Eye Color

Please provide an explanation, H0,for the observed heterochromia.

VARIATION

It appears that the simple DARK is dominant to lightis insufficient.

Eye color is the result of pigmentation of the irisand Rayleigh scattering of light as it passes throughthe turbid medium in the stroma of the iris. The only pigment involved is melanin, which is brown.

-----iris-----

iris

iris

irispigment

Okee Dokee what have we said?Color is the result of lightscattering as it passes thruthe iris and there is onlyone pigment.

lots

little

moderate

• The basis of human eye color. Pigment cells (yellow in the figure) contain brown pigment granules (shown in various intensities from neutral to light brown to very dark brown). The lighter the pigment and the fewer the granules — the lighter the iris color and the lighter the eye. The circles on the left depict irises and the colors that result from the corresponding pigment cell. Blue irises result from minimal pigment and few pigment granules. Green-hazel irises have moderate pigment levels and number of granules. Brown irises have high pigment levels and many granules.

Virginia Beach, the morning after Irene passed.

The eye color issue is the same as the skycolor issue; we aren’t looking for pigmentgenes. We are looking for genes whichcontrol the amount and distribution ofmelanin.

Why is the sky blue,or grey or ……………?

• The blue color of the sky is caused by the scattering of sunlight off the molecules of the atmosphere. This scattering, called Rayleigh scattering, is more effective at short wavelengths (the blue end of the visible spectrum). Therefore the light scattered down to the earth at a large angle with respect to the direction of the sun's light is predominantly in the blue end of the spectrum.

enough, already, back to genes

The QUESTION is not all that differentthan the question of skin color. We haveone or a few pigments and a continuosdistribution of colors to explain.

{Does skin color or eye color change indifferent environments or with age? Ahh,that’s another question for another day.}

Genes which govern eye color:EYCL1,2 & 3 OCA2 = EYCL3=bey2 HERC2 SLC24A4 TYR

SEARCHING for a CANDIDATEThe melanocortin 1 receptor protein is associated with pigment

variation in a wide variety of organisms including humans.

• The melanocortin 1 receptor (MC1R) regulates pigmentation in humans and other vertebrates. Variants of MC1R with reduced function are associated with pale skin color and red hair in humans of primarily European origin. A sequenced fragment of the MC1R gene (mc1r) from two Neanderthal remains has a mutation that was not found in 3700 ∼modern humans analyzed. Functional analyses show that this variant reduces MC1R activity to a level that alters hair and/or skin pigmentation in humans. The impaired activity of this variant suggests that Neanderthals varied in pigmentation levels, potentially on the scale observed in modern humans. The data suggest that inactive MC1R variants evolved independently in both modern humans and Neanderthals.

Looking at variants at MC1R might be productive.

• The MC1R gene provides instructions for making a protein called the melanocortin 1 receptor. This receptor plays an important role in normal pigmentation. The receptor is primarily located on the surface of melanocytes, which are specialized cells that produce a pigment called melanin. Melanin is the substance that gives skin, hair, and eyes their color. Melanin is also found in the light-sensitive tissue at the back of the eye (the retina), where it plays a role in normal vision.

• Melanocytes make two forms of melanin, eumelanin and pheomelanin. The relative amounts of these two pigments help determine the color of a person's hair and skin. People who produce mostly eumelanin tend to have brown or black hair and dark skin that tans easily. Eumelanin also protects skin from damage caused by ultraviolet (UV) radiation in sunlight. People who produce mostly pheomelanin tend to have red or blond hair, freckles, and light-colored skin that tans poorly. Because pheomelanin does not protect skin from UV radiation, people with more pheomelanin have an increased risk of skin damage caused by sun exposure.

• The melanocortin 1 receptor controls which type of melanin is produced by melanocytes. When the receptor is activated, it triggers a series of chemical reactions inside melanocytes that stimulate these cells to make eumelanin. If the receptor is not activated or is blocked, melanocytes make pheomelanin instead of eumelanin.

• Common variations (polymorphisms) in the MC1R gene are associated with normal differences in skin and hair color. Certain genetic variations are most common in people with red hair, fair skin, freckles, and an increased sensitivity to sun exposure. These MC1R polymorphisms reduce the ability of the melanocortin 1 receptor to stimulate eumelanin production, causing melanocytes to make mostly pheomelanin. Although MC1R is a key gene in normal human pigmentation, researchers believe that the effects of other genes also contribute to a person's hair and skin coloring.

• The melanocortin 1 receptor is also active in cells other than melanocytes, including cells involved in the body's immune and inflammatory responses. The receptor's function in these cells is unknown.

• A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on kappa-opioid receptor mediated analgesia. It is unclear whether this gene affects basal pain sensitivity or the efficacy of analgesics acting at the more clinically relevant mu-opioid receptor.

Phenotypic appearance of the patient at (A) 2 years of age and (B) 12 years of age.

SAITOH S et al. J Med Genet 2000;37:392-394

©2000 by BMJ Publishing Group Ltd

OCA2 P gene mutant

• Oculocutaneous albinism type 2 (OCA2) is an autosomal recessive disorder characterised by defective melanin production of the skin, hair, and eyes, which is caused by mutations of the P gene.The specific function of P has not been clarified, although it is likely to act as a transporter in the melanosomal membrane.

• The P gene is located in 15q11-q13, which is deleted in the majority of patients with Angelman syndrome (AS) and Prader-Willi syndrome (PWS). The P gene is not imprinted and both alleles are expressed. PWS and AS patients with typical deletions are thus hemizygous for P. It is also well established that AS and PWS deletion patients usually show hypopigmentation of the skin and hair, and P is suggested to be responsible for this hypopigmentation as well, although the mechanism has not yet been established.

Segregation of the missense mutation in the patient and parents.

SAITOH S et al. J Med Genet 2000;37:392-394

©2000 by BMJ Publishing Group Ltd

segregation of the missense mutation Arrows indicate the position of the basesubstitution, and the number below the arrow indicates the corresponding cDNA nucleotide position.

Segregation of the missense mutation in the patient and parents.

The patient inherited the mutant P allele from his __. The father’s chromosome 15 homologues have basesequence _______. a. GCTGCCAC & GCTACCAC b. GCTGCCAC & CGATGGTG c. CGACGGTG & GCTGCCAC OCA2 is an autosomal recessive. Why isn’t the mother a heterozygote ?

OCA2 isn't just involved in eye color. When it is completely broken, we end up with something called P-gene related oculocutaneous albinism. So to have blue eyes without albinism, OCA2 has to work everywhere except the stroma. So individuals with blue eyes havea mutatation in the control region.The three mutations associated with blueeyes are in an intron.

We have previously shown that a quantitative-trait locus linked to the OCA2 region of 15q accounts for 74% of variation in human eye color. We conducted additional genotyping to clarify the role of the OCA2 locus in the inheritance of eye color and other pigmentary traits associated with skin-cancer risk in white populations. Fifty-eight synonymous and nonsynonymous exonic single-nucleotide polymorphisms (SNPs) and tagging SNPs were typed in a collection of 3,839 adolescent twins, their siblings, and their parents. The highest association for blue/nonblue eye color was found with three OCA2 SNPs: rs7495174 T/C, rs6497268 G/T, and rs11855019 T/C (P values of 1.02#10561, 1.57#10596, and 4.45#10554, respectively) in intron 1. These three SNPs are in one major haplotype block, with TGT representing 78.4% of alleles. The TGT/TGT diplotype found in 62.2% of samples was the major genotype seen to modify eye color, with a frequency of 0.905 in blue or green compared with only 0.095 in brown eye color. This genotype was also at highest frequency in subjects with light brown hair and was more frequent in fair and medium skin types, consistent with the TGT haplotype acting as a recessive modifier of lighter pigmentary phenotypes. Homozygotes for rs11855019 C/C were predominantly without freckles and had lower mole counts. The minor population impact of the nonsynonymous codingr egion polymorphisms Arg305Trp and Arg419Gln associated with nonblue eyes and the tight linkage of the major TGT haplotype within the intron 1 of OCA2 with blue eye color and lighter hair and skin tones suggest that differences within the 5 proximal regulatory control region of the OCA2 gene alter expression or messenger RNA–transcript levels and may be responsible for these associations.

AJHG 80 2007

BROWN EYES BROWN EYES

3/4 1/4This simple model works only if any otherloci affecting eye color are held constant.

Locus 1 has a brown allele which is dominant over the blue allele.

Locus 2 has a green allele which is dominant over blue2,but the brown allele at locus 1 will produce brown eyeswhenever it is present.

12/16 1/16 3/16

BbGg X BbGg

(¼ BB + ½ Bb + ¼ bb) * (1/4GG + ½ Gg + 1/4gg)

1/16 BBGG + 2/16BBGg + 1/16BBgg + 2/16BbGG + 4/16 BbGg + 2/16 Bbgg 12/16 BROWN

1/16 bbGG + 2/16 bbGg 3/16 GREEN

1/16 bbgg 1/16 BLUE

B>(G, g and b)G > b

A father with blue eyes and a motherwith brown eyes have three children.One of the children has brown eyes,one has green eyes and one has blueeyes. What is the father’s genotype?What is the blue eyed child’s genotype?What are the possible genotypes for thechild with green eyes?What is the most likely genotype for thebrown eyed mother?

VARIATION

We are beginning to make sense out of eye colorinheritance, but we haven’t accounted for grey ormany other other colors. What explains the difference between brown andhoney brown.

It’s not very different from hair and skin color. Thereare a few MAJOR genes and many unidentified minor genes.

How do we find candidate loci?