Exploring an age-old question: Can we demystify skin color?

by Dr. Ang Khai Chung

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In February 2009, while I was still a graduate student at Universiti Kebangsaan Malaysia (UKM), I received a call from the Director of Academic Heritage Museum, Emeritus Prof. Dato’ Dr. Hood Salleh, to be present at his office. He introduced me to three professors, two from Penn State College of Medicine, and one from University of Oxford. That fateful meeting changed the focus of my research and career. By June 2009, I was in Hershey, Pennsylvania, joining Distinguished Prof. Dr. Keith Cheng in the quest to complete the global story of human skin colour variation. Assoc. Prof. Dr. Badrul Munir Md Zain and Prof. Dato’ Dr. Mahani Mansor Clyde, who were my PhD supervisors from UKM, continue to be our collaborators in this project.

The genetic basis of the variation in skin colour across the globe is an age-old mystery. Human evolution from darker skin (the ancestral state), towards lighter skin colours involved different genetic mechanisms in people of European vs. East Asian ancestry. The dark skin of African populations is protective in regions with high solar ultraviolet exposure. In contrast, the light skin of Europeans has a selective advantage in northerly latitudes due to higher sun-dependent generation of vitamin D. However, European skin is associated with a 10-20 fold increased risk of melanoma, the deadliest form of skin cancer [1]. Surprisingly, East Asians, although light-skinned, have very low risk of melanoma: their rates of disease are comparable to Africans. In addition, they do not carry the pervasive European light skin colour genes (SLC24A5 & SLC45A2), which means that they must carry a genetic variation that functions similarly.

The Orang Asli children watching a movie as they wait patiently in the hall for their sample to be taken by Dr. Ang and his team.
The Orang Asli children watching a movie as they wait patiently in the hall for their sample to be taken by Dr. Ang and his team.

Intuitively, it should be easy to map for genes responsible for the light skin colour in – for example – East Asians. However, the results will be muddling since skin colour is a trait contributed by multiple genes. In addition, among East Asians, there is a degree of variation in skin colour caused by various polymorphisms, in addition to the primary East Asian skin colour gene. There is a need for one or more populations that are admixed for ancestral and East Asian ancestry, but with minimal European contribution. This requirement is fulfilled by the Senoi, one of three indigenous tribes of Peninsular Malaysia collectively known as the Orang Asli.

Three weeks after joining Dr. Keith’s lab as a postdoc, I was back in Malaysia to collect blood samples of the Orang Asli. For a year, I travelled with various health nurses and students to collect blood samples and also phenotypic skin colour reading of their inner arm. During that period, I criss-crossed Peninsular Malaysia, visiting Orang Asli villages to collect as many samples as possible. Not only had I travelled using a Ford Explorer 4WD and a van, but I also drove my trusty Proton Iswara Aeroback that had served me well during my graduate school to many villages. I am thankful for Dr. Badrul’s students who volunteered and accompanied me during these trips, some of which lasted just a few hours, and others, days! Sadly, I did not have any students volunteering to accompany me the second time. Maybe I worked them too hard, or maybe the adventure of digging out our transport stuck in mud and showering in the river was not their idea of fieldwork!

 The nurses and personnel from Jabatan Hal Ehwal Orang Asli that helped out during one of Dr. Ang’s fieldtrips.
The nurses and personnel from Jabatan Hal Ehwal Orang Asli that helped out during one of Dr. Ang’s fieldtrips.

I collected 492 samples with wide ranges of skin colour [2]. Genetic analysis of these samples confirmed visual observations that, by average, Negrito has the darkest, Proto-Malay the lightest, and Senoi has intermediate and widest range of skin colour. We also found 12.6% of our samples has European alleles (SLC24A5A111T and/or SLC45A2L374F). This result provides the molecular evidence for the possibility of Orang Asli having admixture from South Asians and Europeans. Historically, the most likely origins of European admixture are British, Dutch and Portuguese [3], who are mostly homozygous for both derived alleles.

In more than one occasions during fieldwork, I met families with various ancestries. One particular family from Temerloh, Pahang, has a matriarch who is of Chinese and Senoi ancestry, while their children are married to an Indian, and another to a Chinese. On another field trip to a village near Taman Negara, I met a mother with a child whose father is of European ancestry.

The genetic basis of the variation in skin colour across the globe is an age-old mystery

We have done a number of whole-genome and exome sequencing using our Orang Asli samples that do not carry the European alleles. Our collaborator, Dr. Chan Kok Gan from High Impact Research Center, Universiti Malaya, did part of the whole-genome sequencing that we are currently analysing.

Back in the laboratory in Hershey, once I have identified candidate genes responsible for lightskinned colour, I will remove these genes from zebrafish, a popular pet store fish and now an increasingly valuable animal model for biological research. If a gene codes for lighter skin colour, then the zebrafish will have a lighter colour.

But here we hit a roadblock: using just one population left us with more possibilities than we could test experimentally. In order to reduce the number of candidate genes to a manageable size, we need to find another population with a similarly preserved, ancient gene pool. This is trickier than it might seem. Globalisation means there are less isolated, indigenous populations with a similar genetic ancestry to the Orang Asli. Fortunately, there is still one such population on the Caribbean island that Christopher Columbus spotted over 500 years ago, and locals have now dubbed it “Nature Isle”. The island is the Commonwealth of Dominica, home to the indigenous Kalinago people. They live in a reserve territory and have the West African and Amerindians/ East Asians ancestry that we need to successfully mapped these genes.

Globalisation means there are less isolated, indigenous populations with a similar genetic ancestry to the Orang Asli

I first visited the Kalinago tribe in 2013 for a month. In 2014, I returned for 6 weeks to collect saliva samples from them that will allow meaningful data comparison with the Malaysian tribe and help narrow down our list of candidate genes considerably. We hope, through using these two geographically distant populations, we will be able to narrow down the pool of polymorphisms that are responsible for the lightskin colour in the East Asians.

Dominica, with its charm and allure, also proved to be a physically challenging but memorable sampling experience. Home to the second largest boiling lake in the world, Dominica features lush mountainous rainforests and the Kalinago territory sits on the rugged east region of the island. My previous experiences in navigating and freeing mud-stuck 4WD, proved to be useful in many occasions here.

Hiking in Dominica to one of the Kalinago houses with local nurses to collect samples and conduct skin colour reading.
Hiking in Dominica to one of the Kalinago houses with local nurses to collect samples and conduct skin colour reading.

I continue to love what I am doing as a geneticist. During my graduate school, I studied the relationships of the Orang Asli tribes, and now how humans, globally, are also related. Humans migrated out of Africa, towards South Asia, then separately towards Europe and East Asia. The migration from East Asia, through the Bering Strait to the Americas made us more related than we realise. For me personally, a chance for me to meet all these wonderful people made me appreciate human relationships in a ‘molecular’ way. Every little thing they do, be it by offering a coconut to sharing a part of their catch-ofthe-day with me, motivates me to do what I do in the laboratory. Also, who knows what other adventures I may encounter as I seek to understand, and ultimately hope to demystify human skin colour!

This article first appeared in the Scientific Malaysian Magazine Issue 10. Check out other articles in Issue 10 by downloading the PDF version for free here: Scientific Malaysian Magazine Issue 10 (PDF version)

References

[1] Howlader et al. SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/

[2] Ang et al. (2012) Skin Colour Variation in Orang Asli Tribes of Peninsular Malaysia. PLoS ONE 7(9): e42752.

[3] Carey I (1976) The administration of the Orang Asli. Orang Asli: The Aboriginal Tribes of Peninsular Malaysia. Kuala Lumpur: Oxford University Press. 283–304.

About the Author

Dr. Ang Khai Chung, an evolutionary geneticist, is a Research Associate at Jake Gittlen Laboratories for Cancer Research, Penn State University. He is also the Scientific Director of the Zebrafish Functional Genomics Core at the same university. He continues to travel to various parts of the world to study migration, adaption, phylogenetic relationship and skin pigmentation of human populations. He can be reached at [email protected] Find out more about Khai Chung at http://www.scientificmalaysian.com/members/khaichung/ and http://www.chenglab.com/people/khai-chung-ang/.



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