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Archive for the ‘genomics’ Category

reading matters 7

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She has her mother’s laugh, by Carl Zimmer , science author and journalist, blogger, New York Times columnist, etc etc

content hints – inheritance and heredity, genetics and epigenetics, Darwin and Galton, the Hapsburg jaw, eugenics, Hugo de Vries, Theodor Boveri, Luther Burbank, Pearl and Carol Buck, Henry Goddard, The Kallikak Family, Hitler’s racial hygiene laws, morons, the five races etc, Frederick Douglass, Thomas Hunt Morgan, Emma Wolverton, PKU, chromosomal shuffling, meiosis, cultural inheritance, mitochondrial DNA, Mendel’s Law, August Weismann, germ and soma, twin studies, genetic predispositions, mongrels, Neanderthals, chimeras, exosomes, the Yandruwandha people, IVF, genomic engineering, Jennifer Doudna, CRISPR, ooplasm transfers, rogue experiments, gene drives, pluripotency, ethical battlegrounds.

Written by stewart henderson

July 28, 2020 at 12:22 pm

epigenetics and imprinting 7: more problems, and ICRs

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This image has an empty alt attribute; its file name is screen-shot-2020-02-02-at-10.11.35-pm-1.pngthe only image I can find that I really understand

 

In the previous post in this series I wrote about the connection between two serious disorders, Angelman syndrome and Prader-Willi syndrome, their connection to a missing small section of chromosome 15, and how they’re related to parental inheritance. These syndromes can sometimes also be traced back to uniparental disomy, in which the section of chromosome 15 is intact, but both copies are inherited from the mother (resulting in PWS) or the father (resulting in AS).

So the key here is that this small section of chromosome 15 needs to be inherited in the correct way because of the imprinting that comes with it. To take it to the genetic level, UBE3A is a gene which is only expressed from the maternal copy of chromosome 15. If that gene is missing in the maternal copy, or if, due to uniparental disomy, both copies of the chromosome are inherited from the father, UBE3A protein won’t be produced and symptoms of Angelman syndrome will appear. Similarly, PWS will develop if a certain imprinted gene or genes aren’t inherited from the father. Other imprinting disorders have been found, for example, one that leads to Beckwith-Wiedemann syndrome, though the mechanism of action is different, in that both copies of a gene on chromosome 11 are switched on when only the paternal copy should be expressed. This results in abnormal growth (too much growth) in the foetus. It too has an ‘opposite’ syndrome, Silver-Russell syndrome, in which the relevant protein expression is reduced, resulting in retarded growth and dwarfism. 

But now to the question of exactly how genes are switched on and off, or expressed and repressed. DNA methylation, briefly explained in my first post on this topic, is essential to this. Methyl groups are carbon-hydrogen compounds which can be bound to a gene to switch it off, but here’s where I start to get confused. I’ll quote Carey and try to make sense of it:

… it may be surprising to learn that it is often not the gene body that is methylated. The part of the gene that codes for protein is epigenetically broadly the same when we compare the maternal and paternal copies of the chromosome. It’s the region of the chromosome that controls the expression of the gene that is differently methylated between the two genomes.

N Carey, The epigenetics revolution, 2011 p140

The idea, I now realise, is that there’s a section of the chromosome that controls the part of the gene that codes for the protein and it’s this region that’s differently methylated. Such regions are called imprinting control regions (ICRs). Sometimes this is straightforward, but it can get extremely complicated, with whole clusters of imprinted genes on a stretch of chromosome, being expressed from the maternally or paternally derived chromosomes, and not simply through methylation. An ICR may operate over a large region, creating ‘roadblocks’, keeping different sets of genes apart, and affecting thousands of base-pairs, not always in the same way. Repressed genes may come together in a ‘chromatin knot’, while other, activated genes from the same region form separate bundles.

Imprinting is a feature of brain cells – something which, as of the writing of Carey’s book (2011), is a bit of a mystery. Not so surprising is the number of expressed imprinted genes in the placenta, a place where competing paternal-maternal demands are played out. As to what is going on in the brain, Carey writes this:

Professor Gudrun Moore of University College London has made an intriguing suggestion. She has proposed that the high levels of imprinting in the brain represents a post-natal continuation of the war of the sexes. She has speculated that some brain imprints are an attempt by the paternal genome to promote behaviour in young offspring that will stimulate the mother to continue to drain her own resources, for example by prolonged breastfeeding.

N Carey, The epigenetics revolution, 2011. pp141-2

This sounds pretty amazing, but it’s a new epigenetic world we’re exploring. I’ll explore more of it next time.

References

The epigenetics revolution, by Nessa Carey, 2011

Epigenetics, video: SciShow

Written by stewart henderson

February 2, 2020 at 10:33 pm

epigenetics and imprinting 6: when things go wrong

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some visible signs of Angelman syndrome

So imprinting involves parent-of-origin effects of which we find evidence in certain segments of certain chromosomes, in which genes are switched on or off, depending on inheritance. It often seems that these parent-of-origin effects counter-balance each other, as both parents have their own mutually exclusive way of trying to ensure the continuation of their genetic line.

It’ll be tough (for me) to take this down to a molecular level, but I’ll rely heavily on Nessa Carey’s book. It describes work on chromosome 7 in mice. I should first mention that there’s a convention in naming genes using italics, and the proteins they code for without italics. So there’s a gene in chromosome 7 called insulin-like growth factor 2 (Igf2) which promotes embryonic growth, and is usually expressed from the paternal copy. When researchers introduced a mutation which prevented the gene from effectively coding for the Igf2 protein, the offspring of this mutation were unaffected when the mutated gene was inherited from the mother, but the litter of offspring were much smaller when the gene was mutated in the father, showing that it was the paternal copy of the Igf2 gene that was required for foetal growth.

Fascinatingly for this ‘battle of the sexes’, there’s a gene in mouse chromosome 17 – Igf2r – which acts against the Igf2 protein, stopping it from promoting growth. This gene is also imprinted, from the maternal side. And so it goes.

According to Wikipedia, we now know of at least 80 imprinted genes in humans, mostly related to embryonic and placental growth and development. This is almost twice the amount Carey reported on less than a decade ago, so discoveries in this area are moving fast. As Carey writes, it’s uncertain whether there’s less imprinting in humans than in other mammals (we know of about 150 imprinted genes in mice) or whether they’re just harder to detect. Imprinting evolved about 150 million years ago (how do they know that? – as the much-treasured Bill Bryson would say), and is particularly prevalent amongst placental mammals.

This post was supposed to be about the mechanisms involved in imprinting, but my vast readership will have to wait awhile. I’m going to follow Carey, because I’m learning a lot from her, into the next area she writes about – ‘when imprinting goes bad’. She describes two very different conditions from birth, Angelman syndrome (AS) and Prader-Willi syndrome (PWS). Researchers separately studying these conditions found that the parents of the sufferers were usually healthy, yet everything pointed to something genetic going on, presumably during the production of eggs or sperm.

The separate work on the origins of these two permanently debilitating but very different conditions eventually converged, when it was found that in both AS and PWS, the patients were missing a small, identical stretch of chromosome 15. What caused the two entirely different results of this defect was whether it was inherited from the mother (resulting in AS) or the father (resulting in PWS). So the disorder is epigenetically inherited, a further example of a parent-of-origin effect.

Yet some children inherit these disorders without any deletions to chromosome 15. They have two normal copies of chromosome 15 but not from each parent. Instead they have two copies from the mother and none from the father – called uniparental disomy. In another variation on the theme it was later discovered that AS was in some cases caused by the opposite form of uniparental disomy, in which two normal copies of the chromosome were inherited from the father. So, because the particular region of the chromosome is normally imprinted, it’s essential, for healthy offspring, that the region is inherited in the ‘correct’ way, from each parent.

I’ll be looking at more examples of problematic inheritance and imprinted genes next time.

References

https://en.wikipedia.org/wiki/Genomic_imprinting

Nessa Carey, The epigenetics revolution, 2011

Written by stewart henderson

January 23, 2020 at 12:49 pm

A DNA dialogue 1: the human genome

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what genomics tells us

Canto: I’m often confused when I try to get my head around all the stuff about genes and DNA, and genomes and alleles and chromosomes, and XX and XY, and mitosis and meiosis, and dominant and recessive and so on. I’d like to get clear, if only I could.

Jacinta: That’s a big ask, and of course we’re both in the same boat. So let’s use the magical powers of the internet to find answers. For example, here’s something that confuses me. The Human Genome project, which ended around the year 2000, involved a mapping of the whole human genome, and that includes coding and non-coding genes, and I think it was found to contain 26,000 or so – what? Letters? Genes? Coding genes? Anyway there’s a number of questions there, but they’re not the questions that confuse me. I don’t get that we now, apparently, have worked out the genetic code for all humans, but each of us has different DNA. How, exactly, does our own individual DNA relate to the genome that determines the whole species? Presumably it’s some kind of subset?

Canto: Hmmm. This article from the Smithsonian tells us that the genetic difference between human individuals is very tiny, at around 0.1%. We humans differ from bonobos and chimps, two lineages of apes that separated much more recently, by about 1.2%….

Jacinta: Yes, yes, but how, with this tiny difference between us, are we able to use DNA forensically to identify individuals from a DNA sample?

Canto: Well, perhaps this Smithsonian article provides a clue. It says that the 1.2% difference between us and chimps reflects a particular way of counting. I won’t go into the details here but apparently another way of counting shows a 4-5% difference.

Jacinta: We probably do need to go into the details in the end, but clearly this tiny .1% difference between humans is enough for us to determine the DNA as coming from one individual rather than 7 to 8 billion others. Strangely enough, I can well believe that, given that we can detect gravitational waves and such – obviously using very different technology.

Canto: Yeah the magic of science. So the Human Genome Project was officially completed in April 2003. And here’s an interesting quote from Wikipedia:

The “genome” of any given individual is unique; mapping the “human genome” involved sequencing a small number of individuals and then assembling these together to get a complete sequence for each chromosome. Therefore, the finished human genome is a mosaic, not representing any one individual.

Of course it would have to be a mosaic, but how can it represent the whole human genome when it’s only drawn from a small number? And who were these individuals, how many, and where from?

Jacinta: The Wikipedia article does give more info on this. It tells us that the project isn’t really finished, as we’ve developed techniques and processes for faster and deeper analyses. As to your questions, when the ‘finished’ sequencing was announced, the mosaic was drawn from a small number of anonymous donors, all of European origin.

Canto: But we all originated from Africa anyway, so…

Jacinta: So maybe recent ‘origin’ isn’t so important. Anyway, that first sequencing is now known as the ‘reference genome’, but after that they did sequence the genomes of ‘multiple distinct ethnic groups’, so they’ve been busy. But here are some key findings, to finish off this first post. They found some 22,300 protein-coding genes, as well as a lot of what they used to call junk DNA – now known as non-coding DNA. That number is within the mammalian range for DNA, which no doubt surprised many. Another blow for human specialness? And they also found that there were many more segmental duplications than expected. That’s to say, sections of DNA that are almost identically repeated.We’ll have to explore the significance of this as we go along.

Canto: Yes, that’s enough for starters. Apparently our genome has over 3 billion nucleobase pairs, about which more later no doubt.

References

http://humanorigins.si.edu/evidence/genetics

https://en.wikipedia.org/wiki/Human_Genome_Project

Written by stewart henderson

January 13, 2020 at 11:48 pm