This document summarizes the key genes involved in human pigmentation and melanin production. It discusses how melanocytes produce melanin through an enzymatic pathway within specialized organelles called melanosomes. Several genes have been identified that encode enzymes in the melanin synthesis pathway or proteins involved in melanosome structure and function. The review focuses on genes shown to directly impact melanocyte function and pigmentation, including those responsible for oculocutaneous albinism and normal pigmentation variation in humans. Polymorphisms in the MC1R gene, which encodes a receptor that controls switching between pheomelanin and eumelanin production, have been linked to differences in human hair and skin color.
Dna methylation ppt
definition of Dna methylation ppt
discovery of Dna methylation ppt
types of Dna methylation ppt
history of Dna methylation ppt
process of Dna methylation ppt
mechanism of Dna methylation ppt
methylation in cancer
cytosine methylation
genomic imprinting
Dna methylation ppt
definition of Dna methylation ppt
discovery of Dna methylation ppt
types of Dna methylation ppt
history of Dna methylation ppt
process of Dna methylation ppt
mechanism of Dna methylation ppt
methylation in cancer
cytosine methylation
genomic imprinting
The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15
years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer. Here, we
present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clinical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it
is time to embrace the central role of epigenetics in cancer.
-Basic Concepts in Genetics
-What is Epigenetic?
-History of Epigenetic
-How do epigenetics work?
-Epigenetics and the Environment
-Epigenetic Inheritance
-Epigenetics in Psychiatry
The Role of DNA Methylation in Coronary Artery DiseaseBardia Farivar
Epigenetic studies have identified DNA methylation in coronary artery disease (CAD). How the critical genes interact at the cellular level to cause CAD is still unknown. The discovery of DNA methylation inspired researchers to explore relationships in genomic coding and disease phenotype. In the past two decades, there have been many findings regarding the relationship between DNA methylation and CAD development, and the DNA methylation of critical genes have been found to be significantly changed during CAD, including DNA methylation at homocysteine, Alu and long Interspersed Element 1 (LINE-1) repetitive elements.
A methyl group from S-adenosyl-methionine (SAM) is transferred to the C5 position of the pyrimidine ring of cytosine residues by DNMTs in genomic CpG dinucleotides.
https://www.creative-biogene.com/Services/Drug-Discovery-Services/DNA-Methyltransferase-Screening-and-Profiling.html
Un hecho curioso y bastante llamativo es que la mayoría de los pelirrojos no experimenta el dolor del mismo modo que el resto de la población. Los datos clínicos recogidos hasta la fecha corroboran que los pelirrojos son más difíciles de anestesiar: necesitan de media un 19% más de gas en una anestesia general, son más resistentes a la anestesia local, y parece que también son más sensibles al dolor térmico.
The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15
years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer. Here, we
present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clinical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it
is time to embrace the central role of epigenetics in cancer.
-Basic Concepts in Genetics
-What is Epigenetic?
-History of Epigenetic
-How do epigenetics work?
-Epigenetics and the Environment
-Epigenetic Inheritance
-Epigenetics in Psychiatry
The Role of DNA Methylation in Coronary Artery DiseaseBardia Farivar
Epigenetic studies have identified DNA methylation in coronary artery disease (CAD). How the critical genes interact at the cellular level to cause CAD is still unknown. The discovery of DNA methylation inspired researchers to explore relationships in genomic coding and disease phenotype. In the past two decades, there have been many findings regarding the relationship between DNA methylation and CAD development, and the DNA methylation of critical genes have been found to be significantly changed during CAD, including DNA methylation at homocysteine, Alu and long Interspersed Element 1 (LINE-1) repetitive elements.
A methyl group from S-adenosyl-methionine (SAM) is transferred to the C5 position of the pyrimidine ring of cytosine residues by DNMTs in genomic CpG dinucleotides.
https://www.creative-biogene.com/Services/Drug-Discovery-Services/DNA-Methyltransferase-Screening-and-Profiling.html
Un hecho curioso y bastante llamativo es que la mayoría de los pelirrojos no experimenta el dolor del mismo modo que el resto de la población. Los datos clínicos recogidos hasta la fecha corroboran que los pelirrojos son más difíciles de anestesiar: necesitan de media un 19% más de gas en una anestesia general, son más resistentes a la anestesia local, y parece que también son más sensibles al dolor térmico.
Induced changes in protein receptors conferring resistance to anestheticsJosé Luis Moreno Garvayo
Mientras que los anestésicos generales se han empleado eficazmente durante muchos años, sus bases moleculares exactas siguen siendo relativamente desconocidas. En este estudio de revisión se discuten los hallazgos recientes relacionados con la resistencia a los efectos de la anestesia, como una forma de arrojar luz sobre estos mecanismos.
Mice with a Melanocortin 1 Receptor mutation have a slightly greater minimum ...José Luis Moreno Garvayo
En este estudio se emplearon ratones que tenían una determinada mutación del gen MC1R cuyo resultado era la pérdida de la función génica. En condiciones controladas se compararon los requerimientos anestésicos de estos ratones (que tenían el pelo claro) con un grupo control de ratones fenotípica y genotípicamente normales. Esta investigación corroboró la necesidad de una mayor anestesia en los ratones con la mutación del gen MC1R.
Este estudio sostiene que existen al menos doce genes implicados en el color del pelo y que éstos presentan un total de 45 variaciones diferentes (polimorfismos de un solo nucleótido, SNP por sus siglas en inglés). Otros trabajos han confirmado que algunos genes controlan los diferentes matices, algunos le dan el color, otros el brillo, otros la tonalidad, otros lo hacen más oscuro o más claro, etc.
T. E. Reed emplea un espectrofotómetro de reflectancia para medir exactamente cuáles son los colores del pelo (se trata de un aparato que mide la cantidad de luz que refleja el pelo en diferentes longitudes de onda) explicando un hecho conocido: hay personas que tienen un color intermedio que no se puede clasificar como negro, marrón o amarillo.
Models of Human Diseases Conference (2010) Tetrahymena model by Dr. R. Pearl...Medical Education Advising
The Ciliate Protozoan Tetrahymena thermophila as an important animal model organism
Dr. R.E. Pearlman, York University
Models of Human Diseases Conference
June 29, 2010
Ponent: Francesc Piferrer (ICM - CSIC)
Abstract: La proporció de sexes és un paràmetre fonamental en la demografia de les poblacions. Es presenta el coneixement que actualment es té sobre els mecanismes moleculars que la determinen i com en molts casos hi ha una participació combinada d’elements genètics i factors ambientals. La epigenètica integra la informació genòmica amb la ambiental i és la base de la plasticitat fenotípica Es repassen breument els principals mecanismes epigenètics i diferents mètodes per a avaluar canvis en la metilació del DNA. Seguidament, es presenten exemples de com la epigenètica pot contribuir en la recerca en ecologia i, de passada, en la producció animal. Per acabar, mostrarem alguns exemples de recerca en epigenòmica en poblacions naturals de les Illes Medes, de com petites variacions en les condicions ambientals al principi de la vida tenen conseqüències a llarg termini, i discutirem breument aspectes adaptatius en un context de canvi global.
This presentation on Epigenetics is most advanced and evidence based one. Its Very helpful for Genetics students and research fellows, Reproductive Medicine specialist, Reproductive Biologist, Infertility practitioners
A RESEARCH ON GENOMIC IMPRINTINGGenomic imprinting is the epig.docxransayo
A RESEARCH ON GENOMIC IMPRINTING
Genomic imprinting is the epigenetic phenomenon mostly occurring in gametogenesis. It has independently evolved in flowering plants and mammals. In both organisms, imprinting occurs in the embryo-nourishing tissues; the endosperm and the placenta respectively. Imprinting genes regulate the transfer of nutrients to developing progeny (Beery & Workman, 2011).The genomic imprinting usually occurs when both the maternal and the paternal alleles are present but one allele expresses itself while the other remains inactive ( Engel, N. 2015). Gene imprinting is believed to be important in regulation of growth in embryo and neonate
Experiments on androgenotes and gynogenotes , which are produced by nuclear transplantation, are used to create basis of genomic imprinting. The zygotes from androgenotes and gynogenotes were formed but neither type could undergo more development. From this situation, it is possible to suggest that the maternal and paternal effects are complimentary(Morgan, Li, & O’Neill, 2009). Each genome contains different viable and necessary properties. Another evidence that genomic imprinting has a major role in growth and development comes from a research by Li et al(1993).
Optimal method for gene imprinting is DNA methylation, which is carried out with enzyme DNA methyltransferase in mammals. DNA MTase acts on the DNA sequence 5’-6pG-3’. Primarily higher eukaryotes have CpG islands in their genomes. The islands are hardly methylated in the animal cells, this could be due to the bound transcription factors that block DNA MTase. Those sequences which are methylated are normally not active. Some research also show that methylated sequences can be active (Madek, 1974).
The importance of DNA methylation was demonstrated in the study of mammalian development(Li et al, 1993). They postulated that if mutation was introduced to the DNA MTase gene in embryonic stem cell of a mice, methylation of CpG would be abnormal and the gene expression would be affected (“DNA methylation and demethylation dynamics,” 2015). Gene mutation of DNA MTase was caused by homologous recombination and Southern blot analysis affirmed this (Wilkins, 2010). The genes used were insulin-like growth factors; H19, lgf2 and lgf2 receptor; lgf2r.
Normally H19 gene, whih is a maternal allele, is expressed while the paternal allele is inactive. Inactive paternal allele is methylated but the maternal allele is not; this should be noted carefully. RNase and Northern blot analysis essays procedures demonstrated the effects of decreased levels of DNA methylation on mutant mice. It was brought to light that typical DNA methylation is a requirement to keep for the paternal allele inactive for the H19 gene (Mightiness of science, 2016)
The lgf2 is opposite of the H19 gene in that it is expressed only in a methylated paternal allele. As a result, it is expressed in mice having deficient MTase activity. It is expected that the lgf2 gene wil.
Biology of melanocyte - Professor Torello Lotti, MD - University G.Marconi,...VR Foundation
Although almost everyone has the same amount of melanocytes, the amount and size of the melanosomes and melanin particles produced can differ immensely in humans, resulting in the different races of the world. Dendritic prolongations take contact with nearby keratinocytes, and serve as melanosomes carriers.
Diapositivas de la charla que ofrecí sobre ciencia, arqueología y pensamiento crítico, en el marco de la segunda edición de las charlas Hablando de Ciencia en Málaga 2015
Recopilación de todos los resúmenes y comentarios que se han realizado en el blog Tertulias Literarias de Ciencia acerca del libro Mala Ciencia de Ben Goldacre
Se han hecho públicos los resultados de un prometedor trabajo encabezado por investigadores del Hospital Infantil de Boston y la Facultad de Medicina de Harvard, que ha conseguido recuperar, utilizando terapia génica, parte de la audición de ratones sordos. El artículo, que ha merecido la portada de la prestigiosa revista Science Translational Medicine, promete abrir un abanico terapéutico para el tratamiento de la sordera genética en los seres humanos.
The evolutionary history of the hominin hand since the last common ancestor o...José Luis Moreno Garvayo
Tocheri y colaboradores sostienen que las pruebas moleculares y fósiles tienen importantes consecuencias para la interpretación de la historia evolutiva de la mano dentro de la tribu Hominini. En primer lugar, la parsimonia apoya la hipótesis de que la mano del último ancestro común de los humanos y chimpancés es más probable que es pareciera a la de un gran simio actual en general (Pan, Gorilla, y Pongo), que a la de un simio africano en particular. En segundo lugar, proporciona un contexto para la interpretación de los cambios derivados de la mano que se han desarrollado en diferentes homínidos. Sin embargo, la mayoría de las características primitivas que es probable que estuvieran presentes en el último ancestro común de Pan y Homo se mantienen en las manos de Australopithecus, Paranthropus/primeros humanos, y Homo floresiensis.
Análisis de las proporciones internas de la mano (la longitud de los huesos largos del pulgar y el cuarto dedo) en relación con el tamaño corporal de una muestra de primates actuales y extintos. La muestra la conforma un total de 274 primates entre los que se incluyen macacos, mandriles, gibones, orangutanes, gorilas, chimpancés y Homo sapiens; además de algunas especies extintas de homininos (Ardipithecus ramidus, Australopithecus sediba y Homo neanderthalensis).
El principal objetivo de este trabajo ha consistido en establecer una cronología y datación precisas de los yacimientos Musterienses de Eurasia, ya que éstos contienen las mejores pruebas de la sustitución de un grupo humano (los Neandertales) por otro (AMHs)
The authors report the discovery of Lomekwi 3, a 3.3-million-year-old archaeological site where in situ stone artefacts occur in spatiotemporal association with Pliocene hominin fossils in a wooded palaeoenvironment.
Descripción del mecanismo de acción de la colchina en el tratamiento de la fiebre mediterránea familiar, y de los nuevos medicamentos que se están empleando para tratar esta dolencia.
Interleukin-1 targeting drugs in familial mediterranean fever: a case series ...José Luis Moreno Garvayo
Revisión de los artículos publicados que describen el uso de medicamentos cuyo objetivo es la interleucina-1 en el tratamiento de la fiebre mediterránea familiar. Se describen siete casos en todos los cuales el uso de estos medicamentos fue beneficioso.
Evidence based recommendations for the practical management of familial medit...José Luis Moreno Garvayo
Revisión de la literatura acerca de cuestiones prácticas en relación con la fiebre mediterránea familiar. Sobre la base del análisis de los artículos publicados se exponen las recomendaciones de los expertos tras la celebración de una reunión en Israel donde se expusieron todos los puntos de vista.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Remote Sensing and Computational, Evolutionary, Supercomputing, and Intellige...University of Maribor
Slides from talk:
Aleš Zamuda: Remote Sensing and Computational, Evolutionary, Supercomputing, and Intelligent Systems.
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Inter-Society Networking Panel GRSS/MTT-S/CIS Panel Session: Promoting Connection and Cooperation
https://www.etran.rs/2024/en/home-english/
The ability to recreate computational results with minimal effort and actionable metrics provides a solid foundation for scientific research and software development. When people can replicate an analysis at the touch of a button using open-source software, open data, and methods to assess and compare proposals, it significantly eases verification of results, engagement with a diverse range of contributors, and progress. However, we have yet to fully achieve this; there are still many sociotechnical frictions.
Inspired by David Donoho's vision, this talk aims to revisit the three crucial pillars of frictionless reproducibility (data sharing, code sharing, and competitive challenges) with the perspective of deep software variability.
Our observation is that multiple layers — hardware, operating systems, third-party libraries, software versions, input data, compile-time options, and parameters — are subject to variability that exacerbates frictions but is also essential for achieving robust, generalizable results and fostering innovation. I will first review the literature, providing evidence of how the complex variability interactions across these layers affect qualitative and quantitative software properties, thereby complicating the reproduction and replication of scientific studies in various fields.
I will then present some software engineering and AI techniques that can support the strategic exploration of variability spaces. These include the use of abstractions and models (e.g., feature models), sampling strategies (e.g., uniform, random), cost-effective measurements (e.g., incremental build of software configurations), and dimensionality reduction methods (e.g., transfer learning, feature selection, software debloating).
I will finally argue that deep variability is both the problem and solution of frictionless reproducibility, calling the software science community to develop new methods and tools to manage variability and foster reproducibility in software systems.
Exposé invité Journées Nationales du GDR GPL 2024
The use of Nauplii and metanauplii artemia in aquaculture (brine shrimp).pptxMAGOTI ERNEST
Although Artemia has been known to man for centuries, its use as a food for the culture of larval organisms apparently began only in the 1930s, when several investigators found that it made an excellent food for newly hatched fish larvae (Litvinenko et al., 2023). As aquaculture developed in the 1960s and ‘70s, the use of Artemia also became more widespread, due both to its convenience and to its nutritional value for larval organisms (Arenas-Pardo et al., 2024). The fact that Artemia dormant cysts can be stored for long periods in cans, and then used as an off-the-shelf food requiring only 24 h of incubation makes them the most convenient, least labor-intensive, live food available for aquaculture (Sorgeloos & Roubach, 2021). The nutritional value of Artemia, especially for marine organisms, is not constant, but varies both geographically and temporally. During the last decade, however, both the causes of Artemia nutritional variability and methods to improve poorquality Artemia have been identified (Loufi et al., 2024).
Brine shrimp (Artemia spp.) are used in marine aquaculture worldwide. Annually, more than 2,000 metric tons of dry cysts are used for cultivation of fish, crustacean, and shellfish larva. Brine shrimp are important to aquaculture because newly hatched brine shrimp nauplii (larvae) provide a food source for many fish fry (Mozanzadeh et al., 2021). Culture and harvesting of brine shrimp eggs represents another aspect of the aquaculture industry. Nauplii and metanauplii of Artemia, commonly known as brine shrimp, play a crucial role in aquaculture due to their nutritional value and suitability as live feed for many aquatic species, particularly in larval stages (Sorgeloos & Roubach, 2021).
ANAMOLOUS SECONDARY GROWTH IN DICOT ROOTS.pptxRASHMI M G
Abnormal or anomalous secondary growth in plants. It defines secondary growth as an increase in plant girth due to vascular cambium or cork cambium. Anomalous secondary growth does not follow the normal pattern of a single vascular cambium producing xylem internally and phloem externally.
DERIVATION OF MODIFIED BERNOULLI EQUATION WITH VISCOUS EFFECTS AND TERMINAL V...Wasswaderrick3
In this book, we use conservation of energy techniques on a fluid element to derive the Modified Bernoulli equation of flow with viscous or friction effects. We derive the general equation of flow/ velocity and then from this we derive the Pouiselle flow equation, the transition flow equation and the turbulent flow equation. In the situations where there are no viscous effects , the equation reduces to the Bernoulli equation. From experimental results, we are able to include other terms in the Bernoulli equation. We also look at cases where pressure gradients exist. We use the Modified Bernoulli equation to derive equations of flow rate for pipes of different cross sectional areas connected together. We also extend our techniques of energy conservation to a sphere falling in a viscous medium under the effect of gravity. We demonstrate Stokes equation of terminal velocity and turbulent flow equation. We look at a way of calculating the time taken for a body to fall in a viscous medium. We also look at the general equation of terminal velocity.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
Phenomics assisted breeding in crop improvementIshaGoswami9
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
Salas, V. (2024) "John of St. Thomas (Poinsot) on the Science of Sacred Theol...Studia Poinsotiana
I Introduction
II Subalternation and Theology
III Theology and Dogmatic Declarations
IV The Mixed Principles of Theology
V Virtual Revelation: The Unity of Theology
VI Theology as a Natural Science
VII Theology’s Certitude
VIII Conclusion
Notes
Bibliography
All the contents are fully attributable to the author, Doctor Victor Salas. Should you wish to get this text republished, get in touch with the author or the editorial committee of the Studia Poinsotiana. Insofar as possible, we will be happy to broker your contact.
What is greenhouse gasses and how many gasses are there to affect the Earth.moosaasad1975
What are greenhouse gasses how they affect the earth and its environment what is the future of the environment and earth how the weather and the climate effects.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
Human pigmentation genes: identification, structure and consequences of polymorphic variation
1. Review
Human pigmentation genes: identification, structure and consequences of
polymorphic variation
Richard A. Sturm*, Rohan D. Teasdale, Neil F. Box1
Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia
Received 18 June 2001; received in revised form 20 August 2001; accepted 27 August 2001
Received by A.J. van Wijnen
Abstract
The synthesis of the visible pigment melanin by the melanocyte cell is the basis of the human pigmentary system, those genes directing the
formation, transport and distribution of the specialised melanosome organelle in which melanin accumulates can legitimately be called
pigmentation genes. The genes involved in this process have been identified through comparative genomic studies of mouse coat colour
mutations and by the molecular characterisation of human hypopigmentary genetic diseases such as OCA1 and OCA2. The melanocyte
responds to the peptide hormones a-MSH or ACTH through the MC1R G-protein coupled receptor to stimulate melanin production through
induced maturation or switching of melanin type. The pheomelanosome, containing the key enzyme of the pathway tyrosinase, produces
light red/yellowish melanin, whereas the eumelanosome produces darker melanins via induction of additional TYRP1, TYRP2, SILV
enzymes, and the P-protein. Intramelanosomal pH governed by the P-protein may act as a critical determinant of tyrosinase enzyme activity
to control the initial step in melanin synthesis or TYRP complex formation to facilitate melanogenesis and melanosomal maturation. The
search for genetic variation in these candidate human pigmentation genes in various human populations has revealed high levels of
polymorphism in the MC1R locus, with over 30 variant alleles so far identified. Functional correlation of MC1R alleles with skin and
hair colour provides evidence that this receptor molecule is a principle component underlying normal human pigment variation. q 2001
Elsevier Science B.V. All rights reserved.
Keywords: Melanocyte; Melanin; Tyrosinase; P-gene; MC1R
1. Introduction
The derivation of the full complement of genes from the
human genome sequencing project is but a beginning in the
understanding of the genetic make-up of individuals
(IHGSC, 2001; Venter et al., 2001). The relationship
between having certain genetic characteristics and develop-
ing a phenotype or genetic disease is very complex and
influenced by many factors including the developmental,
environmental, stochastic and epigenetic events involved
in gene expression. Additionally, the gene mapping details
of the human genome only provide the template for under-
standing the role of specific genes in disease with the much
more complicated task of translating this information into a
knowledge of functional genomics.
Considering the general interest in the heritability of
human physical features, it is perhaps unfortunate and
disappointing that so few of them show clear-cut Mende-
lian pedigree patterns. The determinants of human skin,
hair and eye colour fall into the quasi-Mendelian inheri-
tance pattern of a polygenetic trait with a few major genes
of dramatic effect and additional modifier genes. Visible
pigment is synthesised by melanoctyes, the dendritic cells
that lie at the junction of the dermis and epidermis of the
skin, through an enzymatic pathway to produce the biopo-
lymer melanin. During embryonic development melano-
cyte precursor cells (melanoblasts) migrate from the
Gene 277 (2001) 49–62
0378-1119/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved.
PII: S0378-1119(01)00694-1
www.elsevier.com/locate/gene
Abbreviations: ACTH, adrenocorticotropic hormone; ASIP, agouti
signalling protein; BOCA, brown oculocutaneous albinism; DOPA, 3, 4-
dihydroxyphenylalanine; DHICA, 5, 6-dihydroxyindole-2-carboxylic acid;
EGF, epidermal growth factor; MC1R, melanocortin-1 receptor; MITF,
microphthalmia transcription factor; a-MSH, a-melanocyte stimulating
hormone; OA, ocular albinism; OCA, oculocutaneous albinism; PAR2,
protease activated receptor-2; PKA, protein kinase-A; POMC, proopiome-
lanocortin; RHC, red hair colour; SILV, silver; TYRP, tyrosinase related
protein; TYR, tyrosinase
* Corresponding author. Institute for Molecular Bioscience, University of
Queensland, Brisbane Qld. 4072, Australia. Tel.: 161-7-3365-4492; fax:
161-7-3365-4388.
E-mail addresses: r.sturm@imb.uq.edu.au (R.A. Sturm),
nbox@bcm.tmc.edu (N.F. Box).
1
Present address: Department of Molecular and Human Genetics, Baylor
College of Medicine S411, One Baylor Plaza, Houston, TX 77030, USA.
Tel.: 11-713-798-4169; fax: 11-713-798-1445
2. neural crest to the skin, hair follicles and uvea of the eye
and are thus directly responsible for these colour character-
istics. To understand the genetic basis of pigmentation, a
molecular understanding of the gene products expressed in
the melanocytic cell and its cellular interaction with
surrounding keratinocytes that absorb the pigment is
required.
Classic genetic studies of inheritance have provided little
understanding as to the molecular basis of normal variation
in human pigmentation, beyond that intermarriage between
Black and White peoples results in offspring of intermediate
pigmentation (reviewed Robins, 1991; Sturm et al., 1998).
With respect to hair colour intensity, dark hair dominates
more or less over light and with respect to quality, brown/
black dominates over red/yellow. Although hair and skin
melanocytes arise from the same embryonic source, the
genes affecting colour can be expressed independently
with combinations of dark hair and fair skin or fair hair
and tanned skin seen in different human populations. The
influence of environmental and age-related factors that lead
to modification of the pigmentation phenotype are
confounding variables when attempting genetic analysis,
hence evaluation of these traits can become subjective
unless proper controls are in place.
In contrast to the study of human genetics, much has
been learnt about human pigmentation from a comparative
genomics approach (Jackson, 1997). Mouse coat colour
mutants were some of the first traits to be subject to
Mendelian analysis, and over 30 of the genes underlying
these coat colour mutations have now been molecularly
cloned with many found to have a corresponding human
disease phenotype. A subset of these genes preferentially
affect pigment function (Table 1), with several other
genetic loci producing mutations that have more general
developmental or physiological defects that accompany a
pigmentation deficiency (see Albinism database
www.cbc.umn.edu/tad/). This review will focus on those
genes that have so far been shown to act in a melanocyte
specific manner or possibly associated with normal varia-
tion in human pigmentation.
2. Melanocytes, melanosomes and the melanogenic
pathway
The human pigmentary system is dependent on the
production of the light absorbing biopolymer, melanin,
within epidermal, ocular and follicular melanocytes
(Nordlund et al., 1998). Melanocytes within the skin are
situated on the basal layer between the dermis and epidermis
and have a number of dendritic processes that interdigitate
with the surrounding keratinocytes. While pigment synth-
esis occurs within the melanocyte, the majority of pigment
within the skin is found in melanin laden vesicles known as
melanosomes located within the keratinocytes. It has been
the characterisation of proteins that are contained within and
form the melanosomal organelle that has provided the
biochemical understanding of some of the coat colour and
human albinism conditions.
The melanin pigments are of no fixed molecular weight
but are all derived by enzymatic oxidation of the amino acid
tyrosine and eventually produce two types of melanin in
mammalian skin. Major advances in the understanding of
the chemistry and enzymology of the biosynthetic pathway
involved in the synthesis of the eumelanin (black or brown)
and pheomelanin (red or yellow) have now been made
R.A. Sturm et al. / Gene 277 (2001) 49–6250
Table 1
Human pigmentation-related genes
Mouse coat colour Human locus Human chromosome Protein Mutation/Phenotype Function
Melanosome proteins
Albino (c) TYR 11q14-q21 Tyrosinase OCA1 Oxidation of tyrosine, dopa,
Brown (b) TYRP1 9p23 Gp75/TRYP1 OCA3 DHICA-oxidase, TYR
stabilization
Slaty (slt) DCT 13q32 TRYP2 ? Dopachrome tautomerase
Silver (si) SILV 12q13-q14 gp100/pMel17/silver ? DHICA-polymerization/stablin
Pinkeyed dilute (p) OCA2 15q11.2-q12 P-protein OCA2 pH of melanosome
Underwhite (uw) LOC51151 5p14.3-q12.3 AIM-1 OCA4 Homology to Sugar Transporters
Signal proteins
Agouti (a) ASIP 20q11.2-q12 Agouti signal protein ? MC1R antagonist
Extension (e) MC1R 16q24.3 MSH receptor Red Hair G-protein coupled receptor
Pomc1 POMC 2p23.3 POMC, MSH, ACTH Red Hair MC1R agonist
Oa1 (oa1) OA1 Xp22.3 OA1 protein OA1 G-protein coupled receptor
Microphthalmia (mi) MITF 3p12.3-14.1 MITF Wardenburg syndrome type 2 Transcription factor
Melanosome
transport/uptake by
Keratinocyte
Dilute (d) MYO5A 15q21 MyosinVa Griscelli syndrome Motor protein
Ashen (ash) RAB27A 15q21 Rab27a Griscelli syndrome RAS family protein
F2rl1 F2RL1 5q13 PAR2 ? G-protein coupled receptor
3. (Prota, 1992; Nordlund et al., 1998). Tyrosinase can cata-
lyse the first two steps, the hydroxylation of tyrosine to 3, 4-
dihydroxyphenylalanine (DOPA), and oxidation of DOPA
to DOPAquinone (Fig. 1). The eumelanins are derived from
the metabolites of DOPAchrome, whereas the pheomelanins
derive from metabolites of 5-S-cysteinylDOPA. The
isomerization of DOPAchrome to 5, 6-dihydroxyindole-2-
carboxylic acid (DHICA) is catalysed by DOPAchrome
tautomerase and the oxidation of DHICA is performed by
a DHICA-oxidase enzyme. Mice with mutant forms of these
enzymes have been found in the albino, brown and slaty
coat colour loci proposed to produce tyrosinase, and tyrosi-
nase related proteins TYRP1 and TYRP2, respectively, (del
Marmol and Beermann, 1996), though the exact enzyme
activities encoded at some of these loci are yet to be fully
defined.
Identification of other melanogenic enzymes has been
based on the study of mouse coat colour mutations through
the culture of their melanocytes, extraction or expression of
melanosomal proteins and testing for catalytic and func-
tional activities. The silver mouse coat colour has been
found to be due to a mutation that results in the progressive
loss of pigment through the disappearance of melanocytes
from their hair follicles. In vitro studies have found the
silver encoded protein (mouse gp87; human GP100/
PMEL17) to catalyse the polymerisation of DHICA to
DHICA-melanin (Chakraborty et al., 1996; Lee et al.,
1996). Another activity acting in melanoma cells upon the
DHICA substrate has been termed stablin, which prevents
the auto-oxidation of DHICA to melanin, this function has
also been assigned to the silver protein, with the suggestion
that there maybe a steady state relationship between
DHICA-polymerisation and stablin activities (Solano et
al., 2000).
The function of the P-protein encoded by the pink-eyed(p)
dilute mutation has been studied in mouse melanocytes, and
the fact that the phenotype could be partially corrected by
higher concentrations of tyrosine led to the suggestion that it
may be related to the transport of the tyrosine substrate into
the melanosome to assist melanogenesis. Direct biochem-
ical assay has shown no difference in tyrosine transport
between normal and p-melanocytes (Gahl et al., 1995;
Potterf et al., 1998), however antibodies against the P-
protein demonstrated association with the melanosomal
membrane and this intracellular location suggested it
might transport a critical substance between the cytoplasm
and the lumen of melanosomes. In situ tyrosinase activity
requires an appropriate ionic environment, the melanosome
R.A. Sturm et al. / Gene 277 (2001) 49–62 51
Fig. 1. MC1R control of pigment type switching. The POMC precursor is cleaved to give the a-MSH/ACTH ligands for the MC1R receptor which activates the
PKA/cAMP pathway. MC1R signalling induces the maturation of the phenomelanosome containing the TYR molecule to the eumelanosome containing all the
melanogenic enzymes, with the possible active transport of tyrosine or cysteine indicated by the boxed question marks.
4. is known to be an acidic organelle however mammalian
tyrosinases have demonstrated optimal activity at neutral
pH. The potential role of the P-protein as a pH exchange
membrane channel has been examined in normal and p-
melanocytes by measuring acid sensitive stain incorpora-
tion, which was shown to be compromised in p-melano-
somes as recognised using a TYRP1 antibody (Puri et al.,
2000). The regulation of tyrosinase activity in human mela-
nocyte cultures has also been proposed through the finding
of differences in melanosomal pH of those cells cultured
from Black and White skin. Staining of human cells with
a fluorescent weak base showed that the pH of melanosomes
from White melanocytes was acidic whereas those from
Black melanocytes were more neutral, suggesting that an
acidic environment causes suppression of human tyrosinase
activity (Fuller et al., 2001). Neutralisation of melanosomal
pH by vacuolar proton pump inhibitors leads to increased
melanogenesis, melanosome maturation and eumelanin/
pheomelanin ratio of treated White melanocytes (Ancans
et al., 2001a). It has been suggested that the P-protein,
which shares structural similarity with the E. coli Na1/
H1 anti-porter, mediates neutralization of melanosomal
pH by functioning as a channel to reduce the proton concen-
tration inside melanosomes and in this way regulate tyrosi-
nase activity (Ancans et al., 2001b). It is also possible that a
neutralised melanosome is important for the formation of
the high molecular weight melanogenic complex involved
in eumelanogenesis (Section 4).
Tyrosine is not freely permeable through lipid bilayers
and the mechanism for delivery of the initial substrate for
melanogenesis to its catalytic compartment is unknown. The
requirement for a melanosomal tyrosine transporter would
seem obvious, as increasing intracellular concentrations of
either tyrosine or DOPA both result in an increase in mela-
nogenesis. Melanocytes do express receptors that bind tyro-
sine or DOPA (Gahl et al., 1995; Potterf et al., 1998),
however the fact that the P-protein is not responsible for
tyrosine transport still leaves an essential step of melano-
genesis to be resolved. The transport of cysteine essential
for pheomelanogenesis and its potential efflux from the
melanosome that may stimulate eumelanogenesis is also
yet to be investigated (Potterf et al., 1999).
The genetic study of the B-gene allele series associated
with recessive orange-red colouration or hypopigmentation
in makeda fish has resulted in the molecular identification of
another integral melanosomal membrane protein known as
AIM-1 (Fukamachi et al., 2001). The mouse and human
gene orthologs were also reported in this study and the
encoded proteins show strongest sequence and structural
similarity to plant sucrose transporter proteins. Mutations
of the AIM-1 protein (Newton et al., 2001) have now
been found to map to the underwhite mouse mutation series
(Sweet et al., 1998) which effects both eye and coat colour.
The primary defect appears specific to the melanosome as
electron microscopy of the retina showed irregular size,
shape and reduction in the fraction of mature melanosomes.
Moreover, melanocyte cells from underwhite mutant mice
failed to pigment under conditions suitable for normal
mouse melanocytes (Lehman et al., 2000), with epistatic
interactions shown upon breeding with p-mutant mice
producing a significant reduction in the level of eumelanin.
The possible role of AIM-1 in melanosomal transport of a
saccharide molecule(s) is yet to be assessed in relation to the
biochemical pathway of melanogenesis, however glycosy-
lation of the TYRP proteins is known to occur and affect
their activity and intracellular organalle transport.
3. Melanosome ultrastructural components, maturation
and translocation
Ultrastructural examination of melanocytes reveals that
melanosomes are discrete membrane bound organelles
related to lysosomes, produced through the action of the
Golgi and rough endoplasmic reticulum that mature and
pigment as they are transported along the dendritic
processes and extruded into the surrounding keratinocytes
of the skin and hair follicle. Melanocytes of the eye do not
secrete their melanosomes but retain them within their cyto-
plasm (Nordlund et al., 1998). Two major types of melano-
somes are produced and named according to the type of
melanin they contain. The eumelanosome is large
(,0.9 £ 0.3 mm) and ellipsoidal with a highly ordered
glycoprotein matrix that is integral to the production of
the black or brown coloured eumelanin pigments whereas
the red or yellow pheomelanins are produced within smaller
and spherical (,0.7 mm diameter) pheomelanosomes that
are composed of a loosely aggregated and disordered glyco-
protein matrix.
There are quantifiable differences in the degree of mela-
nization and distribution of melanosomes in individuals of
diverse ethnic background (Nordlund et al., 1998).
Although the distribution of melanocytes is essentially
constant, the number, size and packaging of the melano-
somes within the keratinocyte vary. In general, more deeply
pigmented skin contains numerous large melanosomal parti-
cles, lighter pigmentation is associated with small and less
dense melanosomes that are clustered in membrane bound
groups. These distinct distribution patterns are present at
birth and are not determined by sun exposure. Differences
in the degree of melanisation, as well as chemical differ-
ences in the melanin pigments themselves are the determin-
ing factors in the visual gradation of skin and hair colour
(Sturm et al., 1998).
The melanosome has four stages of maturation, Stage I is
common to eumelanogenesis and pheomelanogenesis and
derives from late endosomes from the endoplasmic reticu-
lum. However, in the later stages eumelanosomes are
always ellipsoidal in contrast to pheomelanosomes which
retain a spherical shape. Stage II eumelanosomes demon-
strate a well organised internal structure, in Stage III the
regular and periodic deposition of opaque melanin is evident
R.A. Sturm et al. / Gene 277 (2001) 49–6252
5. upon the matrix with Stage IV melanosomes so melanized
that all internal structure is obscured. Pheomelanosomes
contain only granular material through all four stages of
melanosomal maturation. Tyrosinase has a characteristic
pattern of post-translational glycosylation and plays a role
in the biogenesis of both eumelanosomes and pheomelano-
somes, however TYRP1 and TYRP2 proteins are exclusive
to the eumelanosomes. The intracytoplasmic vesicular
transport and membrane trafficking to melanosomes has
been well characterised (Jimbow et al., 2000).
The translocation process for melanosomes within the
melanocyte is beginning to be understood but melanosomal
transfer to the keratinocytes is not well characterised. Mela-
nosomal movement from the perinuclear area toward the
dendritic processes of the melanocyte is dependent upon
microtubules. Melanocytes from the dilute mouse coat
colour mutation have melanosomes that are concentrated
in the centre of the cytoplasm due to a mutation in the
myosinVa molecule (Wu et al., 1998). This compromises
the ability of melanosomes to move along actin filaments,
producing rapid bidirectional movements between the cell
centre and the periphery, with the myosinVa defect leading
to the failure to capture and retain the organelle at the ends
of dendrites. Another mouse mutation ashen produces a
similar phenotype indicating that it affects a related pathway
and positional cloning has mapped a non-functional muta-
tion within the murine Rab27a gene, a member of the RAS
superfamily of GTPases (Wilson et al., 2000). In normal
melanocytes the Rab27a protein is localised on the cytoplas-
mic face of melanosomes together with myosinVa; in mela-
nocytes from ashen mice that lack Rab27a, myosinVa failed
to attach to melanosomes in the periphery of the dendrites
resulting in rapid bidirectional movement without retention
in the ends of the dendrites (Hume et al., 2001; Wu et al.,
2001). These results indicate that Rab27a provides a recep-
tor binding site for myosinVa to melanosomes and a direct
interaction between the two proteins has been shown by
coimmunoprecipitation (Hume et al., 2001). In addition
Rab27a can rescue melanosome transport in human mela-
nocytes from Griscelli syndrome patients who have partial
albinism associated with defects in melanosome distribution
(Bahadoran et al., 2001).
Human OA1 is the commonest form of ocular albinism. It
is characterised by the appearance of giant melanosomes in
the melanocytes within the retinal pigmented epithelium
and skin. The OA1 protein structure identifies it as a
member of the seven transmembrane G-protein coupled
receptor family and was detected as a melanosomal
membrane glycoprotein (Schiaffino et al., 1999). These
observations suggest that OA1 is involved in melanosomal
organelle formation possibly as a sensor of an unidentified
intra-melanosomal ligand regulating organelle biogenesis
through activation of G-proteins on the cytoplasmic side
of the melanosomal membrane. Analysis of Oa1 deficient
mice generated by gene knockout produced animals anato-
mically indistinguishable by coat colour from normal but
examination of the eye revealed hypopigmentation of the
retina with melanosomes displaying a giant pigment granule
phenotype (Incerti et al., 2000). Recent immunofluores-
cence cell staining of cultured mouse cells has localised
Oa1 to enodolysosomes and revealed that it is not actually
present in mature melanosomes (Samaraweera et al., 2001),
raising the possibility that it functions in intracellular vesi-
cle trafficking to melanosomes.
A major gap in the understanding of the pigmentary
process is the determinants and mechanisms involved in
the transfer of the melanosomes to the surrounding kerati-
nocytes. Four theoretical processes have been proposed,
phagocytosis, endocytosis, physical transfer of melano-
somes through an inter-cellular communication gap or
direct inoculation into keratinocytes. Whatever the mechan-
ism, disruption of this process would be expected to have
severe consequences for pigmentation. Experimental
evidence implicates the keratinocyte receptor PAR2 as
being involved in melanosome transfer (Seiberg et al.,
2000a,b). Activation of the PAR2 receptor can be effected
through protease treatment or with a mimetic of its N-term-
inal tethered peptide ligand which induces pigmentation in
cocultures of human keratinocytes and melanocytes. Inhibi-
tion of the PAR2 receptor with a serine protease inhibitor
resulted in depigmentation when topically applied to the
skin of swine and human skin xenotransplanted onto mice.
Electron microscopy studies found an accumulation of
immature melanosomes inside melanocytes of inhibitor-
treated in vitro epidermal equivalents. No pigmentation
effects of Par2 mutant mice have been reported (Lindner
et al., 2000), but fundamental differences in human and
murine pigmentary systems are to be expected since
human melanocytes localise to the epidermal-dermal junc-
tion whereas in mice they sit predominantly in hair follicles
of the dermal compartment. It is intriguing to note that a
variant allele of the human PAR2 gene has recently been
reported to display reduced sensitivity to trypsin and differ-
ential responses to PAR agonists, but any association with
pigmentation defects are yet to be investigated (Compton et
al., 2000).
4. Identification and genomic structure of human
pigmentation genes: the TYRP and SILV families
The genes encoding the mouse coat colour mutations
described have been molecularly cloned by a variety of
methods and have provided a cornerstone for melanocyte
gene function, moreover their utility is the identification of
analogous phenotypes of human albinism and other pigmen-
tary disorders. Perhaps the most dramatic examples of gene
inactivation in human pigmentation are the albinism pheno-
types of oculocutaneous albinism OCA1 and OCA2, the
myriad of inactivating mutations responsible can be viewed
at the International Albinism database hosted by the Univer-
sity of Minnesota (www.cbc.umn.edu/tad). Mutations in the
R.A. Sturm et al. / Gene 277 (2001) 49–62 53
6. tyrosinase gene (TYR) are responsible for OCA1 with muta-
tions in the P-locus underlying the tyrosinase-positive albin-
ism OCA2 phenotype. The genes and mutations responsible
for other forms of human albinism have also been deter-
mined and collated, OCA3 arising from genetic changes
in TYRP1, and OA1 gene defects in ocular albinism.
The human tyrosinase gene family consists of three
members that produce the TYR, TYRP1 and TYRP2
proteins involved in the catalytic steps of melanogenesis
(Fig. 1), and a tyrosinase pseudogene (TYRL) which is not
active. To determine whether additional members of the
tyrosinase gene family exist the total human genome
sequence was analysed (IHGSC, 2001; Venter et al.,
2001). While individual TYRP members were able to readily
identify the other TYRP genes when the entire human
genome was analysed using tblastn, they failed to detect
any additional genes or sequences that showed significant
homology. Based on this we conclude that no additional
members of the TYRP family exist within the first draft of
the human genome. TYR encodes a 529 aa copper binding
protein with a molecular weight of 55 kD, following glyco-
sylation the molecular weight of the mature protein shifts to
65–75 kD. Comparison of the TYR, TYRP1 and TYRP2
proteins reveals a common protein structure of approxi-
mately 50% similarity which is schematically shown in
Fig. 2A (Cassady and Sturm, 1994). All three enzymes
contain an N-terminal signal sequence, an epidermal growth
factor (EGF) repeat and other conserved cysteine residues
that may be involved in protein-protein interactions, two
metal binding domains A and B that serve as the catalytic
site, and a C-terminal transmembrane domain with a short
cytoplasmic tail. These proteins share a common tertiary
structure, have the potential to associate in a higher order
melanosomal protein complex and contribute to the stability
of complex formation (Jimenez-Cervantes et al., 1998;
Kobayashi et al., 1998).
The human TYR (Giebel et al., 1991; Ponnazhagan et al.,
1994), TYRP1 (Box et al., 1998) and TYRP2 (Sturm et al.,
1995) genomic structures have previously been determined
and show TYR to be encoded by five exons, TYRP1 protein
by seven of eight exons, and TYRP2 by eight exons. Analy-
sis of the exonic regions and splice junction phase shown in
Fig. 2A reveals only one site that is identical in all three
genes, with the final exon containing the C-terminal trans-
membrane region (Sturm et al., 1995). Both the TYR/
TYRP1, and TYRP1/TYRP2 gene pairs share another
common splice junction. This exon-intron boundary study
clearly indicates that the TYRP gene family has evolved
from one common ancestral gene by duplication and subse-
quent divergence with analysis by sequence similarity and
comparative genomic studies (Budd and Jackson, 1995)
supporting the hypothesis that TYR gave rise to TYRP1,
which duplicated to give rise to TYRP2 (Sturm et al.,
1995). These events appear to have at least predated the
evolution of mammals with both TYRP-like genes existing
in birds, fish and axolotl, however a single TYRP1 like gene
in ascidians suggests that triplication of the tyrosinase
family occurred during the early radiation of chordates
(Sato et al., 1999). Given the age of gene duplication, it is
not surprising that there are no paralogous genes flanking
the TYRP loci when the human genomic sequence is exam-
ined. The three TYRP gene structures with their repeat
elements indicated are presented in Fig. 2B. The TYR
locus has not yet been completely resolved with 105 kb so
far assembled, but both the TYRP1 and TYRP2 genes are
now complete with 37 and 60 kb encompassing each locus
presented. The distribution of repetitive elements within
these loci supports the notion that the bulk of the human
genome is derived from the accumulation and decay of
transposable elements (Smit, 1999).
The human SILV gene product PMEL17 was originally
isolated from a cDNA library by screening with anti-tyro-
sinase antibodies and also as the GP100 protein a frequently
recognised antigen on the surface of melanoma tumour cells
by cytotoxic T lymphocytes, later it was found to be ortho-
logous to the mouse silver locus. The deduced amino acid
sequence revealed a 668 aa protein of 70 kD molecular
weight, with a potential signal peptide sequence and a
hydrophobic C-terminal region indicating that it is
membrane bound, consistent with its identification as a
melanosomal matrix protein. The protein contains a PKD
domain (residues 237–307) found in the polycystic kidney
disease protein, and an triplet repeat of a 26 aa motif in the
centre of the protein (residues 315–392) found only twice in
the mouse silver protein. Although there has been some
initial discrepancy as to the structure of the SILV genomic
locus, being reported to contain nine exons spanning 7.9 kb
(Kim et al., 1996) or 11 exons spanning 9.1 kb (Bailin et al.,
1996), it is recognised that two proteins are produced from
the locus. PMEL17 and GP100 proteins are generated by
alternative splicing of the gene product to two competing 30
acceptor sites producting two proteins with potentially
different catalytic activities (Solano et al., 2000). Scanning
of the total human genomic sequence with SILV can detect
one gene of high similarity using a tblastn search, this gene
GPNMB has previously been cloned in a subtractive cDNA
library screen of melanoma cells (Weterman et al., 1995),
but any role in the pigmentation pathway is yet to be inves-
tigated. Interestingly the SILV locus is flanked quite closely
on each side by the CDK2 and DGKA genes at distances of
829 and 193bp, respectively, orientated head to head with
CDK2 in such a way as to allow sharing or overlapping of
gene promoter elements. Any significance of this gene
arrangement is yet to be tested.
The human P-gene transcript associated with OCA2 is
divided into 24 exons with the Human Genome Project
providing an incomplete assembly of 267 kb, again there
are no other P-gene homologues revealed in a tblastn search
of the total genome. The gene encodes an 838 aa open read-
ing frame producing a 110 kD protein that contains 12
transmembrane spanning regions that has been located as
an integral melanosomal membrane protein. In addition to
R.A. Sturm et al. / Gene 277 (2001) 49–6254
7. R.A. Sturm et al. / Gene 277 (2001) 49–62 55
Fig. 2. (A) Chromosomal structure of the human TYRP family members. A schematic illustration of the generic structure of the TYRP-family showing the
position of N-terminal secretory signal peptide (SS), epidermal growth factor-like region (EGF), two metal binding domains (A and B), cysteine rich region
(Cys-rich), and C-terminal membrane spanning domain (TM). Below are representations of the TYR, TYRP1 and TYRP2 proteins with the exons boxed, intron
numbers relative to the coding region are indicated by Roman numerals above the junctions, with the intron phases shown below. The phase interruptions are
listed as 0 - between two codons, 1 - between the first and second nucleotides of a codon, 2 - between the second and third nucleotides of a codon. (B) The
assembled sequence contig from the Human Genome Projects (IHGSC, 2001; Venter et al., 2001) of each TYRP loci are shown below a 5 kb ruler together with
the relative location of exons and interspersed repeat sequences. The non-coding portions of the exons are indicated by open boxes, the coding region by closed
boxes. The relative position of the repeat units identified (Smit, AFA & Green, P RepeatMasker at http://ftp.genome.washington.edu/RM/RepeatMasker.html)
are shown by the key. IHGSC accession/Celera gene identification numbers TYR, 13639321/hCG19690; TYRP1, 13641579/hCG27256; TYRP2, 13627278/
hCG32235.
8. its function regulating pH it may also be involved in the
eumelanin-pheomelanin switch (Section 5). Recently the
P-gene has also been shown to be the basis of a rare but
distinct form of brown albinism (BOCA) in the South Afri-
can population (Manga et al., 2001), however the molecular
pathology of this pigment disorder has not been precisely
determined. P-gene mutations have been reported to
account for only 50% of tyrosinase-positive mutations
suggesting that at least one other locus may be responsible
for clinical manifestations of tyrosinase-positive albinism
(Passmore et al., 1999). Alterations in the human orthologue
of the AIM-1 protein have now been reported to be the basis
of a condition termed OCA4 (Newton et al., 2001) which
phenotypically resembles OCA2, and this may at least in
part explain cases of tyrosinase-positive albinism in which
P-gene mutations have not been found.
5. Regulation of melanogenesis by differential
intracellular signalling
A unifying model of melanogenesis has emerged with the
cloning of two genes that control melanocyte switching
between eumelanin and pheomelanin production (Barsh,
1996). In mice, two interacting loci were identified that
regulate switching between the formation of pheomelano-
somes and eumelanosomes (Fig. 1), the coat colour mutants
Agouti and extension. The wild type Agouti mouse produces
coat hairs that are black at the tips and base but contain a
yellow subapical band which corresponds to a discrete and
pulsatile switch from eumelanin synthesis to pheomelanin
during the anagen phase of the hair cycle. Allele series at
both Agouti and extension may disrupt this wild-type coat
phenotype. The human agouti gene homologue ASIP has
been shown to inhibit the binding of the normal ligand for
the gene product of the extension locus, the melanocortin-1
receptor (MC1R) and block pigmentation (Suzuki et al.,
1997). In mouse, the pituitary hormone pro-opiomelanocor-
tin (POMC) is the prohormone from which a-melanocyte
stimulating hormone (a-MSH) and adrenocorticotrophic
hormone (ACTH) are produced. Both of these peptide
hormones interact with MC1R to stimulate melanin produc-
tion through the cAMP/PKA signalling pathway (Busca and
Ballotti, 2000), inducing changes in protein phosphorylation
and gene expression, largely through the transcription factor
gene product MITF of the microphthalmia locus. Ultimately
this signal results in generation of a mature, eumelanogenic
melanosome that contains along with TYR, the P-protein,
TYRP1, TYRP2 and SILV proteins (Kobayashi et al., 1995;
Lamoreux et al., 1995). In the absence of an MC1R signal
such as through binding of the inhibitory ASIP protein, the
eumelanogenic melanosome is unable to form and the
immature pheomelanosome is produced.
The same Agouti/extension gene nexus controlling mela-
nogenic complex formation may account for the natural red
or yellow pigmentation seen in many mammalian species,
with allele series at one or the other locus accounting for
pheomelanic coat colours. In humans, red hair is the ortho-
logous phenotype to the pheomelanic extension mouse coat
colour, and also due to several variant alleles of the MC1R
gene (Section 6). It seems unlikely that variation at the ASIP
locus may account for any of the variation in red hair colour
seen in human populations as there is no known analogous
phenotype to the agouti banded hair pattern in humans.
Given the lack of phenotypic evidence for the role of
ASIP in human pigmentation, the large size of this genomic
locus in man and the potential for regulatory sequence poly-
morphism, there has been little interest in searching for
polymorphism at this locus that may influence human
pigmentary phenotypes. Some polymorphism screens have
been performed on the ASIP coding region but no functional
variability has yet been identified (Voisey et al., 2001).
A report of a rare mutation within the POMC gene produ-
cing the MSH/ACTH ligands has suggested that variability
at this gene could also account for a small proportion of red
hair (Krude et al., 1998), however, the concurrent MC1R
variant genotype status was not reported in this pedigree to
exclude this locus as a cause of the red hair. A transgenic
Pomc gene knock-out mouse ablating a-MSH/ACTH
production has been generated (Yaswen et al., 1999),
although the mice displayed a yellowish tinge to their coat
this change was quite subtle, suggesting that there is
substantial ligand-independent constitutive signalling from
the murine Mc1r receptor.
6. Functional polymorphism in human pigmentation
genes
Many alleles responsible for OCA1 albinism have been
identified in the TYR locus, but ethnic differences in the
tyrosinase protein are rare and the simplistic expectation
that TYR polymorphism would be a principle component
underlying normal variation of human pigmentation is
unfounded. Results obtained from melanocytes cultured
from Black and White skin do correlate melanin content
with in situ tyrosinase activity, there being up to 10-fold
higher catalytic activity in darker skin types (Iozumi et
al., 1993), but despite this large difference in tyrosinase
activity there is no difference in the amount of enzyme
(Fuller et al., 2001). Activation of the tyrosinase enzyme
within the melanosomal organelle must somehow explain
these differences and in support of this hypothesis there are
similar levels of activity once the enzyme is isolated from
the melanosomal compartment implicating pH as a potential
control mechanism (Ancans et al., 2001a,b).
The influence of TYRP1 and TYRP2 proteins on the
stability of tyrosinase (Jimenez-Cervantes et al., 1998;
Kobayashi et al., 1998) also present these loci as candidates
to play a major role in normal variation in human pigmenta-
tion. Genetic variation within each locus has been screened
in a collection of Australian Caucasian individuals selected
R.A. Sturm et al. / Gene 277 (2001) 49–6256
9. for different hair colours without any report of non-synon-
ymous polymorphism (Box et al., 1998). Of the other genes
identified as important in eumelanin versus pheomelanin
synthesis, the SILV and P-genes remain as potential candi-
dates for some of the common pigmentary differences in
human populations. The SILV loci has not yet been screened
for polymorphism or associated with any form of OCA.
Although a number of polymorphisms have been reported
in the P-gene that are apparently variable in frequency in
some human populations (Lee et al., 1994), they are yet to
be screened for association with common human pigmenta-
tion differences. The collective absence or low level of
polymorphism within the TYRP gene family argues that
differences in common patterns of melanisation are not
produced by differences in the encoded catalytic activity
of these enzymes, although different TYRP protein levels
or enzymatic activities are integral to the pigmentary differ-
ences in human populations. It is the control of these
proteins in the melanosome that acts as the chief determi-
nant of pigmentation phenotype and it is this regulation that
must be understood.
The MC1R locus has provided one of the most obvious
examples of the power of comparative genomics for identi-
fying candidate genes underlying human complex genetic
traits such as pigmentation. Cloning and identification of the
mouse extension locus as the Mc1r gene was followed soon
after by the report that human MC1R genetic variation was
associated with red hair colour (Valverde et al., 1995). Since
this discovery, a number of studies have shown the MC1R
gene to be highly polymorphic, with over 30 variant alleles
so far reported in Caucasian populations from the British
Isles, Holland and Australia (Valverde et al., 1995; Box et
al., 1997; Smith et al., 1998; Flanagan et al., 2000; Palmer et
al., 2000; Bastiaens et al., 2001; Box et al., 2001a,b) and
these have been compiled in Table 2. Two additional studies
have also examined the frequency of MC1R variants in
Asian and African populations, which have shown little
MC1R coding region variability in the African population
(Rana et al., 1999; Harding et al., 2000).
Nine common amino acid missense changes with MC1R
allele frequencies greater than 1% are shared in Caucasian
populations. In each case allele frequencies were similar in
the study populations, except for the Asp294His variant
reported at 11% in the Scottish population examined by
Valverde et al. (1995) which may be explained by ascertain-
ment bias. In each study which has correlated genetic with
phenotypic features, three of the common variants with
amino acid substitutions Arg151Cys, Arg160Trp and
Asp294His (RHC alleles) are strongly associated with red
hair and fair skin.
In the largest study of human pigmentation to date, the
MC1R genotype of 859 Caucasian individuals was deter-
mined and variant alleles correlated with pigmentation
phenotype (Palmer et al., 2000). Over 60% of redheads
carried two or three variants and none carried a wildtype
MC1R genotype, all 71 redheads in this study carried at least
one variant, and 45 carried two of the five variants exam-
ined. Furthermore, 66% of all study members carrying two
RHC alleles were redheads, while only 8% of those carrying
a single RHC allele were redheads. In this study Val60Leu
and Asp84Glu were not associated with hair colour, though
this is not entirely clear as Val60Leu has previously been
reported at a higher frequency in those with fair/blonde or
light brown hair colour (Box et al., 1997), and it may act as a
partially penetrant recessive RHC allele (Flanagan et al.,
2000) as may Asp84Glu (Flanagan et al., 2000; Bastiaens
et al., 2001).
The associations between MC1R variants and skin colour
in general reflect those seen for hair colour where the
frequency of MC1R alleles increases as skin colours lighten.
The common variant alleles Val92Met and Arg163Gln have
failed to show association with any hair or skin colours (Box
et al., 1997; Palmer et al., 2000; Box et al., 2001a), however
the minor alleles Arg142His and Ile155Thr may also act as
recessive RHC alleles when in combination with the three
common RHC alleles (Flanagan et al., 2000; Bastiaens et
al., 2001). In addition to the nine common MC1R variants
present in Caucasian populations, numerous low frequency
variants have been identified (Table 2).
The same three RHC alleles associated with pigmentation
have also been associated with increased risk of melanoma
and non-melanocytic skin cancers such as Basal Cell Carci-
noma and Squamous Cell Carcinoma (Smith et al., 1998;
Palmer et al., 2000; Bastiaens et al., 2001; Box et al.,
2001a). This observation is perhaps not surprising given
that pigmentary traits of fair skin, lack of tanning response
and propensity to freckle have also been identified as risk
factors for these forms of skin cancer. Nevertheless, these
associations clearly point to the necessity for understanding
the genetic component of multifactorial disease as an essen-
tial step in implementing targeted strategies for community
disease management and prevention.
Although a clear model of MC1R signalling in eumela-
nin/pheomelanin switching is emerging in the mouse (Furu-
mura et al., 1998; Furumura et al., 2001), few attempts have
been made to assess the molecular basis and functional
consequences of genetic variation at MC1R in humans,
and an integrated understanding of the role of these variants
in influencing melanocyte signal transduction, gene expres-
sion, pigmentation and proliferation is eagerly awaited.
Culturing of human melanocytes of defined MC1R genotype
may provide the best experimental approach to defining the
functional consequences for pigmentation of each MC1R
allele (Abdel-Malek et al., 2000). Expression of variant
MC1R receptor alleles in heterologous cell lines have
been used to examine the cAMP stimulating capacity in
response to a-MSH (Frandberg et al., 1998; Schioth et al.,
1999). These studies have suggested that the Val60Leu
variant has a significantly reduced capacity to stimulate
intracellular cAMP when compared to wild-type MC1R,
and an ,2-fold lower affinity for a-MSH than the wild-
type was demonstrated for the Val92Met variant. The
R.A. Sturm et al. / Gene 277 (2001) 49–62 57
10. Arg151Cys, Arg160Trp and Asp294His variants have also
been shown to be totally unresponsive or severely impaired
in their ability to stimulate cAMP production following a-
MSH treatment. Although MC1R variants clearly impair
cAMP signalling, these studies make little distinction
between the RHC and non-RHC variants which is seen in
R.A. Sturm et al. / Gene 277 (2001) 49–6258
Table 2
Frequency of MC1R variant alleles in human populations
Varianta
Nucleotide change Allele frequency in Caucasian population (%) Allele frequency (%)
Australiab
N. Europec
Scotlandd
Irelande
Hollandf
Chineseg
Africanh
Pro18Ala 52C . G ,0.5
86insA ,0. 5 ,0. 5 ,0.5
Val60Leu 178G . T 12.4 15 12.7 8.3
Ala64Ser 190G . T 0. 7
Arg67Gln 200G . A 1
Phe76Tyr 227T . A ,0.5
Asp84Glu 252C . A 1.1 1.5 0. 7 2 1
Ala81Pro 241G . C ,0.5
Val92Met 274G . A 9.7 8.7 7.4 7 7
Thr95Met 284C . T ,0.5 , 0.5 ,0.5
Val97Ile 289G . A , 0.5
Ala103Val 308C . T 1.1
Gly104Ser 310G . A ,0.5
Leu106Gln 317T . A , 0.5
Leu106Leu 318G . A 1
Arg142His 425G . A 0.9 0.6 0.8
Arg151Cys 451C . T 11.1 9.9 1.2 4.8
Arg151Arg 453C . G ,0.5
Ile155Thr 464T . C 1 0.9 0.7 ,0.5
Arg160Trp 478C . T 7.1 8.7 8.5 10.5
Arg163Gln 488G . A 5 4.8 2.8 5.2 70
Val173del ,0.5
Val174Ile 520G . A ,0.5
537insC ,0.5 ,0.5 ,0.5
Pro230Leu 689C . T ,0.5
Pro230Pro 690G . A ,0.5
Gln233Gln 699G . A ,0.5
His260Pro 779A . C 0.5
Ile264Ile 792C . T ,0.5
Cys273Cys 819C . T 0. 9
Lys278Glu 832A . G ,0.5
Asn279Ser 836A . G ,0.5
Asn279Lys 837C . A ,0.5
Ile287Met 861C . G 1
Asp294His 880G . C 2.8 3.6 11.1 3.4 0. 8
Phe300Phe 900C . T 7
Thr314Thr 942A . G , 0.5 10 57
Ser316Ser 948C . T Other
Reference 1, 2, 3 4 5 6 7 1, 8 6, 8 6
(1) Box et al., 1997; (2) Sturm et al., 1998; (3) Box et al., 2001b; (4) Flanagan et al., 2000; (5) Valverde et al., 1995; (6) Harding et al., 2000; (7) Bastiaens et al.,
2001; (8) Rana et al., 1999
a
Individual variants presented without consideration of reported disequilibrium between some alleles.
b
1627 independent haplotypes derived from a collection of twins from Queensland schools (Box et al., 1997, 2001b); Sturm et al., 1998 first reports 537insC;
T314T variant has been routinely observed but frequencies not reported.
c
Haplotypes derived from 167 individuals from the British Isles and Northern Europe (Flanagan et al., 2000), also presented in part in Harding et al., 2000.
d
Haplotype frequencies recalculated from the percentage of 135 individuals carrying variants taking into account homozygotes, presented in Valverde et al.,
1995.
e
Haplotype frequencies recalculated from the percentage of 71 or 102 (Asp84Glu and Asp294His) individuals carrying variants taking into account
homozygotes, presented in Smith et al., 1998.
f
Haplotype frequencies calculated from the percentage of 385 control individuals carrying taking into account homozygotes, presented in Bastiaens et al.,
2001.
g
Box et al., 1997 examined 10 Chinese individuals; Haplotype frequencies in Rana et al., 1999 include 60 individuals from East and Southeast Asia.
h
Harding et al., 2000 calculated frequencies based on 106 African haplotypes; Rana et al., 1999 examined 25 African individuals.
11. the genetic data now available. There is a definite need for
further studies examining the cellular responses co-ordi-
nated by this receptor and how they impact on skin colour,
freckling, tanning, and melanocyte proliferation.
7. Conclusions and perspectives
Pigment gene identification in humans has proceeded
largely through a comparative genomics approach based
on analogous phenotypes seen in mouse coat colours (Jack-
son, 1997), combined with the study of severe hypopigmen-
tation phenotypes characterising defective genes (Nordlund
et al., 1998). Although there are numerous mutations affect-
ing melanocyte and therefore pigmentary system function,
the best candidates for the genetic variation that underlies
the wide variety of pigmentation phenotypes in human
populations are genes such as the TYRP and SILV gene
family members and the P-gene that are restricted in expres-
sion to the melanocyte itself. Indeed, it is the characterisa-
tion of these genes as molecular components of the
melanosomal organelle and its maturation which have
provided a genetic foundation for present studies into the
human pigmentary system. Unfortunately, not all genes
directing human melanogenesis will be identified by either
comparative genetic approaches or through examination of
melanocyte cell defects. Fundamental differences are possi-
ble between the mouse and human pigmentary systems such
as melanosomal pH stimulation of melanogenesis directed
by the P-protein (Fuller et al., 2001; Ancans et al., 2001a,b),
location of melanocytes in the mouse dermal follicles as
opposed to the human epidermis, and the extrusion of mela-
nosome particles to cutaneous keratinocytes as the basis for
skin colour is not relevant for study in the mouse. There may
well be keratinocyte-specific genes or pathways such as
PAR2 that control the fate of the melanosome once it has
been formed within the melanocytes (Seiberg et al.,
2000a,b).
The MC1R gene is the only pigmentation gene identified
so far that plays a major role in human skin and hair colour
phenotypes, to the extent of demonstrating almost Mende-
lian recessive inheritance in the case of red hair. Three RHC
variant alleles of the receptor are strongly associated with
red hair and fair skin when carried in the homozygous state.
These alleles are at high frequency in the Caucasian popula-
tion (Table 2), and it is notable that a recent study of skin
sunsensitivity has also shown an association of MC1R geno-
type with degree of tanning after repeated sun exposure
(Healy et al., 2000). Those individuals who carry a single
MC1R variant allele were intermediate in their ability to tan
when compared to those of wildtype genotype who tan well
and do not sunburn, and those with two variant alleles with
pale skin who do not tan and sunburn easily. This hetero-
zygote effect indicates that dosage of MC1R variant alleles
is important and that RHC alleles may not behave in a
strictly recessive manner.
The evolutionary forces responsible for the spectrum of
human skin tones are ambiguous, and probably reflect a
relationship to climatic environment occupied by particular
populations. Pigmentation as a well characterized pheno-
type provides a model system for connecting genetic varia-
tion to phenotypic variation in an evolutionary context, and
by exploiting this knowledge it is possible to examine how
genotypic and phenotypic processes have acted in modern
human evolution. The influence of environment as a selec-
tive pressure for skin colour has led to the postulate that in
Northern European populations there has been selection
against dark skin in places where levels of ambient sunlight
are low so as to prevent rickets when the diet is poor in
vitamin D (Robins, 1991), whereas there is selection for
dark skin in geographical areas of high UV-exposure to
prevent sun-burn/skin cancer, photolysis of folate and
protection of the sweat glands to ensure the integrity of
somatic thermoregulation (Jablonski and Chaplin, 2000).
There have been conflicting molecular inferences made
when using the MC1R variant coding region alleles with
regard to the mechanism of selection operating at this
locus during human evolution. In an early study the
MC1R coding region was examined in 121 individuals
sampled from several different geographical population
groups, but with a focus on the Asian community (Rana et
al., 1999). They reported changes in five non-synonymous
sites and one synonymous site together with the consensus
allele and concluded that as the pattern of MC1R diversity
was lower in African populations than in those from North-
ern Europe that this was due to diversity selection. In
contrast, a larger study (Harding et al., 2000) examining
ten non-synonymous and six synonymous sites together
with the wildtype allele in 776 samples from Africa, Asia
and Europe, reported that the most common MC1R haplo-
type was the consensus allele, and that the root of all human
MC1R diversity is a haplotype common in Africa and equa-
torial Asia but found at low frequency elsewhere. The low
MC1R diversity in the African population was interpreted
by this group as being due to the functional constraints
operating to maintain cutaneous pigmentation, where any
divergence from dark skin produced through MC1R gene
mutation and corresponding loss of eumelanogenesis
appears to be evolutionarily deleterious. However, compar-
ison of the level of divergence between the chimp and
human MC1R sequences together with selective ascertain-
ment of functional mutations associated with red hair
suggested that neutral selection has occurred in Europe,
with a relaxation of the strong functional constraints that
operate in Africa. There were several caveats to this conclu-
sion, as nucleotide diversity at MC1R is several times higher
than the average nucleotide diversity in human populations.
High nucleotide diversity with common variation at non-
synonymous sites suggests that MC1R variation is an adap-
tive response to selection for different alleles in different
environments (Owens and King, 1999).
The characterisation of the MC1R locus and examination
R.A. Sturm et al. / Gene 277 (2001) 49–62 59
12. of its polymorphic states in different human populations will
provide insight into the selective forces operating in the
evolution of modern humans. It is the first such human
pigmentation gene to allow such a genotype-phenotype
analysis and evolutionary study, however genes of equal
importance may exist in the human genome, remain to be
identified and examined. The availability of the total human
genome sequence, combined with functional genomic
analysis, will hopefully provide these tools in the near
future.
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