Log in

Rosemary's Journal
[Most Recent Entries] [Calendar View] [Friends]

Below are the 20 most recent journal entries recorded in Rosemary Warner's LiveJournal:

[ << Previous 20 ]
Saturday, December 24th, 2011
10:10 am
Advent Science Day Twenty-Four
So. What's all this about human eye colour, then? Remember how you were taught in high school that brown is dominant, and blue is recessive? And how the one awkward kid with green eyes always left disappointed?

Well... you'll be unsurprised to hear that it is, in fact, more complicated than that.

We'll start with the bit that isn't a lie. Brown eyes are dominant. Even having one copy of "the brown eyed gene" will mean you probably have brown eyes. There are, however, several "brown eyed genes" governing the production and deposition of melanin in the iris, all of which need to work to give you those brown eyes.

So, from what we've learned so far, we can deduce that blue, the "recessive" colour, is the absence of brown, and the colour of an unpigmented iris? Sadly not. A completely unpigmented iris is a pinkish-grey colour deriving from the visibility of its blood supply, and can be found in albinos, ie people with no melanin *anywhere*. Blue eyes come from a genetic mutation that massively downregulates melanin production in the stroma of the iris, ie the layers closest to the surface. The lower layers still contain melanin, which can be demonstrated by dissection and microscopy.

So how does that make eyes blue? The answer is physics, more specifically, Rayleigh scattering, which I am not even going to pretend to understand myself, save that light with longer wavelengths (ie red and yellow) is preferentially absorbed by the melanin in the lower layers of the iris, leaving the shorter blue and purple wavelengths to be reflected and then scattered in the stroma. This is similar to the effect that causes the sky to be blue on a sunny day, and also means that yes, blue eyes *can* change colour according to lighting conditions.

The next colour to look at is grey. It is thought that grey irises reflect and scatter light in a similar way to blue, but in a much less frequency-dependent way (Mie scattering). The best theories we have so far for why this happens is that grey eyes have more collagen deposits than blue eyes, or that they simply have slightly more melanin than blue eyes.

Next, we'll look at the little-known (in humans) eye colour amber. Amber eyes are low on melanin, like blue eyes, but have deposits of pigments called lipochromes in the iris, which is, well, an amber colour. The genetics of amber eyes are poorly understood, probably because it is rare to carry genes that produce amber eyes without also carrying at least one brown-eye gene, which would mask it.

Green eyes are usually a combination of a strong blue colour with either some amber pigment or a little melanin in the stroma of the iris, effectively putting a yellow filter over the blue structural colour to produce green.

Hazel is a catch-all term for greenish-browns, often with concentric rings of different colours caused by different amounts of melanin deposition different distances from the pupil.

And how about violet eyes, the mainstay of terrible Mary Sue fanfic? In the real world, they are a result of incomplete albinism- melanin producing genes that just about work, a little bit, but can't really produce enough pigment to convey proper protection against the sun. Tiny amounts of structural blue colour as described above combine with the red colour of the iris' blood supply to make eyes that appear violet. So if you ever see a Mary Sue with violet eyes but hair that is any colour other than white-blonde, you can now get as annoyed as I do about it :D

It's also worth taking away from this article that blue and green eyed people *still have melanin in their irises*. So while it's rare for two light-eyed people to have a brown-eyed child, it's far from impossible, and should not be taken as more than circumstantial evidence to doubt paternity.

To end on a final, awesome note: I didn't actually know about the amber eye gene(s) until I researched this article. My dad has bright green eyes and my mum dark brown, so I'd always been a bit confused about how I got these strange golden brown eyes that weren't explained in any of the textbooks. But now it seems abundantly clear that my mum is heterozygous for the dark brown gene, and my dad's green eyes are presumably the result of one amber gene over blue. Allowing me to inherit my dad's visible amber gene and (presumably) my mum's invisible one.

http://en.wikipedia.org/wiki/File:HumanFemalewithAmberIris.jpg - eyes like mine!

Happy Christmas.

P.S. Any questions from the floor? I will try to answer them between now and new year.
Friday, December 23rd, 2011
2:39 pm
Advent Science Day Twenty-Three
Temperature Sensitivity

So, remember how I blithely mentioned about the agouti gene, which restricts black pigmentation in horses to the points, ie nose, ears, feet and tail? Today I'm going to tell you how it works.

We covered ways in which proteins can fail to fold properly due to gene mutations on Day Fourteen. However, there are proteins which can fold properly at, say, 30 degrees celsius, but the increased molecular motion will make them fall apart at the 37-40 degrees that is normal mammalian body temperature.

So, if you have one of those mutations in a melanin-producing protein, you can see why the extremities of the body, where surface temperature is likely to be colder, are darker, because more of the melanin-producing protein is present in its working form.

The same effect can be seen in many mammals- Siamese cats are very well known, as are Himalayan rabbits and guinea pigs, all of which in their most common form are white with dark noses, ears, feet and tails.

And it explains why Siamese kittens are born pure white. Awww.

Temperature sensitive mutant plants and even moulds are a very useful biological model- it's one of the few ways to study the effects of a gene being turned on or off in the same individual organism as opposed to across a population.
Thursday, December 22nd, 2011
4:09 pm
Advent Science: Day Twenty-Two
A case study: horse coat colour. For no reason other than that it's one of the most complex visible genetic systems that is fully understood and predictable. Also, it's cool.

There are two basic genes on which the rest of horse colour and patterning is built: the Black/Red gene and the agouti gene. Black is dominant over Red, so only a homozygous Red horse will display the red colour. A plain Red horse is "chestnut", and a plain black horse is (possibly slightly surprisingly) "black". The agouti gene is a modifier on the black pigment, restricting it to the "points", ie nose, tail, ears and feet, of the horse. Agouti is dominant, explaining the relative rarity of true black horses (they need to be homozygous for two recessive genes), and gives rise to the familiar "bay" colouration, a chestnut body with a varying amount of black hair concentrated at the extremities of the horse.

Chestnut and Bay: http://en.wikipedia.org/wiki/File:Horsescd1l-095.jpg

The next category of genes is "dilution" genes, which predictably reduce the amount of pigmentation produced in the horse's skin. There are three well known ones, dun, cream and champagne. Dun is a dominant gene that lightens Red to a yellowish colour and Black to a mousy brown, often with darker legs and a strip along the back. Bay Dun is the stereotypical colour of Przewalski's horses, the only true wild horses, and thought to be (based on cave paintings) the colour of horses pre-domestication. Another dilution gene, Cream, is interesting genetically because while it is technically dominant, it is highly dosage-dependent, ie a horse with only one Cream allele will be much darker than one with two. Thus, Red is diluted to a similar yellowish colour to Dun but without the darker markings, giving rise to the Palomino and Buckskin colours (single-allele dilution of chestnut and bay respectively) and Cremello (double dilution of chestnut). Cream can also act on black hair, but not so strongly, resulting in black horses that are slightly dark brown, and prone to sun-bleaching. Other similar dilution genes exist, and possession of two or three of them is one way of getting a "white" horse that actually turns out to be a pale cream colour when genetically tested.

Bay Dun: http://en.wikipedia.org/wiki/File:Unsortedanimal_1.jpg
Palomino: http://en.wikipedia.org/wiki/File:Palomino_Horse.jpg
Cremello: http://en.wikipedia.org/wiki/File:Akhalteke_craem.jpg

Next, we look at genes that cause multicolour patterning. These are all of the form "colour-and-white" - although many of them look like a white horse with small coloured patches, genetically they take one of the above mentioned base colours and add white bits to it. These can cause a huge variety of patterns, and are another way of getting a "white" horse- these horses are actually a coloured with all-over white markings. British English uses "piebald" for a white-on-black horse and "skewbald" for a white-on-another-colour horse. The white patterning genes all add in a dominant fashion to the previously explained colour schemes, though it is possible for a horse with one of these genes to actually not display any visible white marks.

Some "white" genes are lethal when homozygous dominant- foals are born healthy and completely white but do not have a functional large intestine- this is known as Lethal White Syndrome. For this reason, genetic testing has become very useful when breeding horses with white patterning, as you can then avoid crossing two horses with one copy of the lethal white gene. Such a cross would result in, as with Mendel's pea plants, 1/4 chance of a solid coloured foal (two recessive alleles), a 1/2 chance of a white-patterned foal (one dominant, one recessive) and a 1/4 chance of a foal suffering from Lethal White syndrome. Given that the same 1/2 chance of a patterned foal is present when crossing a white-patterned and a solid horse, with no risk of Lethal White, arranging the former mating would seem negligent at best.

Small coloured spots on a white background (or more properly a white overlay with small spots of the base colour) are caused by a gene called Leopard, and cause effects stereotypical of Appaloosa horses, as shown below. There is a small "halo" around each spot where the skin is still dark but the hair growing from it it white.

Tobiano patterning: http://en.wikipedia.org/wiki/File:Irish_Tinker_horse.JPG
Sabino patterning: http://en.wikipedia.org/wiki/File:SabinoTestedNegforOLWS.jpg
Appaloosa "leopard" pattern: http://en.wikipedia.org/wiki/File:Appaloosa_stallion.JPG

The final major gene we will look at is the Grey gene. A Grey horse, regardless of what other colour genes it carries, will start off showing the colour dictated by those other genes, and then slowly fade to white hair as it gets older. A grey horse can start off any other colour combination as above, and the Grey gene is dominant. A grey horse is distinguishable from a white one by its dark skin, which will remain pigmented even when the hair growing from it has faded to pure white.

Young grey horse: http://en.wikipedia.org/wiki/File:Lippizaner_DSC02439.JPG
Older grey horse, now almost completely white-haired: http://en.wikipedia.org/wiki/File:Andalusier_3_-_galoppierend.jpg

So how *do* you get an actually white horse? There is another dominant gene which, if present, will produce a completely white coat. A true-white horse can be distinguished from cream or grey by its pink skin and hooves- compare and contrast the picture of the older grey horse above with the white below.

White horse: http://en.wikipedia.org/wiki/File:DominantWhiteHorsesD.jpg

There are of course other genes that can add on to this basic set, the most obvious being Roan (white hairs intermingled with whatever other coat colour the horse has), Sooty (similar, but with dark hairs), and Pangare, which lightens the belly and the insides of the legs.

So, putting this all together, to determine how a horse got its colour, you ask in order:
1. Is the base colour red or black?
2. If red, is the agouti gene present to cause black points?
3. Are there any dilution genes present?
4. Are there any white patterning genes present?
5. Does the horse carry the Grey gene?

As all the genes described in 2-5 are dominant, you can then work out what colour foals can (and can't) be born to horses with particular coat colours. And probably pay obscene amounts of money to studs as a result ;-)

And finally, I apologise for any misuses of terminology related to horses. I am a geneticist, not a horse person...
Wednesday, December 21st, 2011
9:54 pm
Advent Science Day Twenty-One
So, yesterday I casually mentioned tissue matching in organ transplantation. What's going on there, I hear you ask. That it is genetic should be pretty obvious, given that close relatives are far more likely to be able to provide transplantable tissue, and that unrelated transplant donors are generally of the same race as the recipient.

The answer lies in a set of cell surface proteins called antigens, which are expressed from a group of genes called the Major Histocompatibility Complex (MHC). There are quite a lot of these genes; in humans, there are 140 known genes in the MHC, spanning 3.6 million base pairs (that's about 0.1% of your entire genome).

These genes are known for being highly polymorphic, ie there are hundreds of different alleles of them known in the population- so many that other than identical twins the odds of two individuals having the same set are far, far higher than the number of people on the earth. They also recombine (swap bits around between the maternal and paternal chromosomes) far more often than other cells, when making gametes (sex cells).

So, every human has a unique pattern of these things, and the closer yours are to your transplant donor, the less strong the immunosuppressant drugs you need to stop you rejecting it. Huzzah!

So why doesn't a pregnant mother reject her foetus? Well, the placenta doesn't express the most prevalent antigens at all, thus avoiding detection by the mother's immune system (placental tissue is made by the baby, not the mother) and only expresses just enough of some others to avoid being tagged as a foreign object by the mother for having no MHC proteins at all. And then it forms a syncitium, a thick barrier made of layers of maternal and foetal cells which blocks any migratory immune cells from crossing between mother and baby.

It's not perfect; you may have heard of rhesus disease, which is caused when a rhesus-negative mother (see day 11) gives birth to a rhesus-positive baby. It is highly likely that during the birth, the mother and baby's blood will meet, which causes the mother's body to raise antibodies against the rhesus protein in the baby's blood. This is usually fine for the *first* baby, which is no longer inside the mother by the time the antibodies are there in sufficient concentration to do any damage, but subsequent pregnancies with a Rh+ baby can end up with anaemia in the baby due to small numbers of anti-rhesus antibodies managing to cross the placenta. Happily, modern medicine can deal with this, with Rh- women in developed countries routinely being given an injection of anti-rhesus antibodies towards the end of pregnancy so that these antibodies will destroy the foetal red blood cells before the mother's immune system has time to discover them and react.

So basically it's a balancing act that usually works.
Tuesday, December 20th, 2011
7:21 pm
Advent Science Day Twenty

Once upon a time there was a woman named Karen Keegan who needed a kidney transplant. So they tested her three sons to determine if any of them had sufficiently matching tissue to make a transplant viable.

And the results of the tests came back, and showed that she was not the mother of her children. Now, one might assume some horrible mix-up at a maternity hospital at this point, but it was also clear from the tests that all three brothers had the same father. Further testing of extended family members showed that Keegan's sons were definitely related to her, just not to the extent that she could be their mother.

At first, the doctors were really rather confused. And then they realised that Karen Keegan was a chimera- she somehow had some organs with one set of DNA, and others with another. Her blood sample, which had been used to carry out the genetic test, had the other genes to her ovaries and thus the ones she had passed to her children.

Chimerism is caused by the fusion of fraternal twin zygotes, usually only a few days after fertilisation. The end result is a perfectly "normal" person, and the vast majority of chimeras go undetected. It's now thought that people with two eyes of different colours are likely to be chimeric, and the very rare cases of true hermaphroditism, ie a person with both male and female sex organs, are probably likewise found in chimeric humans.

It is thought that identical twin embryos can fuse as well, but of course this is pretty much undectable if the fusion completes. There is a suggestion that conjoined twins can sometimes be the result of incomplete fusion as well as incomplete splitting of embryos.
Monday, December 19th, 2011
5:29 pm
Advent Science Day Nineteen
Today, I am going to tell you about tortoiseshell cats.

First, here is a gratuitous excuse for a picture of a tortoiseshell cat, showing the characteristic ginger and brown mottled patterning: http://en.wikipedia.org/wiki/File:Long-haired_tortoiseshell_DSCF0193.JPG

You may be aware that the vast, vast majority of tortoiseshell cats are female, and the few male ones are pretty likely to be infertile. It should be obvious, then, that the sex chromosomes are involved somewhere down the line, and this is indeed the case.

At the stage of embryonic development where the zygote consists of a few hundred cells, all but one X chromosome shuts down and is never heard from again. This chromosome becomes a small structure at the edge of the nucleus called a Barr body, which is the usual diagnostic tool for detecting chromosomal abnormalities- for example a male with Klinefelter Syndrome (XXY sex chromosomes) will have one Barr body per cell, whereas a chromosomally normal male would have none. As a side note, it is demonstrable from this that the developmental differences in women with Turner Syndrome (has only one sex chromosome, an X) are all laid down in the very early embryo, as after that stage *all* women have only one active X chromosome per cell.

So, how does this make a tortoiseshell cat? There is a gene on the X chromosome that has two alleles, which for the sake of simplicity we will call Orange and Black. So in a heterozygotic female cat, ie one with one copy of Orange and one copy of Black, the few tens of cells which will later become the skin of the cat will all randomly have one of these genes inactivated and thus solely express the other one. And each one of these cells will divide during later development to become a patch of skin cells all with ginger or black fur, thus leading to the random mottled effect.

This effect is known as mosaicism, and for obvious reasons the vast majority of human females (and a few males) are in fact a chromosomal mosaic. However, genes which make this obvious from visual inspection don't really exist in humans.

Male cats, of course, have only one X chromosome, expressing either the Orange or the Black gene. Which, of course, also explains why the majority of pure-ginger cats are male; the Orange allele is recessive, and inherited in the same way as colour-deficieny in humans (explained yesterday). The very rare male tortoiseshell cat has the equivalent of Klinefelter Syndrome in humans, and is XXY.
Sunday, December 18th, 2011
10:57 am
Advent Science Day Eighteen
Sex Linkage

Everything I've explained so far has dealt with genes on chromosomes 1-22, ie all the chromosomes that aren't the sex chromosomes. So, what happens if a gene is on one of the sex chromosomes?

You probably know that females have two X chromosomes and males have one X and one Y chromosome*. Now, the Y chromosome is actually rather smaller than the X chromosome, and contains very few genes other than those required to cause a person to be male. (yes, female is in some ways a default.) However, the X chromosome does actually contain quite a lot of genes whose absence causes a disease.

This is why there are so many more boys than girls with colour vision deficiencies**- at least one of the genes required for normal colour vision in humans is situated on the X chromosome, which means boys have only one chance to get a working copy, but girls have two. This also means that a woman with a colour deficiency is guaranteed to pass it on to her sons, but cannot have a daughter with it unless her father also has it. The daughters of a colour-deficient father are, of course, guaranteed to be at least carriers of that allele, while his sons cannot.

THe other famous sex-linked condition is haemophilia, a disease in which sufferers' blood does not clot properly due to a mutation in one of the genes that codes for a protein which signals the blood clot formation process. At this point, you may remember that haemophilia is a condition which *only* affects boys. Actually the truth is rather less pleasant: girl foetuses with haemophilia are non-viable.

On that lovely note, I will stop for today, and tomorrow look at some of the weirder effects that can be caused by sex linkage.

*I am aware that this is a very simplistic view. This is a series about genetics rather than gender.

**The popular term for red/green deficiency and indeed several other less common forms is "colour-blindness", which is actually a rather misleading term; actual complete lack of colour vision is extremely rare, whereas the inability to see one colour while able to discern others perfectly well is rather more common.
12:08 am
Advent Science Day Seventeen
Yes, I know it's after midnight. I actually wrote it this morning and forgot to post it...

So, what's a carrier of a genetic disease, then? Well, in the case of a recessive single-gene disease, it's someone who is heterozygotic for that gene, ie they have one dominant, healthy allele, and one recessive, disease-causing allele. As with Mendel and his pea plants, if two "carriers" have children, one in four of them will have two recessive alleles and hence the disease.

Simple, right? Actually, no. You'll be able to work out from what I've already told you that a carrier of a disease will be expressing the diseased protein as well as the healthy one, in roughly equal amounts. These individuals do not have the disease because, in most cases, either half the amount of healthy protein is enough, or the body will detect that it doesn't have enough and upregulate production of that protein. Which will, of course, also upregulate production of the diseased version, which will hang around the cell doing nothing until it is tagged by the recycling machinery and broken up to have its parts reused.

So, you'll be unsurprised to here that there are instances in which there *are* effects from having one healthy and one diseased copy of a particular gene, the textbook example here being sickle-cell anaemia. Patients with this condition have a mutation in haemoglobin, the protein that carries oxygen in the blood, which causes the haemoglobin molecules to clump together and bend the red blood cell into a curved shape which not only is less efficient at carrying oxygen, but has more trouble fitting down the narrowest capillaries to provide that oxygen to the tissues that need it.

People with two faulty copies of this gene have the predictable symptoms of being unable to oxygenate their body properly, and a higher potential for organ problems caused by the capillaries supplying blood being blocked. One copy "just" leaves you needing to be careful if you take a lot of exercise or go somewhere with a low oxygen level like up a mountain, or if you have other blood-related conditions as well, which is only to be expected as half your haemoglobin is faulty.

So, why is sickle cell anaemia so prevalent? There are areas of Africa in which 25% of the population have either one or two copies of the faulty gene, despite the selection pressure against having sickle cell anaemia. The answer lies in the prevalence of malaria in the same areas- heterozygotes for sickle cell disease have blood cells that are harder for the Plasmodium parasite that causes malaria to infect. SO these people are less likely to die young of malaria, and thus more likely to pass on their malaria-resistance gene that "just happens" to have horrible disadvantages attached...
Friday, December 16th, 2011
1:13 pm
Advent Science Day Sixteen
Two case studies today, because examples really are the best way to teach this sort of thing.

The first is cystic fibrosis, which is the most common single-gene serious (ie, life-shortening) condition among people of European descent. CF is caused by a fault in a gene that codes for a protein that transports chloride ions across cell membranes, and is particularly interesting for this series because one missing amino acid (in the most common form of CF) can have such wide-ranging effects across the whole body. The most well-known symptom is that the natural mucus in the lungs forms too thick and sticky, making it hard to cough up and also a breeding ground for bacteria of various types. However, pretty much anywhere there is epithelium (surface cells) there are chloride ion channels, and this results in problems with things getting stuck in the digestive tract, low fertility (due to blocking of narrow tubes) and liver disease due to bile duct obstruction.

The *other* interesting thing about cystic fibrosis is that it varies greatly in severity. It's actually entirely possible for a mild version to remain undiagnosed until the patient is in their thirties and forties, and their body is no longer able to compensate as it did, or at least until fertility problems present themselves in adulthood.

And after the past couple of weeks, you should be able to understand how you can have a mild version of a single gene disease. While the most common cause of CF is a mutation in which one amino acid is deleted from the protein, rendering it completely non-functional, there are other known mutations in the same gene. Some of these produce protein that, as mentioned yesterday, works just about well enough that the patient can live a life relatively free of medical treatment, though may still struggle when exercising due to impaired lung function.

The other disease we'll take a brief look at is Huntington's Disease, because it's unusual in that it's actually a *dominant* gene that causes it. Huntington's is a neurodegenerative disease, and the reason that it is still so prevalent despite being a dominant gene is that, unlike most genetic disorders, the symptoms do not usually become noticeable until the patient is around forty years old, and therefore is quite likely to have already bred and passed on the gene.

So. How on earth do you get a dominant genetic disorder when we've already covered in detail how a recessive gene is a *lack* of normal protein? The reason lies in a loop region of the protein in question, which is called Huntingtin. This loop consists of a long chain of the amino acid glutamine, coded for by the sequence CAGCAGCAGCAGCAG etc etc. In people who do not suffer from Huntington's, this loop region is around 10-30 glutamines long. However, the longer this region is in the DNA, the more unstable is the replication machinery's bond to the DNA, and this can result in mutations that increase the number of CAG repeats present.

And when that number reaches a threshold of about 35 repeats, a misfolded version of huntingtin is produced, and it is that which causes the degeneration of the central nervous tissue over time. And it doesn't matter if you also have a copy of the gene that produces the functional protein- if you have any of the mutant form, you will eventually get the disease. Interestingly, though, the longer your glutamine repeat section is, the earlier in your life symptoms are likely to appear.

Tomorrow: You have probably heard about "carriers" of genetic diseases. We'll look at what that actually means, and (surprise surprise!) why it is not actually as simple as all that! Again!
Thursday, December 15th, 2011
6:55 pm
Advent Science Day Fifteen
So, yesterday I explained how even a small genetic mutation can make a non-functional protein, and then I said it's not as simple as all that. The reason for this is that proteins are not just "functional" or "not functional"- many small mutations actually make proteins that just about work, ish.

A good example of this is actually human eye colour, although I am going to be simplistic here. You probably know that brown eyes are dominant over blue eyes, and can probably guess by now that the "recessive" gene that causes blue eyes is actually a lack of brown-producing gene. The fun bit is that blue eyes are not actually a *complete* lack of pigment. People with blue eyes still produce a small amount of the brown pigment melanin, which over the unpigmented pinkish colour of the iris, produces a bluish colour. It's worth noting here that albinism is the "no pigment at all" version of this mutation This is, again, a simplistic view, as there are actually several proteins which are necessary for melanin production, but we can ignore that for the moment.

So, how does that work? We'll take a hypothetical pigment producing protein here, which picks up a mutation that converts a positively charged amino acid to an uncharged one of about the same size. The protein isn't entirely happy; it's not holding together as well as the unmutated (wild type, to use the technical term) version. However, it just about clings on, and manages to catalyse the reaction to make melanin at maybe 20% of the rate the wild type would. It's just not enough to make brown eyes, but it is enough to make a difference to the colour of the iris.

And yes, there are mutations that don't really have an effect on protein function at all- sometimes you can insert, delete or change an amino acid and be entirely unaware of it. It's also possible to have one mutation cancel out another- this is termed a "rescue" mutation in genetics. To drag out our example of the positive-to-negative-charge mutation again, if our hypothetical protein with a positive instead of a negative charge at the crucial place on the binding site meets its binding partner that has a negative instead of a positive, the interaction may well work, when if only one of the two mutations were present, it would not.
Wednesday, December 14th, 2011
11:21 am
Advent Science: Day Fourteen
So, how does a gene mutation make a non-functional protein? Well, that's one of the big questions, really. I'm going to simplify it to four major types of failure, although as this is biology, things aren't actually all that clear cut...

Our first type of error is a substitution mutation that sticks a stop codon in the middle of the protein. I explained on Day Six that there are three combinations of three base pairs that encode a signal to stop making protein, so it should be pretty obvious what happens if there is one before the end of the protein- you get a truncated protein. Which doesn't work.

Our next type of error is termed a "frame shift" error. Back to Day Six again, remember where I said a ribosome reads a strand of mRNA in three-base sections, to determine which amino acid to add to the emerging protein? Well, if you insert or delete one or two bases, the entire thing gets thrown off, different groups of three are read, and a completely different protein will come out the other end. Very often this will introduce a stop codon, but even if it doesn't, you still won't have the original protein.

OK, but what if you have simply changed one base pair to another, resulting in one amino acid difference? The results can still be spectacular; imagine a protein which is held together by the interactions of a positively charged and a negatively charged amino acid. Change the positive charge to a negative charge, or vice versa, and those two amino acids won't want to be anywhere near each other. The result: one unfolded or misfolded protein, that can't actually perform its function.

Even if the protein folds properly, it may turn out that it still doesn't work. For instance, an enzyme may require a very specific shape in the active site, ie the part of the protein that catalyses the reaction, or a binding site to another molecule might be misshapen and therefore non-functional.

By now, you may well be thinking "I bet it's not as simple as all that." Well, it's not. And tomorrow we'll look at why.
Tuesday, December 13th, 2011
11:53 pm
Advent Science: Day Thirteen
OK. Here's the big thing that I still remember the light-dawning moment I was told it for the first time.

A recessive gene is just a non-functional mutation.

Wait... what? Think about the recessive genes you know. They can all be viewed as a *lack* of something. Lack of height in pea plants, lack of antigenic proteins on blood cells, lack of skin pigmentation.

All these recessive alleles I've been talking about over the last few days are mutations of (one of the) dominant alleles, mutations which for some reason have left the ensuing protein non-functional. The only difference between what are commonly called "recessive genes" and "genetic diseases" in many cases is merely that the recessive gene, like ginger hair, or a lack of earlobes, isn't actually harmful. (remember that in genetics, "not harmful" very often means "does not affect this individual's chances of breeding.)

Of course, there are edge cases here, too. Is skin colour a genetic disease? Well, in Africa, where we're pretty sure humans first evolved, there is heavy selection pressure against having pale skin. The intensity of the sunlight means that pale-skinned humans will at best burn, and at worst get raging skin cancer before they can pass on their pale-skinned genes, while dark-skinned humans have a lot better natural protection against the sun. However, in Scandinavia, having pale skin is actually an *advantage*, because the low levels of sunlight make it difficult to synthesise vitamin D. So pale skin that lets more light through to the deep layers where Vitamin D is made is selected for. The sunlight in Africa is strong enough that dark skin will get enough to make sufficient vitamin D.

I'm not going into population genetics in any detail here, because the subject is just too big to cover. However, examples like the above one give some insight into why two geographically separated populations of the same organism can eventually evolve into two separate species.

Tomorrow, I will explain how gene mutations can make non or partially functional proteins. And then we will be able to look at genetic diseases and conditions in more detail.
Monday, December 12th, 2011
8:43 pm
Advent Science Day Twelve
Even More Complicated Genetics

So... how do the genetics for a continuous spectrum like height work?

Well. I'm going to be horribly simplistic about this one for a while, and say: Imagine there are ten height-controlling genes, which have a dominant allele, "makes you taller" and a recessive allele, "doesn't make you taller". These genes make you taller by different amounts, of course; in some of them, the recessive forms will lead to actually dangerously low levels of growth. So, let's assume that "normal" (medical definition thereof) humans have the "makes you taller" allele of between 2 and 8 of these genes. Environmental factors, of course, also affect height, smoothing out the distribution of heights into a nice neat spectrum.

This is of course not actually true, but as a model it explains why height follows approxaimtely a normal distribution (most people have 4-6 of our 10 hypothetical genes). It *also* explains why height of children often, but not always, is related to height of parents. People with more "makes you taller" genes are more likely to pass more on to their children. But it also explains why two short people can have a surprisingly tall child; a hypothetical short mother with only genes 1, 2 and 3 can have a child with a hypothetical short father with only genes 4, 5 and 6, giving the child a small chance of getting all six and thus ending up on the tall side.

Another obvious example is skin colour. You have probably seen the news stories in which two people have children of radically differing skin colours. If we take another ten hypothetical genes, all of which add more pigment to the skin, and then two parents with mixed ancestry and five (different) "makes it darker" genes each, it's easy to see how it's possible for them to have children with either most of them, or very few.

Tomorrow: Just what is a recessive gene anyway?
Sunday, December 11th, 2011
3:00 pm
Advent Science Day Eleven
More Complicated Inheritance Patterns

So, yesterday's gene had two alleles. What happens if you have *more* than two alleles? For this, we're going to look at human blood groups, which are controlled by one gene with three alleles, which you'll be familiar with: A, B and O. Now, O is recessive, just like short pea plants, but A and B are what's termed "co-dominant". That is, each one can be expressed to produce its own phenotype, regardless of whether the other is present or not.

This is how we get the four blood groups. Remember that you have two alleles out of the three available ones, one inherited from your mother, the other from your father. They can be the same or different. Because A and B are codominant, but both dominant over O, if you have AO or AA, you will be group A, and if you have BO or BB, you will be group B. People in group AB must have AB, ie one A allele and one B allele, and as the O allele is recessive, to be group O you must be OO.

I am going to digress here to tell you why that has ramifications for blood transfusions here. Basically, A and B are both proteins known as antigens that sit on the surface of red blood cells. An antigen is a protein that is recognised by the immune system of another organism as foreign, which will result in the cell's destruction. O, however, is an allele that does *not* code for a functional antigen. Because your body doesn't want to recognise its own blood as foreign, if you have the A allele, your immune system does not produce anti-A antibodies, and exactly the same is true of people with B and anti-B antibodies.

So, if you have AB blood, you have no blood-cell-eating antibodies and can receive blood from any blood group. A and B can receive blood both from their own group and from O, and group O can only receive blood from other group O people. Note that this means group O blood can be given to anybody, which makes it very useful for transfusing into people with acute blood loss if there isn't time to test for their blood group.

But what about the rhesus factor, I hear you ask? Well, that's a separate gene, with two alleles, positive being dominant over negative. Rh+ people can receive Rh- blood, but the reverse is not true. So yes, more properly, it is O- blood that can be transfused into anyone. However, as a single gene with two alleles, it's not as interesting as the ABO system, so I mostly ignored it :p

Tomorrow: Examples of inheritance controlled by more than one gene!
Saturday, December 10th, 2011
11:58 am
Advent Science Day Ten
Inheritance, and dominant and recessive genes

There exist different versions of the same gene. These are called "alleles", and each allele may have a different function. We are going to take one of the experiments carried out by Gregor Mendel, who is widely credited with the discovery of single-gene inheritance, namely height of sweet pea plants.

Now, remember way back last week sometime when I said that you inherit two copies of each chromosome, one from your mother and one from your father? Well, this means that you have two copies of each gene, and they can be the same (homozygous) or different (heterozygous). In the case of sweet pea plants, there is a gene that determines the final height of the plant that has two alleles, one Tall and one Short.

The interesting bit is that if the plant has *any* Tall alleles, regardless of if it has one or two, it will be tall. Only two copies of the Short allele will result in a short plant. Thus, we term Tall the "dominant" allele and "short" the recessive allele, meaning that its phenotype (the result of having that particular gene) will only be seen if there is no dominant allele present. In a few days we'll learn *why* some alleles are dominant over others.

Now, Mendel noticed this, and started to wonder how the Tall and Short traits are passed from parent to child. So, he took a pure-breeding strain of Tall plants (we'll call their genotype, ie which alleles of the height gene they have, TT), and a pure breeding strain of Short plants (we'll call them tt, because conventionally a dominant allele is represented by a capital letter and a recessive allele of the same gene is represented by a lower-case letter), and cross-bred them. This resulted, obviously, in offspring which had the genotype Tt, ie one Tall allele and one Short allele, and thus, because Tall is dominant, all the offspring were Tall.

Then, he crossed all those Tt offspring again. Now, this is where it gets interesting, because it turned out that 3/4 of the resultant plants were tall, and 1/4 were short. How does that work?

Consider the possibilities of which alleles that second generation of offpsring inherited from each parent. With a 50/50 chance of getting T or t from each, you get four possibilities: TT, Tt, tT and tt. Remember that T is dominant, so only the offspring with tt will be short. And there you have your 3:1 ratio.

Tomorrow we'll look at situations in which things aren't as clear cut and simple as this one...
Friday, December 9th, 2011
2:16 pm
Advent Science Day Nine: With Apologies for all the Biochemistry
So, how does the body know when to express a gene anyway?

OK. That's actually quite a big question, but we'll look at it in bits. The first bit is that I lied to you slightly when I said a gene is a piece of DNA that codes for one protein. It actually consists of the protein coding portion, and regulatory sequences before and after it. These regulatory sequences can be bound to by proteins that govern their transcription- some binding proteins inhibit transcription, others facilitate it.

A common example of this is the TATA box, so called because it has the sequence TATAAA (often followed by more As), which facilitates binding by a protein imaginatively named "TATA-binding protein, or TBP). When TBP is bound to this sequence of DNA, it helps the two strands unwind from each other (needed for transcription, as explained in day five), then bends the DNA and invites other enzymes needed for transcription to come and join the party. This sequence is found in around twenty percent of all genes in multicellular organisms.

Of course, there have to be more specific sequences, and there are. We haven't found all of them by any means yet, and we don't fully understand the mechanisms by which the ones we have found work.

I will take as an example here the lactose-digesting proteins of E.coli. Now, it would be very inefficient for E.coli to express lactose-digesting enzymes when it didn't have any lactose to eat, or when it had its preferred carbon source, glucose, instead. So, it has a gene that makes a protein that binds to the genes that code for the lactose-digesting enzymes, preventing their transcription. By default, this repressor gene is always expressed, so the cells don't digest lactose. There are two signals that switch on expression of lactose-digesting enzymes: one is the presence of lactose, the other is the absence of glucose.

I've already mentioned that E.coli prefers to eat glucose to lactose when it can. So it follows that *both* the triggers for lactose digestion must be present in order to express the lactose-digesting enzyme. And this is indeed the case: lactose binds to the repressor protein, changing its shape to one that can no longer bind to DNA. Thus, a low level of expression is permitted, which is useful in case the cells run out of glucose and need to bootstrap lactose digestion. In the absence of glucose, another molecule called cAMP, whose presence is inversely proportional to the amount of glucose around the place, enables better and faster binding of the DNA transcription machinery to the lactose-digesting genes, causing them to be expressed much faster.

That all seemed a bit complicated. Unfortunately, that is actually one of the simplest control mechanisms- they can involve hundreds and thousands of different molecules all interacting with each other. In fact, a lot of gene expression, especially in a multicellular organism, is really a consensus between an awful lot of factors, which makes at least me wonder why it doesn't go wrong more often.

Happily, that's about as complicated as the biochemistry in this series is going to get. For the next few days, we take a step back from the molecular level and start to look at inheritance patterns, and eventually explain what a recessive gene actually *is*. At this point, I will be able to explain why the eye colour example taught in schools is in fact a horrible lie...
Thursday, December 8th, 2011
8:23 pm
Advent Science: Day Eight
Your Genome And You

Your genome contains approximately 3.2 billion (US billion) base pairs of DNA. If it could be laid out end to end, it would be about two metres long, and 2.4nanometres wide.

We still don't know how many genes there are. Before the Human Genome Project, it was estimated at around 100-150000, based on numbers estimated for smaller and less complex organisms. Now we have an approximately complete human genome sequence, the estimates are getting much smaller, with the first suggestions after the Genome Project falling between 30 and 40000. We currently know of around 20000 protein coding sequences in the genome, with another couple of thousand sequences that look like protein coding sequences but that haven't been confirmed yet...

...wait. Look like a protein coding sequence? Well, these are sequences that start with a start codon, end with a stop codon, and have a decent length of coding DNA in between (bits of the genome that do not code for proteins tend to have stop codons all over the place). However, they are sequences for which we have yet to find the corresponding protein in the human body, or evidence that the gene is actually expressed anywhere. There are also some genes that are never translated into proteins, for instance the messenger and transfer RNA molecules mentioned on Day Five.

It's thought that somewhere between 1.5 and 2% of the human genome actually codes for proteins. So, barring the tiny fraction that as mentioned above codes for functional RNA... what is all the rest?

The answer to a lot of it is "we don't know". It's commonly referred to as "Junk DNA" although many scientists are hesitant to use such a term until we're absolutely certain it doesn't do anything. Especially because some of it *does*.

Some non-coding DNA *actually* doesn't do anything. The genome contains various nonsense repeats, random bits which are often thought to be the remnants of viruses that have incorporated into the host DNA and been passed on, and pseudogenes- things that used to be genes, but have mutated away from a functional form, or have been accidentally duplicated without the surrounding sequences needed to be transcribed. It is some of these sequences which are used for DNA fingerprinting in criminal and paternity cases- the lengths of some known pieces of "junk" DNA varies so much between individuals that take enough of them and you have a unique genetic "fingerprintt".

However, another major sort of non-coding DNA is regulatory sequences- bits of DNA which can regulate the expression of the genes they surround. This is clearly non-coding DNA with a function, Which leads us neatly onto tomorrow's question: How does the body know when and where to express a gene?
Wednesday, December 7th, 2011
11:05 am
Advent Science: Day Seven
Protein Folding - this one's a bit long...

In order to actually be useful, protein chains need to fold up into their final shapes. Now, remember how yesterday I told you about how amino acids have side chains with different chemical properties? Some of these come into play here, for instance, two cysteines can bind to each other through a disulphide bond* (the same is not true of any other amino acid under normal cellular conditions). Other important factors that come into play are hydrophobicity (how much an amino acid repels water), whether it is negatively, neutrally or positively charged, and how much space it takes up. Hydrophobic and hydrophilic amino acids will tend to bunch together in like-minded groups, and obviously positive and negative charges are attracted to each other.

Linked here is an example diagram of a simple protein structure: http://users.soe.ucsc.edu/~pinal/p1/comp_1F.PNG . They get a *lot* more complex than that! You can follow the amino acid chain from the start (red) to the end (blue) through the colours of the rainbow to see how the backbone is folded, first into helices, and then a cylindrical structure. The actual protein, of course, will look like a solid blob, because atoms take up space rather than being represented by a single line as in the diagram.

An awful lot of computing resources are currently going into trying to predict what shape a protein will be when folded from its sequence. We are really not very good at doing that from scratch yet, but what we do have is a large database of protein structures that have been solved using spectroscopic methods. So what we do is predict structures (and therefore often functions, too) by comparing the sequence of a newly discovered protein with already known similar ones in the databases, and extrapolating.

Protein structure is, of course highly related to function. A protein that forms a pore or transport channel in a cell membrane will by necessity have a hole through the middle, and myosin, the major component of muscle fibres, is long and thin. Something else very important about proteins is that many can be induced to undergo conformational changes, for example by binding to a small molecule. This is a fundamental aspect of molecular biology that is outside the scope of this series, but it should be obvious that a protein that floats around the cell quite happily and then changes shape (in order, say, that it can then bind to DNA) when a hormone is bound to it is a very useful signalling mechanism.

So... where are proteins found? The answer is, basically, everywhere. Proteins are the "building blocks" of all life- they make up large parts of your organs, your skin, your muscles. And they also tell the body where to put all the other bits that *aren't* proteins- all the fat, the bone, the energy stores, and when to release them again. They make up the scaffolds that hold your DNA, and they even control making more of themselves. Proteins are fundamental.

From all this you should be able to deduce that proteins folding up into the correct shape is very important. And you'll be unsurprised to hear that proteins folding up *wrongly* can be a cause of disease. The most famous examples of this are diseases such as BSE (aka Mad Cow Disease), which wrecks the brain through buildup of misfolded proteins which eventually cause tissue damage and cell death... and you can't function with spongy holes in the brain. The reason thes misfolded proteins, known as prions, are so nasty is that they can find other molecules of the protein they are the misfolded version of and turn them into copies of themselves. This, of course, is how BSE was spread- by feeding cows central nervous tissue from other, diseased cows.

So, at the end of the first week, we know what DNA is, and how it's stored and copied. We know how DNA instructs the body to make proteins, and we know that proteins are what makes you *you*. So with that groundwork under our belts, we can now start to look at variations between individuals of the same species, learn to use the horrible words "dominant" and "recessive" properly, and explain genetic diseases!

*Again, you do not need to know what one of these is. For the chemists among you, in oxidising conditions, such as those usually found in a cell, the two -SH groups on two cysteines will bond together to form -S=S- , one of the few chemical (as opposed to electrostatic or hydrogen) bonds in the higher structure of a protein.
Tuesday, December 6th, 2011
11:26 am
Advent Science: Day Six
So, what's a protein? I've run out of excuses to skirt around this one, so...

A protein is a molecule made up of a chain of "building blocks" called amino acids, which are small molecules with (simplistically) a positively charged end and a negatively charged end. The proteins in all life found on Earth are made up of twenty types of these, all with the same chemical structure except for one group (the "side chain"). Amino acid side chains can be as simple as a hydrogen atom, or as complex as a small carbon chain with a benzene ring on*. They can be negatively or positively charged, they can attract or repel water (hydrophilic vs hydrophobic), and they can force a protein into a particular structure. So. You have a backbone chain with the bit that varies sticking out of the side. This may be sounding slightly familiar...

So, how do genes make proteins? Well, remember that messenger RNA that just left the nucleus after transcription and landed on a ribosome? Three bases of DNA (ie, three nucleotides) code for one amino acid in a protein, and therefore so do three bases of RNA. A group of three bases that encodes an amino acid is known as a codon.

The next obvious question is: if there are 20 amino acids, and a codon is three base pairs long, surely that means there are 64 available codons, so what happens to all the rest of the code-space? The answer is redundancy; all but two amino acids are coded for by more than one codon. There are also special codons: AUG codes for methionine but is also a signal for "start making protein here" (yes, this does mean all proteins begin with a methionine), and there are three codons that do not encode an amino acid at all, but instead send a "stop making protein now" signal.

So, given all that, you may begin to have an idea how a ribosome makes proteins. The missing link here is another type of RNA called Transfer RNA (tRNA), which is a small length containing the complimentary bases to those that encode each amino acid, chemically bonded to a molecule of that amino acid. The ribosome exposes the messenger RNA three bases at a time to the cell, and the complimentary bases of an appropriate tRNA attach to it. The ribosome then takes the amino acid off the tRNA and attaches it to the emerging chain of protein. Following this, the tRNA disengages and the cycle begins again.

But proteins aren't actually as simple as just being an amino acid chain. Tomorrow, we'll look at how these chains fold up to make functional proteins, and diseases that can be caused by failing to do so properly.

*If you don't know what that means, look up hydrocarbon chemistry. Understanding that is not essential to Advent Science, but it's interesting nonetheless.
Monday, December 5th, 2011
4:18 pm
Advent Science: Day Five
So. we have a genome. We can store it, and we can copy it. But how do we make everything else out of it?

Here, we meet the Central Dogma of molecular biology, as named by Francis Crick, the co-discoverer of the structure of DNA. Namely, that sequence information is transferred from DNA, to RNA (ribonucleic acid, a similar molecule), to proteins. For the purposes of Advent Science, I shall tell you that one gene codes for one protein.* This is generally used as a definition for "a gene", in fact: a length of DNA that encodes a protein.

Let me repeat that, because it's the thing that underpins the entire field of genetics. Genes code for proteins. When we say someone "has the brown-eye gene", what we mean is that they have the gene that makes the protein that makes brown pigment in the eyes.

So, first we need to get the genetic information encoded in the DNA into a usable state for the cell to read it and make proteins from it, which is called transcription. When a cell receives an instruction to express a particular gene (we'll get back to how that happens in a week or so), the relevant chromosome uncoils, the histones that that gene is wound round fall off, and another set of enzymes (you may begin to detect a common theme here) bind to the DNA, "read" it, and in a similar manner to the DNA replication discussed on Day Two, creates a strand of this other molecule called RNA. Crucially, it creates a strand of RNA that only contains that gene's information. RNA, as discussed two paragraphs ago, is a molecule with a very similar structure to DNA, with one major difference: instead of the nucleotide Thymine, it instead has a similar one named Uracil.

When the strand of RNA is formed, it will fall off its complementary strand of DNA and head out of the nucleus, where it will bind to a ribosome, which is the protein synthesis machinery found in every organism from the simplest bacteria right up to vertebrates like us.

Ribosomes "read" these strands of RNA, more properly known as "messenger RNA" and make the protein that each strand encodes. Now, I realise I have spent all this time not actually telling you what a protein *is*. That's because it's going to take me a day of digression to do so, which will happen tomorrow...

*Those of you with degree level knowledge of genetics will know that this isn't strictly true, but it serves our purposes well enough.
[ << Previous 20 ]
About LiveJournal.com