Monday: 18 December 2006
As I’ve written and edited this, I’ve had to wonder if it’s “colorblindness” or “color blindness”. I confess to a nongermanic reluctance to string a word out that long, but I still haven’t come to a conclusion. So I’ve interspersed both throughout. Of course there will be those who will point out, quite properly, that it’s “colour blindness”. In the choice of nationalistic variants to which I’m involuntarily constrained I’ve been perforced to stick to American English, which is probably a really bad idea. 
Unreasoning consistency is the hobgoblin of small minds and we can up the ante by pointing out that it doesn’t maximize your google hits, either.
The first thing to know about the genetics of colorblindness is that there are a lot of forms of it, and most don’t mean you can’t see color. In most, you are missing one or two colors. There’s a lot of terminology and some genetics here, but let’s not be weenies, and dive right in.
Color Perception Conditions:
Trichromat: If you’re normal, you almost certainly have three kinds of color-sensing cones in the back of your eye, red, green, and blue cones. You’re a trichromat. (I say “almost certainly” because there are a very few women who are tetrachromats - they have four kinds of cones. And we are talking human, or rather, primate here. Birds and many reptiles may be tetrachromats, and turtles have *five* kinds of cones, one sensing well into the ultraviolet. What a rich color world turtles must live in!)
Dichromat: If you have only two of the three cones, you’re missing out on a color. In addition, the loss of a set of cones means a dimming of vision of objects that are that color.
Monochromat: If you have only one of the three cones, you see in shades of only one color, with many objects of other colors appearing extremely dimly. Monochromats are much rarer than dichromats.
Achromatopsia: Complete color blindness. None of the cones work.
Color Condition Types:
Dichromats:
Three prefixes: prot-, deut-, and trit-. Prot- refers to the red cones, deut- to the green cones, and trit- to the blue cones.
Two suffixes: -anopia (complete loss) and -anomaly (partial loss). A gene mutation can cause a completely obliterated protein, and lead to complete loss. But many mutations may only slightly change the protein for that gene, so that there is simply a partial loss or weakness of a particular color perception.
So a protan lacks in some way complete red perception. If he has protanopia, it’s complete lack of red; it he has protanomaly, it’s a partial lack of red.
Protans and deutans have what we would call red-green colorblindness, the most common form. The difference is in which gene is mutant. Tritans have blue colorblindness.
Monochromats:
If you are blue-monochromat, you see only in blue. If you are red-monochromat, you see only in red. If you are green-monochromat, you see only in green. Monochromats are rare because two genes must be mutant.
Although I say there are a lot of forms of colorblindness, perhaps the main oddity is that there are so few, and that they follow just four patterns, rather than the myriads we might expect if color were perceived in a simple, direct way - one cone per color. Taken all together though, all the common inheritance modes are covered, so colorblindness is a great way to learn genetics.
And look too how the colorblindness conditions show up. First, there’s no real yellow color blindness, and that should remind you that there are no yellow cones. And the colorblindness patterns are red-green and blue-yellow, just the same color opponent patterns that I mentioned yesterday. The phenotypes that have been known for centuries reflect what we now know of the genetics. It all fits together.
The Genes: There are six genes that have to do with how cones function. Genes code for proteins, so if a gene becomes mutated the protein may not work anymore, or may work slightly differently.
Autosomal recessive inheritance: Achromatopsia
We can dispense with three of these six genes right now: CNGA3, CNGB3, and GNAT2 have to do with basic cone machinery. Mutations in any of these cause problems with ALL cones, regardless of color, and the result is achromatopsia - complete color blindness. They are found on Chromosomes 2, 8, and 1, respectively. So they are autosomal, and all known mutations are recessive. About 1 in 10,000 people has achromatopsia.
Oliver Sacks, the neurologist, tells the story of “The Island of the Colorblind”, Pingelap, in the Western Pacific, where 10% of the small population has achromatopsia. This is far higher, 1000-fold greater, than the normal frequency of 0.01%, and is a great example of genetic drift and bottlenecking.
Apparently a typhoon killed most of the inhabitants of the island in 1775. One of the survivors had achromatopsia, and his descendents now “just by chance”, an operative key phrase along with “small population” in genetic drift, have a very high frequency of a very rare disease. (For more interesting fare along these lines, look up Tristan da Cunha.)
Achromatopsia doesn’t just show its effects in the inability to see color. During daylight the vast majority of our vision comes through our much less sensitive cones - the far more sensitive night-vision black-and-white rods are swamped out by the bright light. So people with achromatopsia, and no low-light cones, are effectively blinded in daylight, and are essentially nocturnal. And they are practically blind in terms of center vision, since there are very few rods in the cone-congested center of the back of the retina. A whole list of the problems experienced by achromats can be found here.
Autosomal Recessive Inheritance. Everyone needs to know how read a pedigree. Here’s one for something like achromatopsia:
Mutations for achromatopsia are recessive and on an autosomal (non-sex) chromosome. Circles are female, squares are male, and a blackened shape means the individual has the condition.
Let’s call the normal version of the gene (any of the above three cone genes, for instance) “A". Then the mutated abnormal version is ”a". To have achromatopsia, you have to be “aa”, and I assigned that genotype to each of the black boxes and circles above. I could then deduce almost all the genotypes of all the other individuals. If you don’t have the disease, you might be “AA”, but you might also be a normal carrier: “Aa”.
One of the hallmarks of a recessive condition is that it sometimes skips a generation. Look at individuals 1 and 2 in generation I. They don’t have the condition. But we know they must be carriers (both “Aa”) since one of their kids has it, and since he’s “aa” he must have gotten one from his mom and one from his dad. Ergo.
And look at the kids 3 and 4 in generation II. Neither of them have it, although one of their parents did. Any parent who has an autosomal recessive disease ensures that all of his or her kids will be at least carriers, because that’s all he or her has to give them, a lousy “a". Thus all kids will be ”Aa".
Human Chromosomes. Everyone needs to know about their chromosomes.
Each of our cells (except for sex cells) has 46 chromosomes, and there is where all of our 25,000 or so genes reside. Two are sex chromosomes and 44 are autosomes, meaning they aren’t sex determining. In the figure below, everyone has two copies of each of Chromosomes 1 through 22. Women have two X chromosomes (XX) and men have an X and a Y chromosome (XY).
Notice that Y chromosome. About all it’s good for is making a male; it only has 70-odd genes that have to do with reading maps and refusing to ask for directions or putting the lid down on a toilet seat. It’s an itty bitty thing, and this has consequences.
The X chromosome has many important genes - everyone needs at least one, and males have only one. For females, if something goes wrong on one of the X chromosomes, it’s covered by a normal gene on the other X. For males, if something goes wrong with one of the X chromosomes, that’s it - dude has it. The Y chromosome has nothing to cover it with.
This is the basis for sex-linked inheritance, and men get sex-linked diseases far more often than women because they have only one X chromosome.
Sex-Linked Inheritance: Red-Green (Protans and Deutans):
This takes care of two of the remaining three genes: OPN1LW (or opsin 1, red opsin) and OPN1MW (opsin 1, green opsin). Both of these genes are on the X chromosome, and they sit right next to each other. Sometimes there’s more than one copy of green opsin, and that makes for some additional interesting conditions.
Red-green colorblind folk cannot distinguish red from green. If they have two copies of a mutated red opsin gene, then they can’t see red, and all red and green objects are shades of green. If they have a mutated green opsin gene, then they can’t see green, and all red and green ojbects are shades of red.
In front of these two genes is a stretch of DNA, the LCR, that regulates the function of the the two opsins. It can also be mutated, and in that case the individual will not be able to see anything but blue and yellow.
Red-green colorblindness is the most common of all, found in 8% of males and 0.5% of females. Notice that discrepancy. It’s found much more often in males because males only have one X chromosome and so if they have a mutant opsin of either type they will have the disease.
Sex-linked Inheritance. How red-green colorblindness is inherited:
In the figure below, the people with the disease are colored fully red. Carriers have normal vision, but one X chromosome is mutant - call it “Xc”. An “XcX” is therefore a carrier. Only females can be carriers, since males with an “Xc” are “XcY” and are always colorblind.
The hallmark of a recessive sex-linked condition is that males have it more often than females. But there are a few other truisms:
If a female has it, all of her sons will have it. A son always gets his X chromosome from his mother (because he gets his other chromosome, the Y, from his father, of course).
The daughters of a female who has the disease will always be carriers, since they get one of their X chromosomes from their mother and one from their father.
If a male has it, all of his daughters will be carriers. A daughter always gets one of her X chromosomes from her father, and he has only one lousy Xc to give her.
But the main point is that males have it much more often than females. And even so the frequency of red-green colorblindness is very high. One reason is that there are at least two ways to get it, through red opsin mutants and through green opsin mutants. But the other reason is that those two genes sit next to each other on the X chromosome and can recombine sexually during meiosis, the famous “crossing over” that you’ll undoubtedly remember learning about so long ago. And that generates new versions that very often don’t work, increasing the frequency.
Autosomal Dominant Inheritance: Blue-Yellow Colorblindness (Tritans):
The sixth and last gene that has to do with colorblindness is OPN1SW (or opsin 1, blue opsin). This gene is not found on the X chromosome. It is on Chromosome 7 and is autosomal. Mutations are also dominant over normal opsin, so anyone who has even one copy of the mutant is blue-yellow colorblind. By the way, although they say “blue-yellow colorblind”, tritans can usually see yellow. They can’t distinguish between shades of purple, blue, or green though.
This is about as rare a condition as achromatopsis, 8 in 100,000 people have it.
Dominant autosomal pedigrees:
In the pedigree below, people who are tritans are colored in blue. Since the condition is rare, it’s very unusual to see a tritan who is “BB”, where “B" is the mutant allele and ”b" is the normal one.
The hallmarks of a dominant autosomal mutation:
It never skips a generation. If it doesn’t appear in the next generation, it never will again (unless it appears from outside the family).
If a parent has an autosomal dominant disease, half the kids will have it. Males and females get it equally.
The last point has particular tragedy for people who have Huntington’s Disease, a dominant mutation that causes destruction of brain and only kicks in when you’re in your 40s or 50s, after you’ve already had kids. Half of them will have the disease.
This takes care of a major part of the genetics of color blindness. There are other oddities, such as unilateral colorblindness (one eye colorblind, the other normal), the possible existence of women who are tetrachromatic, having four types of cones instead of just three. There are other, rarer ways, to get many of these conditions genetically. But this should be enough.
In addition to the links I mentioned at the bottom of yesterday’s post, here are some of the websites that were helpful in filling in holes:
More Color Vision
Color Vision and Disease Frequencies
Genetic Tests and Diseases
Achromatopsia
Unreasoning consistency is the hobgoblin of small minds and we can up the ante by pointing out that it doesn’t maximize your google hits, either.The first thing to know about the genetics of colorblindness is that there are a lot of forms of it, and most don’t mean you can’t see color. In most, you are missing one or two colors. There’s a lot of terminology and some genetics here, but let’s not be weenies, and dive right in.
Color Perception Conditions:
Trichromat: If you’re normal, you almost certainly have three kinds of color-sensing cones in the back of your eye, red, green, and blue cones. You’re a trichromat. (I say “almost certainly” because there are a very few women who are tetrachromats - they have four kinds of cones. And we are talking human, or rather, primate here. Birds and many reptiles may be tetrachromats, and turtles have *five* kinds of cones, one sensing well into the ultraviolet. What a rich color world turtles must live in!)
Dichromat: If you have only two of the three cones, you’re missing out on a color. In addition, the loss of a set of cones means a dimming of vision of objects that are that color.
Monochromat: If you have only one of the three cones, you see in shades of only one color, with many objects of other colors appearing extremely dimly. Monochromats are much rarer than dichromats.
Achromatopsia: Complete color blindness. None of the cones work.
Color Condition Types:
Dichromats:
Three prefixes: prot-, deut-, and trit-. Prot- refers to the red cones, deut- to the green cones, and trit- to the blue cones.
Two suffixes: -anopia (complete loss) and -anomaly (partial loss). A gene mutation can cause a completely obliterated protein, and lead to complete loss. But many mutations may only slightly change the protein for that gene, so that there is simply a partial loss or weakness of a particular color perception.
So a protan lacks in some way complete red perception. If he has protanopia, it’s complete lack of red; it he has protanomaly, it’s a partial lack of red.
Protans and deutans have what we would call red-green colorblindness, the most common form. The difference is in which gene is mutant. Tritans have blue colorblindness.
Monochromats:
If you are blue-monochromat, you see only in blue. If you are red-monochromat, you see only in red. If you are green-monochromat, you see only in green. Monochromats are rare because two genes must be mutant.
Although I say there are a lot of forms of colorblindness, perhaps the main oddity is that there are so few, and that they follow just four patterns, rather than the myriads we might expect if color were perceived in a simple, direct way - one cone per color. Taken all together though, all the common inheritance modes are covered, so colorblindness is a great way to learn genetics.
And look too how the colorblindness conditions show up. First, there’s no real yellow color blindness, and that should remind you that there are no yellow cones. And the colorblindness patterns are red-green and blue-yellow, just the same color opponent patterns that I mentioned yesterday. The phenotypes that have been known for centuries reflect what we now know of the genetics. It all fits together.
The Genes: There are six genes that have to do with how cones function. Genes code for proteins, so if a gene becomes mutated the protein may not work anymore, or may work slightly differently.
Autosomal recessive inheritance: Achromatopsia
We can dispense with three of these six genes right now: CNGA3, CNGB3, and GNAT2 have to do with basic cone machinery. Mutations in any of these cause problems with ALL cones, regardless of color, and the result is achromatopsia - complete color blindness. They are found on Chromosomes 2, 8, and 1, respectively. So they are autosomal, and all known mutations are recessive. About 1 in 10,000 people has achromatopsia.
Oliver Sacks, the neurologist, tells the story of “The Island of the Colorblind”, Pingelap, in the Western Pacific, where 10% of the small population has achromatopsia. This is far higher, 1000-fold greater, than the normal frequency of 0.01%, and is a great example of genetic drift and bottlenecking.
Apparently a typhoon killed most of the inhabitants of the island in 1775. One of the survivors had achromatopsia, and his descendents now “just by chance”, an operative key phrase along with “small population” in genetic drift, have a very high frequency of a very rare disease. (For more interesting fare along these lines, look up Tristan da Cunha.)
Achromatopsia doesn’t just show its effects in the inability to see color. During daylight the vast majority of our vision comes through our much less sensitive cones - the far more sensitive night-vision black-and-white rods are swamped out by the bright light. So people with achromatopsia, and no low-light cones, are effectively blinded in daylight, and are essentially nocturnal. And they are practically blind in terms of center vision, since there are very few rods in the cone-congested center of the back of the retina. A whole list of the problems experienced by achromats can be found here.
Autosomal Recessive Inheritance. Everyone needs to know how read a pedigree. Here’s one for something like achromatopsia:
Mutations for achromatopsia are recessive and on an autosomal (non-sex) chromosome. Circles are female, squares are male, and a blackened shape means the individual has the condition.
Let’s call the normal version of the gene (any of the above three cone genes, for instance) “A". Then the mutated abnormal version is ”a". To have achromatopsia, you have to be “aa”, and I assigned that genotype to each of the black boxes and circles above. I could then deduce almost all the genotypes of all the other individuals. If you don’t have the disease, you might be “AA”, but you might also be a normal carrier: “Aa”.
One of the hallmarks of a recessive condition is that it sometimes skips a generation. Look at individuals 1 and 2 in generation I. They don’t have the condition. But we know they must be carriers (both “Aa”) since one of their kids has it, and since he’s “aa” he must have gotten one from his mom and one from his dad. Ergo.
And look at the kids 3 and 4 in generation II. Neither of them have it, although one of their parents did. Any parent who has an autosomal recessive disease ensures that all of his or her kids will be at least carriers, because that’s all he or her has to give them, a lousy “a". Thus all kids will be ”Aa".
Human Chromosomes. Everyone needs to know about their chromosomes.
Each of our cells (except for sex cells) has 46 chromosomes, and there is where all of our 25,000 or so genes reside. Two are sex chromosomes and 44 are autosomes, meaning they aren’t sex determining. In the figure below, everyone has two copies of each of Chromosomes 1 through 22. Women have two X chromosomes (XX) and men have an X and a Y chromosome (XY).
Notice that Y chromosome. About all it’s good for is making a male; it only has 70-odd genes that have to do with reading maps and refusing to ask for directions or putting the lid down on a toilet seat. It’s an itty bitty thing, and this has consequences.
The X chromosome has many important genes - everyone needs at least one, and males have only one. For females, if something goes wrong on one of the X chromosomes, it’s covered by a normal gene on the other X. For males, if something goes wrong with one of the X chromosomes, that’s it - dude has it. The Y chromosome has nothing to cover it with.
This is the basis for sex-linked inheritance, and men get sex-linked diseases far more often than women because they have only one X chromosome.
Sex-Linked Inheritance: Red-Green (Protans and Deutans):
This takes care of two of the remaining three genes: OPN1LW (or opsin 1, red opsin) and OPN1MW (opsin 1, green opsin). Both of these genes are on the X chromosome, and they sit right next to each other. Sometimes there’s more than one copy of green opsin, and that makes for some additional interesting conditions.
Red-green colorblind folk cannot distinguish red from green. If they have two copies of a mutated red opsin gene, then they can’t see red, and all red and green objects are shades of green. If they have a mutated green opsin gene, then they can’t see green, and all red and green ojbects are shades of red.
In front of these two genes is a stretch of DNA, the LCR, that regulates the function of the the two opsins. It can also be mutated, and in that case the individual will not be able to see anything but blue and yellow.
Red-green colorblindness is the most common of all, found in 8% of males and 0.5% of females. Notice that discrepancy. It’s found much more often in males because males only have one X chromosome and so if they have a mutant opsin of either type they will have the disease.
Sex-linked Inheritance. How red-green colorblindness is inherited:
In the figure below, the people with the disease are colored fully red. Carriers have normal vision, but one X chromosome is mutant - call it “Xc”. An “XcX” is therefore a carrier. Only females can be carriers, since males with an “Xc” are “XcY” and are always colorblind.
The hallmark of a recessive sex-linked condition is that males have it more often than females. But there are a few other truisms:
If a female has it, all of her sons will have it. A son always gets his X chromosome from his mother (because he gets his other chromosome, the Y, from his father, of course).
The daughters of a female who has the disease will always be carriers, since they get one of their X chromosomes from their mother and one from their father.
If a male has it, all of his daughters will be carriers. A daughter always gets one of her X chromosomes from her father, and he has only one lousy Xc to give her.
But the main point is that males have it much more often than females. And even so the frequency of red-green colorblindness is very high. One reason is that there are at least two ways to get it, through red opsin mutants and through green opsin mutants. But the other reason is that those two genes sit next to each other on the X chromosome and can recombine sexually during meiosis, the famous “crossing over” that you’ll undoubtedly remember learning about so long ago. And that generates new versions that very often don’t work, increasing the frequency.
Autosomal Dominant Inheritance: Blue-Yellow Colorblindness (Tritans):
The sixth and last gene that has to do with colorblindness is OPN1SW (or opsin 1, blue opsin). This gene is not found on the X chromosome. It is on Chromosome 7 and is autosomal. Mutations are also dominant over normal opsin, so anyone who has even one copy of the mutant is blue-yellow colorblind. By the way, although they say “blue-yellow colorblind”, tritans can usually see yellow. They can’t distinguish between shades of purple, blue, or green though.
This is about as rare a condition as achromatopsis, 8 in 100,000 people have it.
Dominant autosomal pedigrees:
In the pedigree below, people who are tritans are colored in blue. Since the condition is rare, it’s very unusual to see a tritan who is “BB”, where “B" is the mutant allele and ”b" is the normal one.
The hallmarks of a dominant autosomal mutation:
It never skips a generation. If it doesn’t appear in the next generation, it never will again (unless it appears from outside the family).
If a parent has an autosomal dominant disease, half the kids will have it. Males and females get it equally.
The last point has particular tragedy for people who have Huntington’s Disease, a dominant mutation that causes destruction of brain and only kicks in when you’re in your 40s or 50s, after you’ve already had kids. Half of them will have the disease.
This takes care of a major part of the genetics of color blindness. There are other oddities, such as unilateral colorblindness (one eye colorblind, the other normal), the possible existence of women who are tetrachromatic, having four types of cones instead of just three. There are other, rarer ways, to get many of these conditions genetically. But this should be enough.
In addition to the links I mentioned at the bottom of yesterday’s post, here are some of the websites that were helpful in filling in holes:
More Color Vision
Color Vision and Disease Frequencies
Genetic Tests and Diseases
Achromatopsia
