Race, Genetic Ancestry, and Health: A Direction for Anthropological Genetics in the 2010′s?

Batai, K. and R. A. Kittles (2013). “Race, Genetic Ancestry, and Health.” Race and Social Problems 5(2): 81-87.

In June 2013 edition of Race and Social Problems journal, we published this review article.  I think, for anthropologists who have a training in genetics, it is an interesting direction that we should explore more.  When I was almost done with my dissertation work, I began to think what I could do after I got my degree.  I was dissatisfied with anthropological genetics.  Although I was excited to investigate human genetic variation and evolution and had fun learning and teaching (I am still interesting in these topic and continue to explore), I felt “so what?”  I understand the importance of understanding migration history and genetic variation in the world, but I felt that anthropologists and many people, mostly wealthy people, are interested in human past and variation mostly only for their intellectual interests.  Who really care about our findings?  Are they really useful knowledge?

Then, I began thinking about using anthropological perspectives and methods to help other people.  I contacted my current mentor, Dr. Rick Kittles, to see if I could do genetic research on health disparities.  I learnt genetic epidemiology, a study of roles of genetics in determining or influencing disease risk in families or populations.  In the genetic epidemiology, a lot of population genetics knowledge and methods are applied to the basic epidemiological research design.  More recently, genetic epidemiologists are showing interests in gene and environment interactions.  Here, environment refers to lifestyle and socio-cultural factors.  Gene and environmental interactions is basically what anthropologists call “bio-cultural perspective,” but genetic epidemiologists think more statistically.

In the U.S., we see a great racial health disparities.  Differences in access to health care and health screen can explain a part of health disparities, but there are more complex, genetic, biological, and socio-cultural factors that are intertwined with ‘race.’  Anthropologists are trained to understand this complex relationship.  We can bring different insights in the genetic research of health disparities from scientists who were trained in other fields, and we can contribute to biomedical science in unique ways.

Genes associated with human pigmentation traits in Genome-Wide Association Studies (GWAS)

Although there are many issues, Genome-Wide association study (GWAS) has been a powerful method to identify genetic variants associated with phenotypic traits.  GWAS is generally used to find genetic variants associated with disease, but it also found variants associated with anthropometric traits, such as height and BMI.  Also, there are several GWAS mainly among people of European descents aiming to find genetic variants associated with pigmentation characteristics (hair, eye, and skin color, freckles, and skin sensitivity to sun or tanning ability) (e.g., Eriksson, 2010; Han, 2008; Kayser, 2008; Liu, 2010; Nan, 2009; Sulem, 2008; Sulem, 2007)   These GWAS identified variants associated with pigmentation characteristics on SLC45A2 (Chr5), IRF4 (Chr6), TYRP1 (Chr9), TYR (Chr11), KITLG (Chr12), SLC24A4 (Chr14), OCA2/HERC2 (Chr15), MC1R (Chr16), and ASIP (Chr20).  These studies showed very strong association of variants in these genes with hair color, eye color, freckles, sensitivity to the sun, and tanning ability.

However, because the skin color does not vary much in European populations, these GWAS were not very successful showing the association between genetic variants and skin pigmentation, and only one of these studies, in which people of non-European descents were included, successfully showed the association between skin color and an IRF4 variant (Han et al. 2008).

Another GWAS among South Asians demonstrated the association of skin color with variants in two genes (SLC45A2 and TYR), but the study also found that another gene, SLC24A5 (Chr15) is associated with skin color (Stokowski et al. 2007).  The association of SLC24A5 variants with skin color in African Americans has been reported previously (Lamason et al. 2005).  More recently, Kenny et al. report that an amino acid change in TYRP1 associated with blond hair among Solomon Islanders (Kenny, 2012).

Identifying these genetic variants is important not only to understand major human phenotypic variation and the mechanism of evolution of pigmentation traits, but also to find variants that may be associated with skin cancer and to understand the risk factors for vitamin D deficiency.  Because of admixture, African Americans exhibit a great range of skin color, so they are desirable for genetic study of skin pigmentation.

Eriksson, N., J. M. Macpherson, et al. (2010). “Web-Based, Participant-Driven Studies Yield Novel Genetic Associations for Common Traits.” PLoS Genet 6(6): e1000993.

Han, J., P. Kraft, et al. (2008). “A Genome-Wide Association Study Identifies Novel Alleles Associated with Hair Color and Skin Pigmentation.” PLoS Genet 4(5): e1000074.

Kayser, M., F. Liu, et al. (2008). “Three Genome-wide Association Studies and a Linkage Analysis Identify HERC2 as a Human Iris Color Gene.” American Journal of Human Genetics 82(2): 411-423

Kenny, E. E., N. J. Timpson, et al. (2012). “Melanesian Blond Hair Is Caused by an Amino Acid Change in TYRP1.” Science (New York, N.Y.) 336(6081): 554.

Lamason, R. L., M. A. Mohideen, et al. (2005). “SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans.” Science (New York, N.Y.) 310(5755): 1782-1786.

Liu, F., A. Wollstein, et al. (2010). “Digital Quantification of Human Eye Color Highlights Genetic Association of Three New Loci.” PLoS Genet 6(5): e1000934.

Nan, H., P. Kraft, et al. (2009). “Genome-Wide Association Study of Tanning Phenotype in a Population of European Ancestry.” J Invest Dermatol 129(9): 2250-2257.

Stokowski, R. P., P. V. K. Pant, et al. (2007). “A Genomewide Association Study of Skin Pigmentation in a South Asian Population.” American Journal of Human Genetics 81(6): 1119-1132.

Sulem, P., D. F. Gudbjartsson, et al. (2008). “Two newly identified genetic determinants of pigmentation in Europeans.” Nat Genet 40(7): 835-837.

Sulem, P., D. F. Gudbjartsson, et al. (2007). “Genetic determinants of hair, eye and skin pigmentation in Europeans.” Nat Genet 39(12): 1443-1452.

TYR and OCA2: two genes associated with skin pigmentation in African Americans

Shriver, M. D., E. J. Parra, et al. (2003). “Skin pigmentation, biogeographical ancestry and admixture mapping.” Human Genetics 112(4): 387-399.

Previously, I wrote about correlation between West African Ancestry (WAA) estimates and skin color among African Americans and African Caribbeans (here).  They used 33 ancestry informative markers (AIMs) that have large frequency differences between African and European populations.  Three of these markers are candidate genes for skin pigmentation (TYR, OCA2, and MC1R), so they examined, if these skin color candidate genes are associated with skin color (Melanin Index measure using the DermaSpectrometer).

Two pigmentation candidate genes (TYR and OCA2) and many other AIMs were associated with M Index without adjusting for WAA.  When they adjust for WAA, only TYR remained significant.  Then, they used ADMIXMAP, admixture mapping software, to find segments of genome that are associated with skin pigmentation because of the differences in their genetic ancestry.  In this analysis, TYR and OCA2 are associated with skin color, but not MC1R.

Their analyses demonstrated that two pigmentation candidate genes (TYR and OCA2) likely to cause differences in skin color between African and European populations.  TYR produces an enzyme, tyrosinase, which catalyzes the first two reactions in the melanin synthesis pathway.  Mutations in OCA2, or P gene, cause the common type of albinism.

I hope to review follow-up research projects later to further understand genes involved in production of dark skin in African and African American populations.

Geneticists tend to overemphasize the importance of genetic factors for resolving the ethnic health disparities

Sankar, P., M. K. Cho, et al. (2004). “Genetic Research and Health Disparities.” JAMA: The Journal of the American Medical Association 291(24): 2985-2989.

We (geneticists, media, students, etc) tend to focus on the genetic aspects of research and overemphasize on the importance o f genes on human evolution, health, etc.  As an anthropologist, I tried to be careful about it and I tried to consider socio-cultural aspects as well, but I admit that I often focus on genetic aspects more than socio-cultural aspects.  In this article, Shankar et al (2004) argue that overemphasizing genetic factors in ethnic health disparities research can have negative impacts.

Although they are well aware of many factors causing ethnic health disparities, researchers tend to overemphasize the potential benefits of their genetic research resolving the health disparities problems.  One of the reasons why geneticists overemphasize on genetic factor is their funding.  U.S. National Human Genome Research Institute (NHGRI) took an initiative to address the health disparities.  The negative consequence is that the attention shifts away from real social-cultural problems that need to addressed, but are difficult to fix, such as poverty, unequal access to health care, diet, etc.  Also, overemphasizing genetic factors may reinforce the racial rebelling and stereotyping.

It is true when we write grant proposals and papers, we have to say that our findings from genetic research can uniquely contribute to resolve the existing problems.  We do not mean to overemphasize, but it is important to note that research findings can be very important.  In addition, we scientists loose objectivity and tend to thick findings from our research project is so special.

The correlation and variability of African genetic ancestry and skin color among African Americans

Parra, E. J., R. A. Kittles, et al. (2004). “Implications of correlations between skin color and genetic ancestry for biomedical research.” Nature Genetics 36: S54-S60.

Shriver, M. D., E. J. Parra, et al. (2003). “Skin pigmentation, biogeographical ancestry and admixture mapping.” Human
Genetics 112(4): 387-399.

 

These articles are getting little old, but their findings are interesting and important.  They examined the correlation between skin pigmentation and estimated African ancestry.  Using a DermaSpectrometer, skin color measurements (melanin index) were taken inner part of arm where the UV rarely hit.  African genetic ancestry was estimated using 33 ancestry informative markers (AIMs).

They found that estimated African ancestry was significantly correlated with melanin index, as expected, but more interestingly melanin index and estimated African ancestry vary greatly.  This means that functional genes that determine the skin color are located somewhere else on the genome and the allele frequencies of these skin pigmentation gene variants differ greatly between ancestral populations (e.g., Africans and Europeans for African Americans).  They explain that because African Americans are recently admixed, we are observing the results of the population structure that existed in their ancestral populations.

Skin color is a very heritable trait.  If skin color is determined largely by genes, one may expect to see small variability of melanin index of African Americans with 100% African ancestry, but that is not the case.  They observed a great variation in melanin index of African Americans with 100% African ancestry.  Because skin color is polygenic traits, there are many different genes that determine the skin color, so natural variation in skin color should exist in Africa.

The research was conducted when only a few candidate genes linked to skin color were found, and they confirmed that two candidate genes for skin pigmentation, TYR and OCA2 are significantly associated with melanin index in African Americans (actually, Shriver and colleagues were working on other projects looking for skin color genes when these articles came
out).

How variable is the skin color and melanin index in Africa?  There are research projects that demonstrated that skin color varies among sub-Saharan African populations, but has anybody systematically investigated how variable the skin color is within an African population?

Genetic evidence of Indian Ocean slave trade from Indian Siddis

Shah, Anish M., R. Tamang, et al. (2011). “Indian Siddis: African Descendants with Indian Admixture.” American Journal of Human Genetics 89(1):154-161.

Compared to Tran-Atlantic slave trade, Indian Ocean Slave trade is less known, maybe less understood, but has longer history.  Indigenous Africans were captured and traded by other Africans, Arabs, and Europeans.  Some of the slaves were sent to Middle East and South Asia.  Sub-Saharan African mtDNA haplogroups have been found among the Middle Eastern populations and the frequencies range from 9 to 34%.  Sub-Saharan African Y chromosome haplogroups are rare, but are also found among the Middle Eastern Arab populations.  Richards et al. (2003) and Quintana-Murci et al. (2004) argue that these sub-Saharan African mtDNA haplogroups were brought to the Middle East and reached South Asian through the Arab slave trade.  African females were incorporated into Islamic societies, but African males did not have much chance of reproduction.

In this article, Shah et al. (2011) demonstrate that Siddis, or Habishis, from India, the descendants of slaves from Africa, have genetic characteristics of sub-Saharan Africans.  They genotyped 850,000 autosomal SNPs, 32 Y chromosome biallelic markers, and 17 Y chromosome STR and sequenced mtDNA hypervariable region I.

Among Siddis, sub-Saharan genetic contribution estimated based on autosomal SNPs is quite large ranging 62.3-74.4% and they are plotted more closely to HapMap Yorubans than Indians, Europeans, or Asians on the PC plot.  Contrary to the previous studies, they found more male sub-Saharan contribution to the Siddis than female contribution.  You could expect this from the Indians marriage rule of endogamy, but gene flow between the Siddis and neighboring ethnic groups or communities was unidirectional.  They found South Asians and Eurasian genetic
contribution to the Siddis from their neighboring communities, but they did not find Sub-Saharan genetic contribution from the Siddis to neighboring ethnic groups.

Genetic studies to understand slave trade are usually conducted using uniparental markers (mtDNA and Y-chromosome).  The molecular genetic and analytical techniques to trace the origin are relatively simple, but the problem is that you are tracing only two lineages (maternal and paternal) out of thousands of possible ancestors for a particular individual.  By analyzing autosomal markers, you are getting genetic information of all the ancestors.  Recent advancement in molecular genetics allows researchers to genotypes many single nucleotide polymorphisms (SNPs) per individual.  Sometime in the future, it will be possible to genotype over 1 million SNPs per individual without huge cost.  Down side of this is that it requires more sophisticated statistical and analytical techniques.

References:

Quintana-Murci L, Chaix R, Wells S, Behar DM, Sayar H, Scozzari R, Rengo C, Al-Zaheri N, Semino O, Santachiara-Benerecetti AS, Coppa A, Ayub Q, Mohyuddin A, Tyler-Smith C, Mehdi SQ, Torroni A, and McElreavey K (2004) Where west meets east: the complex mtDNA landscape of southwest and Central Asian corridor. American Journal of Human Genetics 74:827-845.

Richards M, Rengo C, Cruciani F, Gratrix F, Wilson JF, Scozzari R, Macaulay V, and Torroni A (2003) Extensive female-mediated gene flow from Sub-Saharan Africa into Near Eastern Arab Populaitons. American Journal of Human Genetics 72:1058-1064.

Evolution and human skin color: how do Jablonski and Chaplin explain skin color variation?

Jablonski, N. G. and G. Chaplin (2002). “Skin Deep.” Scientific American October: 74-81.

I have written about Jablonski and her work on evolution of skin color and roles of Vitamin D before (here).  This article published in Scientific America in 2002 is today widely read by undergraduate anthropology students.  In this article, Jablonski and Chaplin reject that skin cancer is the major evolutionary factor for dark-colored skin in Equatorial areas.  They suggest that
Vitamin D and folic acid are two important factors of biological adaptation responding varying level of UV radiation, and cultural adaptation and recent migration were also important factors understanding the observed geographical pattern of skin color.

The people living in equatorial areas, whether they have dark colored or light colored skin, can get enough sun light to synthesize Vitamin D.  However, they have to have dark colored skin to protect them from harmful UV radiation.  Overexposure to the UV radiation can cause skin cancer, and skin cancer is deadly to the individuals, but it does not reduce reproductive success of individuals, because people usually have skin cancer after reproductive age.  Instead, overexposure to UV ration may lead to reduced reproductive success of individuals, because overexposure to UV radiation may reduce the level of folate, an essential Vitamin B, in their blood.  The low level of circulating folate is associated with higher risk of babies with spina bifida and low sperm counts.

For those people living in high latitude areas, where they can get enough sun light to synthesize Vitamin D only in limited time of the year, having light-colored skin is advantageous.  In high latitude areas, people with dark colored skin tend to have low level of circulating Vitamin D, and low level of circulating Vitamin D is associated with problems with bone development and maintenance, and immune system, etc (see here).

Probably, her major contribution is to publicize how evolution can explain skin color variation around the world and to demonstrate that the field of anthropology can help people appreciate the genetic and biological variation that exists in the world.

Human populations in genetic studies and ethnic grouping in Africa

In human population genetic and anthropological genetic studies, ethno-linguistic grouping is often used to define populations, sample units, but MacEachern (2000) and Braun and Hammonds (2008) have criticized the use of ethno-linguistic grouping in genetic studies, particularly for African societies.  In this post, I just want to put up a note on why ethno-linguistic grouping is problematic.

First, Fried (1968) noted that there is no such thing as tribes that Americans and Europeans think of.  Following this view, Chimhundu (1992) and many others believe that ethnic identity in Africa was artificially created after the European contact.  European colonial governments and missionaries categorized people based on cultural similarities and territories that people occupy, but they did not understand how African societies were organized and there were no fixed boundaries.  In some cases, many different groups were categorized under a single ethnic group (Chimhundu, 1992), while in other cases, some groups shifted their ethnic affiliation responding to political and economic changes (Niehaus, 2002).  So, a collective identity as Shona, Tsonga, Shangaan, or Mijikenda did not exist before the European contact.

Second, because ethnic groups were artificially created by Europeans, people who speak different languages were grouped into a single ethnic group (Errington, 2001).  Europeans viewed linguistic diversity in a community as a sign of barbarism or savage, so they chose a few languages as lingua franca.  These languages spread reducing the linguistic diversity.

Should we keep using ethno-linguistic grouping in genetic studies?  Are there better ways to define sampling units?

References:

Braun, L. and E. Hammonds (2008). “Race, populations, and genomics: Africa as laboratory.” Social Science & Medicine 67: 1580-1588.

Chimhundu, H. (1992). “Early missionaries and the ethnolinguistic factor during the ‘invention of tribalism’ in Zimbabwe.” Journal of African History 33: 87-109.

Errington, J. (2001). “Colonial Linguistics.” Annual Review of Anthropology 30: 19-39.

MacEachern, S. (2000). “Genes, tribes, and African history.” Current Anthropology 41(3): 357-383.

Niehaus, I. (2002). “Ethnicity and the boundaries of belonging: reconfiguring Shangaan identity in the South African Lowveld.” African Affairs 101: 557-583.

Persistence of racial thinking in the online communities

There are arguments on Afrocentrism, Eurocentrism, and criticisms against these ethnocentrisms in the online communities, such as blogs and YouTube.  For example, some argue whether ancient Egyptians were black Africans or not, while others question if the first Europeans looked more like modern Africans or not.  Despite anthropologists, geneticists, and educators’ efforts to eradicate racial thinking among the public, I believe that these arguments exist because of persistence of racial, or typological thinking among the human population geneticists as well as the public.

Keita and Kittles (1997) argue that racial thinking, not racist thinking, persists in the studies of human evolution through use of phylogenetic trees to show evolutionary relationship of human groups and by estimating divergence time between major racial groups(e.g. Cavalli-Sforza et al., 1994; Nei and Roychoudhury, 1993).  Weiss and Long (2009) also argue that some human geneticists have replaced ‘old racial classification’ with more sophisticated scientific methods identifying human population clusters using multilocus genetic data and Structure-like population genetics methods (e.g. Rosenberg et al., 2002; Li et al., 2008). 

One underlying assumption that racial thinking and clustering approach is based on is relative reproductive isolation because of lack of gene flow (e.g., Andreasen, 2004; Cavalli-Sforza et al., 1994; Risch et al., 2002).  People, including human geneticists, with racial thinking believe that human populations have had very limited gene flow, where there are geographic barriers and linguistic, cultural, and political differences.  They also focus on biological, genetic, linguistic, and cultural differences between different groups, while assuming that there are genetic, cultural, and linguistic similarities within a human group.

However, many anthropologists and human geneticists believe that gene flow between different human groups is common and there are great biological, genetic, cultural, and linguistic variations even within small human populations (e.g., American Association of Physical Anthropologists statement on race; Livingston, 1962; Tishkoff et al., 2009).  Therefore, the clusters that human geneticists identified should not be equated with racial groups. 

So, where did the ideas of Black Africans, Europeans, Asians…. come from?  These ideas were developed based on stereotypes of people living in different parts of the world, probably very recently, after the colonial era (American Anthropological Association statement on race).  Ancient Egyptians and the first Europeans probably did not have self-identities as Africans, Caucasians, or Europeans.  Ancient Egypt was multi-ethnic state. 

Note: This also posted on the blog section of AnthroGenetics website.

Reference

American Anthropological Association Statement on Race

American Association of Physical Anthropologists – AAPA Statement on Biological Aspects of Race

Andreasen, R. O. (2004). “The cladistic race concept: a defense.” Biology and Philosophy 19: 425-442.

Cavalli-Sforza, L. L., R. Menozzi, et al. (1994). The History and Geography of Human Genes. Princeton, NJ, Princeton University Press.

Keita, S. O. Y. and R. A. Kittles (1997). “The persistence of racial thinking and the myth of racial divergence.” American Anthropologist 99: 534-544.

Li, J. Z., D. M. Absher, et al. (2008). “Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation.” Science 319(5866): 1100-1104.

Livingstone, F. B. (1962). “On the non-existence of human races.” Current Anthropology 3: 279-281.

Nei, M. and A. K. Roychoudhury (1993). “Evolutionary relationships of human populations on a global scale.” Molecular Biology and Evolution 10(5): 927-943.

Risch, N., E. Burchard, et al. (2002). “Categorization of humans in biomedical research: genes, race and disease.” Genome Biology 3(7): comment2007.2001-2007.2012.

Rosenberg, N. A., J. K. Pritchard, et al. (2002). “Genetic Structure of Human Populations.” Science 298(5602): 2381-2385.

Tishkoff, S. A., F. A. Reed, et al. (2009). “The Genetic Structure and History of Africans and African Americans.” Science 324(5930): 1035-1044.

Weiss, K. M. and J. C. Long (2009). “Non-Darwinian estimation: My ancestors, my genes’ ancestors.”Genome Research 19(5): 703-710.

American Anthropological Association Statement on Race

Two years after AAPA’s statement of race, American Anthropological Association (AAA) also published their statement on the race.  Like AAPA statement of race, AAA statement of race follow the tradition of anthropologists and rejects the biological and genetic basis of racial classification.  There are also differences between AAPA and AAA statement of race.  While AAPA focuses on explaining the non-existence of biological race, AAA statement of race focuses on the historical, social, and cultural aspect of race.  In this post, as I did for AAPA statement of race, I will evaluate AAA race statement with new multilocus genetic data in mind.

First, it addresses that science does not support biological and genetic basis of the race.  A great amount of genetic variation exists within each racial group.  There is a great deal of overlapping of phenotypic variation, because the gene flow between different groups of humans is common.   Classification of humans based on physical characteristics is arbitrary and subjective.

Second, it reviews that historical context of how racial classifications are used and justified in the Western Societies.  Race as a way of categorizing people is developed during the colonial era and used to rationalize social and political relationship between Europeans and conquered indigenous groups and to legitimatize the socio-political power of Europeans.  Historical examples are numerous, including slavery in the U.S. and the Nazi Germany.

Finally, it stresses that today anthropologists understand that there is a great variation in human behavior, not because of genetic makeup, but because of culture, learned behavior.  

The basic argument is that concept of race is socially and culturally constructed.  However, they have to address why many genetic studies keep showing the genetic differences among human racial groups and why and how genetic and biological differences are maintained, if race is socially constructed.