The Pennsylvania State University The Graduate School College of the Liberal Arts HUMAN SKIN PIGMENTATION VARIATION: A PHENOTYPIC, GENOTYPIC, AND EVOLUTIONARY PERSPECTIVE A Thesis in Anthropology by Heather Lynne Norton © 2005 Heather Lynne Norton Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy August 2005 ii The thesis of Heather Lynne Norton was reviewed and approved* by the following: Mark D. Shriver Associate Professor of Biological Anthropology Thesis Advisor Chair of Committee Kenneth M. Weiss Evan Pugh Professor of Biological Anthropology and Genetics Jeffery A. Kurland Associate Professor of Biological Anthropology and Human Development Kateryna Makova Assistant Professor of Biology Dean R. Snow Professor of Anthropology Head of the Department of Anthropology *Signatures are on file in the Graduate School iii ABSTRACT Skin pigmentation varies both within and between human populations. Broad patterns of variation between human populations tend to follow geographic clines that are highly correlated with the amount of UVR striking the surface of the earth. Many have suggested that the broad patterns of human pigmentation variation reflect changes due to natural selection while others feel that sexual selection is a better explanation. The purpose of this dissertation is to improve current understanding of localized patterns of pigmentation variation in Island Melanesia, the genes underlying that variation, and the potential role that natural selection has played in determining global patterns of pigmentation. To assess phenotypic variation across a localized geographic region I analyzed quantitative measures of skin and hair pigmentation in 1135 Island Melanesians. While skin pigmentation variation in the region has likely been constrained by natural selection the patterns of variation that I observed within and between islands suggests that localized patterns of variation may have been influenced by genetic drift and/or sexual selection. The population history of the region is characterized by intermittent waves of migration and long periods of isolation and drift in some islands. This has led to complex population substructure across the region that complicates the interpretation of genotype- phenotype associations that I observed between the OCA2 and ASIP genes and skin pigmentation and the MC1R gene and hair pigmentation. To control for this stratification in future studies I proposed a method using a panel of neutral markers that will be able to differentiate between different subpopulations in the region iv Pairwise locus-specific FST is used to detect signals of selection in six pigmentation candidate genes in six geographically diverse populations. Four of the six genes show high pairwise FST values that may be indicative of population divergence due to selection. All four were confirmed to be associated with normal skin pigmentation variation using admixture mapping. I also typed these four loci in the CEPH-diversity panel to confirm these signals of selection. Two of these genes, OCA2 and ASIP, are associated with pigmentation differences between lightly and darkly pigmented populations. The distribution of the light and dark alleles at OCA2 A355G in the CEPH- diversity panel suggests that polymorphism at OCA2 may be quite old; the high frequency of the light OCA2 allele in the Khoisan sample is consistent with this interpretation. The distribution of the light and dark alleles at ASIP A8818G in this sample set suggests that the ASIP dark allele is most common in Africa and occurs at much lower frequencies elsewhere, including at least some (but not all) Island Melanesian populations. MATP and TYR show strong signals of European-significant divergence, suggesting that lighter skin in European populations may be due to mutations independent of those associated with lighter pigmentation in East Asian populations. This is consistent with the genotyping results in the CEPH-diversity panel, which demonstrated that the light allele in each gene occurs at its highest frequency in Europe and declines rapidly as one moves east and south. This dissertation has highlighted the potential for localized variation in human skin and hair pigmentation to have been shaped by genetic drift or sexual selection while still being constrained by natural selection. It has also demonstrated the importance of being able to control for population stratification in genotype-phenotype association v studies. Lastly, it used a locus-specific FST-based method to identify pigmentation candidate genes that may have been subject to selection. vi TABLE OF CONTENTS List of Figures..............................................................................................................ix List of Tables ...............................................................................................................xi Acknowledgements......................................................................................................xiii Chapter 1 Background and Introduction.....................................................................1 Introduction...........................................................................................................2 Phenotypic Variation ............................................................................................6 Pigmentation and Racial Classification................................................................10 Origins of Phenotypic Variation...........................................................................13 Photoprotection..............................................................................................14 Vitamin D Hypothesis ...................................................................................15 Folic Acid Hypothesis ...................................................................................16 Concealment..................................................................................................17 Thermoregulation ..........................................................................................17 Disease Resistance.........................................................................................19 Melanin Biosynthesis............................................................................................19 Pigmentation Candidate Genes.............................................................................22 Conclusions...........................................................................................................27 Literature Cited.....................................................................................................28 Chapter 2 Skin and Hair Pigmentation Variation in Island Melanesia.......................46 Introduction...........................................................................................................47 Materials and Methods .........................................................................................50 Measurement .................................................................................................51 Island Classification ......................................................................................53 Linguistic Classification................................................................................53 Neighborhood Classification.........................................................................55 Latitude/longitude Classification...................................................................56 Statistical Analysis ........................................................................................58 Results...................................................................................................................58 Sex-based Differences...................................................................................58 Effects of Increasing Adult Age....................................................................59 Linguistic Phylum .........................................................................................60 Island .............................................................................................................62 Neighborhood................................................................................................63 Latitude and Longitude..................................................................................67 Interaction Effects .........................................................................................68 Discussion.............................................................................................................68 Sex-based Differences...................................................................................68 vii Age ................................................................................................................70 Linguistic Phylum .........................................................................................72 Island and Neighborhood Variation ..............................................................75 Latitude and Longitude..................................................................................85 Conclusions...........................................................................................................88 Acknowledgements...............................................................................................89 Literature Cited.....................................................................................................90