoto, I., & Heard, E. The dynamics of imprinted X inactivation during preimplantation development in mice. Cytogenetic and Genome Research 113, 318–324 (2006)

Penny, G. D., et al. Requirement for Xist in X chromosome inactivation. Nature 379, 131–137 (1996) doi:10.1038/379131a0 (link to article)

Rastan, S., & Robertson, E. X chromosome deletions in embryo-derived (EK) cell lines associated with lack of X chromosome inactivation. Journal of Embryology and Experimental Morphology 90, 379–388 (1985)

Sado, T., et al. Regulation of imprinted X-chromosome inactivation in mice by Tsix. Development 128, 1275–1286 (2001)

Sleutels, F., & Barlow, D. P. The origins of genomic imprinting in mammals. Advances in Genetics 46, 11–163 (2002)

Stavropoulos, N., et al. A functional role for Tsix transcription in blocking Xist RNA accumulation but not in X-chromosome choice. Proceedings of the National Academy of Sciences 98, 10232–10237 (2001)

Wutz, A., & Jaenisch, R. A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Molecular Cell 5, 695–705 (2000)

Xu, N., et al. Transient homologous chromosome pairing marks the onset of X inactivation. Science 311, 1149–1152 (2006) doi:10.1126/science.1122984

———. Evidence that homologous X-chromosome pairing requires transcription and Ctcf protein. Nature Genetics 39, 1390–1396 (2007) doi:10.1038/ng.2007.5 (link to article).

What Do Colour Blind People See?

There are almost three million colour blind people in the UK - that is enough to fill Wembley stadium more than 30 times.

The NHS describes colour vision deficiency as when someone finds it difficult to identify and distinguish between certain colours.

It is a common genetic condition but, is often poorly understood by trichromats (people with normal colour vision).

We asked politics professor Dr Oliver Daddow and footballer Nick Bignall, who both have colour vision deficiency, about their experience of being colour blind.

In a colour vision deficiency test you are asked to identify the number or symbol inside the circle.

Image caption,

Autumn can be frustrating when, to Dr Daddow, the reds and greens just look like rusty brown

'My mum thought I was Picasso'

Dr Daddow, a politics professor at The University of Nottingham, is what he called moderate-to-severe green deficient.

He can see green but it's a very dull version and this can lead to difficulty seeing other colours too.

He found out he was colour blind when we was in primary school:

"I was maybe six or seven, I was painting the sky purple, whatever that is, I was painting tree trunks green, and the grass as brown. My mum thought I was Picasso, but unfortunately it's wasn't quite that good," he said.

Dr Daddow's mum labelled his coloured pencils to help him, but as he got older he found challenges in other subjects:

"Physics I really struggled with, like testing how to rewire plugs. I couldn't tell the colours apart, so I was shorting loads of plugs in physics all the time.

He also struggled in Chemistry when trying to read litmus paper dipped in acid. Litmus paper is an indicator that can be red or blue. Red litmus turns blue in alkalis, while blue litmus turns red in acids.

"I'd be told off for saying brown," said Dr Daddow.

"Anything involving graphs, coloured pie charts, bar charts - couldn't do any of that," he said.

Image caption,

Autumn can be frustrating when, to Dr Daddow, the reds and greens just look like rusty brown

Image caption,

Choosing a ripe banana in the morning can be difficult when you're green deficient

'If you're only relying on colour alone, you're in trouble'

Now, Dr Daddow makes sure most of his research is text-based since graphs and bar charts aren't always accessible for him.

His said election time is a challenge, since data is often presented with colours to represent the different political parties and, unless they have secondary labeling, he cannot use them.

Thanks to his expertise, he can identify the main parties and work from there, but "for people who don't know much about politics, 90% of the charts I look at just aren't accessible."

'If you're only relying on colour alone to convey meaning, you're in trouble," he said.

Image caption,

Choosing a ripe banana in the morning can be difficult when you're green deficient

'A lot of coaches didn't take it into consideration'

Nick Bignall is a semi-professional footballer who plays for Bracknell Town. He also has colour vision deficiency.

There are a few combinations he finds difficult to separate: reds and browns from yellows and oranges, and any colours that are close are hard to differentiate.

He was diagnosed with colour vision deficiency in primary school. He remembers he would pick up the brown pencil thinking it was red.

Growing up, Nick came up with strategies to help him at school - for example, knowing to get a second opinion on certain colours.

But when he started playing football he encountered some difficulties.

"A lot of coaches didn't take it into consideration, it's not that they weren't bothered about it, they just weren't aware it was an issue.

"They would go into the bib bag and throw out yellows and oranges and lime greens, and I would be thinking in my head, I don't know which one's which.

"It was an issue that I kept quiet for a while. Looking back I probably thought it was because I didn't want to stand out - it can be quite daunting to mention as a kid that there's an issue or say to the group, 'I'm struggling here'," he said.

The science bit

Do all colour blind people see the same thing?

No.

We all see colour through special cells in our eyes called cones. We have three types of cones which absorb red, blue or green light.

These three cones work together for us to see the full visible spectrum. But, in colour blindness, one cone cell type doesn't function properly. This means that people with colour vision deficiency cannot see the full visible spectrum, and instead see many colours the same.

What colour blind people see depends upon the type and severity of their condition.

Many different colour combinations can cause confusion. The most common problems are distinguishing between reds, greens, browns, yellows and oranges, and between blues, purples, and dark pink, but it varies from case to case.

Can some people only see in black and white?

Yes, but it's extremely rare.

There is a type of colour blindness where people can see no colour at all, this is called monochromacy, or achromatopsia. People with monochromatic vision see in different shades of grey ranging from black to white, like an old television set.

But monochromacy is extremely rare and occurs only in approximately 1 in 33,000 people.

Are men more likely to be colour blind than women?

Yes, but women can be colour blind too.

Although colour blindness can arise as a side effect of some diseases, in the vast majority of cases it is inherited - caused by a genetic fault passed on to a child by their parents.

Colour blindness is carried on the X-chromosome. Men only have one X chromosome, but women have two. A woman therefore must inherit colour blindness on both X-chromosomes to be colour blind, which means it's less likely.

Around one in 12 men inherit red/green colour blindness but only one in 200 women.

Any advice?

There is currently no cure for inherited colour blindness, so it's all about finding the right coping strategies.

"With any impairment, visible or not, it's the time and the energy you take just to try and keep up with everyone else," said Dr Daddow.

He said the best thing to do is to be open and ask for help when you need it and that, even if you feel like a burden, you have to speak up or people won't know to help out.

Nick said he wishes he had asked his parents, his coach and his friends for help when he was struggling at training.

"Let your friends know. One of the fears for me was being different, and being seen as a bit weaker or something like that.

"Other kids might make fun of you, they might not, by telling an adult it can be dealt with a lot easier," he said.

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