Dr. Joseph L. Graves, Jr. Dean, University Studies & Professor of Biological Sciences, North Carolina A& T State

1. The Meaning of Race in Medicine12th Annual Summer Public Health Research Videoconference on Minority HealthUniversity of North Carolina at Chapel HillSchool of Public HealthJune 26, 2006 • Dr. Joseph L. Graves, Jr. • Dean, University Studies & Professor of Biological Sciences, North Carolina A& T State University. • Fellow, American Association for the Advancement of Science

2. For a fuller treatment see: • J.L. Graves, The Emperor’s New Clothes: Biological Theories of Race at the Millennium, Rutgers University Press, 2001, 2005; The Race Myth: Why We Pretend Race Exists in America, Dutton Press, author’s preface to the soft cover edition, 2005.

3. Note on Definitions: Biological Race • morphology (phenotype) • Geographical location • Population based (frequency of genes) Socially Constructed Race: Arbitrarily utilizes aspects of morphology, geography, culture, language, religion, etc. in the service of a social dominance hierarchy.

4. Carolus Linnaeus - 1735 • Introduces binomial classification system for organisms. He describes four sub-species of humans: Homo sapiensamericanus, the Americas; Homo sapienseuropaeus, Europeans; Homo sapiensasiaticus, Asians; and Homo sapiensafer, Africans. • He did not explain how or why these groups are different. He also includes Homo sapiens monstrosus, which included people with deformities, mythological giants, and the Khoikhoi people of southern Africa; and Homo sapiens ferus, which described wild children found abandoned in forests. • Relies on morphological/behavioral features, Europeans are gentle, optimistic and inventive, while Asians are stiff and greedy.

5. Naturalists of the 19th century naturalists used morphological traits to classify races: • Darwin doubted whether human races were real. • Describes the racial multiplication problem, 2 – 63 races named. • Calls human races, protean or polymorphic, in The Descent of Man, 1871. • Darwin pointed out that most of the physical differences noticed by naturalists could not have any significance, if so they would have been removed by natural selection. Charles Darwin

6. Linneaus and the 19th century naturalists were wrong because phenotypic characters are discordant. • The physical features used to define America’s social races do not reveal our evolutionary history, Cavalli-Sforza and Edwards 1964, and Montagu 1974. • Genes that control skin color are not linked to those that determine skull shape or body proportions. Fig 2.2.3, Cavalli-Sfroza, Menozzi, and Piazza., 1994

7. Populations have different combinations of physical traits. • The failure of physical variation to define races occurs because different portions of the genome are selected by different factors in any given environment. • For example, solar intensity may change consistently along a N – S gradient, this may impact some genetic systems, but not others. • Meanwhile, other portions of the genome may be impacted by the presence of a specific parasitic disease, different diets, different rain fall, or altitude.

8. By 1950 serious doubt existed concerning both morphological and geographical conceptions of race. UNESCO Statement of 1950 From the Preamble • Racial doctrine is the outcome of a fundamentally irrational system of thought and is in glaring conflict with the whole humanist tradition of our civilization. It sets at nought everything that UNESCO stands for and endeavors to defend. By virtue of its very Constitution, UNESCO must face the racial problem… • In the body: From the biological standpoint, the species Homo sapiens is made up of a number of populations, each of which differs from the others in the frequency of one or more genes… New York Times, July 17, 1950

9. Population subdivision is weak in humans. • Compared to other large bodied mammals, humans have little genetic differentiation between their populations. • Humans have considerable genetic overlap across the genome -- We have also maintained relatively high levels of gene flow throughout our history, Wright’s FST = 0.156. Black bar represents humans compared to other mammals, such as white tailed deer, gray wolves, or Grant’s gazelle; data from Templeton (1998, 2002.)

10. Estimate of gene flow between human subpopulations • Wright’s Fst for human data = 0.156 • We can calculate the effective population size and the migration rate for humans by the equation: Fst = 1/(4Nm + 1) • Thus Nm = 1.35 • Thus modern human genetic diversity can be explained by the long term average of 1.35 individuals per 25 years, or 13.5 per 250 years, or 135 per 2,500 years. • Thus sporadic movements that over long periods of time that average out to these values could easily explain human genetic diversity. Fig. 2.15.1, Cavalli-Sfroza, Menozzi, and Piazza 1994.

11. Isolation by distance Humans best fit a gene flow, isolation by distance model, Templeton, 2002. This means that human populations that live closest to each other, share the most genetic variation in common. Figure 2.3 Templeton 2002

12. Human migration 101 • Anatomically modern humans evolve in Africa > 160,000 ybp. • Some leave Africa sometime around 75,000 - 55,000 ybp. • Replace Neanderthals in Europe and archaic humans around the world. • Arrive in Western hemisphere between 34,000 and 18,000 ybp. • Multiple migrations in different pre-historic periods, followed by different migrations in historical periods.

13. Polymorphic alleles found in all world populations, 86% Polymorphic alleles unique to a given continent, 10% Polymorphic alleles unique to a specific local population, 4% Most genetic variation is shared between geographically separated populations

14. Nucleotide similarities • Identical twins: 10,000/10,000 • Siblings 9,995/10,000 • Unrelated individuals: 9,990/10,000 • Human/Chimp: 9,900/10,000 • Human/Flowering plant: 6,700/10,000 However, with a genome estimated at 3 billion base pairs, unrelated humans can be different at 3,000,000 base pairs.

15. Estimates of genetic distance are dependent upon how they are calculated. Methods that examine DNA directly reveal more variation than can be seen at the protein level, particularly if portions of the genome that are not coded are included. Coding sequences produce transfer RNA’s, ribosomal RNA’s, or proteins, while non-coding sequences include introns, regions that flank coding regions, regulatory sites, and pseudogenes. In Eukaryotes most of the genome is non-coding. For example, it has been estimated that as much as 95% of human DNA is non-coding.

16. Non-coding DNA and ancestry Genetic changes in introns and pseudogenes (often called “junk DNA”), do not face selection and therefore accumulate mutations freely. Thus, non-coding segments are exceedingly useful for establishing ancestry. This is because due to chance historical events, populations can differ in allele frequencies at these loci. Fst data from Tischkoff and Kidd, 2004

17. Non-coding DNA and ancestry II Rosenberg et al. Science 298, 2002 utilized an algorithm called structure. They examined the sequences of individuals from various populations and Showed they could be clustered in a variety of ways.

18. Non-coding DNA and ancestry III Tischkoff and Kidd 2004, Least Squared tree for 37 populations, using 80 loci with ~ 620 alleles. The populations used are described in Allele Frequency Database (ALFRED). However, ALFRED is still very incomplete, missing suitable data on many regions of the world, including North Africa. In addition, the populations had different characteristics, some were indigenous, while others had greater amounts of admixture.

19. Within Population Distribution in the Genetically Defined Clusters of Wilson et al. 2001. Wilson et. al. in Nature Genetics, 29: 265-69, 2001 using a panel of 39 microsatellite markers showed that genetic variants of drug metabolizing enzymes can be clustered into four groups. However the four groups did not match the common social definitions of race.

20. Actual membership in B Cluster This is true because the population sizes are different. Thus every genetically defined cluster will have significant numbers of Chinese, simply due to China’s size. If other populations are included, such as India, these figures would shift again. Thus, we should expect all suitably large populations to have people from all drug metabolizing clusters.

21. Greater numbers of microsatellite markers (326) were able to correlate self-identification with genetic clustering. Tang, et al. 2005 used Structure with K = 2, 3, 4 or more clusters. When K = 2, Chinese/Japanese emerged as a group from all others, K = 3, gives African Am., Eu. Am. & Mex. Am., & Chinese/Japanese; and K = 4 is shown above.

22. Structuring non-coding genetic variation weakly revealed candidate markers for hypertension. Approximately 5% of the markers tested showed any significant difference between normatensive and hypertensive individuals. For the Chinese sample it Was about 4.4%, Mexican American 5.7%, and European American about 4.3%. The paper did not report whether the significant markers were similar for all Populations tested.

23. Gene Flow & Admixture • There is a wide variety of admixture percentages in North Americans with African descent. • Recent measures suggest that the average African Americans has on average 17 - 20% European admixture. • Also there could be as much as 10% American Indian admixture. • Therefore, could be as much as a 30% probability of African American genetic predisposition actually originated in Asians and Europeans. • Remember also that Asians and Europeans began their genetic odyssey in Africa, hence at any specific locus, a European or Asian may have an allele that was originally African, as opposed to one that originated outside of Africa. Only 6% of the individuals in this study who self-identified as African American had a majority of their genetic markers indicating African Origin – this would differ by region. However, 93% of self-identified European Americans had the majority of their genetic markers originating in Europe. Self identified American Indians would show the African American pattern and at present, self-identified Asian Americans would show the European pattern, Sinha et al. 2006, NEJM, 354(4): 421-22.

24. However, populations differ in specific coding gene frequencies:phenylketonuria– mechanism, mutation/selection balance or genetic drift. Note, that while the Chinese and Japanese belong to the same genetic cluster as determined by SNP’s, they differ in orders of magnitude in phenylketonuria frequency and while Nigerians and Icelanders are in different clusters they have near identical frequencies of blood group O.

25. Summarized from Table 1, Tate and Goldstein, Nature Genetics 2004

26. Summarized from Table 1, Tate and Goldstein, Nature Genetics 2004

27. End Notes

28. The intellectual program of social dominance • The history of all hitherto existing society, is the history of individual and groups of males attempting to sub-ordinate other males and females (social dominance.) • Hierarchical society may have been fixed in our primate lineage: Orangutans, Gorillas, Chimpanzees, and humans. • Found in all societies that produced a social surplus, such as Egyptian, Greek, Roman, Aztec, Chinese, Japanese, etc. • Intellectual programs were developed to justify some groups garnering more of the society’s production than others. This ultimately translated into that group’s greater material well-being, such as health, emotional satisfaction, and reproductive advantage.

29. Any genetic explanation of intelligence would require that environments were equalized. No such equality of environments exists or has ever existed for minorities in America. Furthermore, this is impossible since by definition the social environment of minorities must be different from that of majorities. The environments are made even more disparate by the social dominance of the European population.

30. Affirmative action for the dominant population • The vast majority of federal and state government actions have differentially benefited people of European descent. • Consider the Indian Removal Act of 1830, the five civilized tribes were forced to give up the land that now comprises most of Tennessee, Georgia, Kentucky, and Mississippi. • They were forcibly moved west of the Mississippi River, 4,000 of 18,000 died during the “trail of tears.” • They were promised this land, “as long as the waters run and the grasses grow.” Well we know what happened to that promise.

31. Give me your huddled masses: so long as they are “white.” • US immigration policy was biased toward “races” that could be assimilated into America. • This meant in practice that 19th century immigration was to match the composition of the country in the 1824 census (mainly Anglo-Saxons, Irish, Swedes, Germans, and other northern Europeans. • After slave importation stopped, there was virtually no legal immigration of Africans or Afro-Caribbeans. • Congress passed the Chinese Exclusion Act in 1880. • Japanese immigration to the US begins in earnest in the early 20th century.

32. Governmental action creates modern America, leaves out non-whites • Housing act of 1949 makes homes affordable for the first time. • Between 1934 – 1962, FHA guarantees 120 billion dollars of home loans. • Less than 2% are made to non-whites. • The suburbs are born, housing values are determined by how “white” your neighborhood is.

33. Social dominance can increase risk of toxic exposure. Race/ethnicity, income, and home ownership (NJ, 2003.)

34. Social hierarchy harms those who are dominated • Neuroscience has begun to look at many genetic variants between individuals that correlate to behavior, such as addiction. • Cocaine addiction is linked to dopamine transporters, genetic variation exists in humans at these loci.

35. One type of such harm has been shown experimentally in other primates • Social subordinate Macaques were more likely to self-administer cocaine (addiction.) • This was lower in monkeys housed alone or who were socially dominant. • African American college students who reported suffering racist harassment were twice as likely to use tobacco daily, Bennett et al. 2005, AJPH. Morgan et. al. Nature Neuroscience, Vol. 5 No. 2, February 2002.

36. Studies of malnutrition in rats showed that maternal effects on adult health extended over several generations. We have already seen that differential stress exposure plays a role in predisposing some African Americans to hypertension. Offspring of alcoholic mothers show FA in their teeth, FA has been linked to lower IQ in college students. Numerous studies show that lasting adult pathology can result from stress in the maternal environment: Desai et al. 1995; Hales et al. 1996; Napoli et al. 1997; Waterland and Garza 1999; Mustillo, S. et al. 2004; Collins et al., 2004. Another recent study showed parental exposure to racial discrimination had negative impacts on the mental health of their pre-school aged children, Caughy et al. 2004. The impact of environmental differences is complex

37. Distribution of Sickle Cell Anemia Allele is discordant with “race.” • Distributed at high frequency in “Negroids and Caucasoids.” • Seen as “Black” disease in U.S. due to importation of slaves derived from W. Africa.

38. Malaria in the USA • Did the presence of the allele help “Blacks” fight off malaria relative to “Whites” in North America? • In the early 20th century, an estimate of Blacks heterozygous for the sickle cell trait was about 8%. • Yet, in 10 southern states, Blacks suffered 25/100,000 death rate v. only 7/100,000 for whites in 1921 – 1923 (who supposedly did not have the allele.) • Grover 1937, J. Negro Education (6), 281.

39. Genetic variation & hypertension • A number of gene loci have been associated with increased risk of hypertension. • AGT -- which codes for angiotensinogen a protein made by the liver and circulates in excess • ACE – angiotensin converting enzyme

40. Genetic variation & hypertension II • At the angiotensinogen locus the 235T mutant has tyrosine switched for methionine. • In Euro-Americans, 235T is associated with an increased risk of hypertension. • The 235T allele is found at a frequency of 85% in African Americans. • However, 235T is not associated with increased hypertension risk in Nigerians. Cooper, Rotimi, Ward 1999, pg. 42.

41. Genetic variation & hypertension III • At the ACE locus there is a common alu insertion polymorphism that affects the activity of this enzyme. • The D allele is characterized by an absence of these alu insertions, and thus have higher enzymatic activity. • The available evidence shows that the enzymatic activity of II, ID, and DD genotypes are similar in Nigerians, Jamaicans, and in the United States (all populations.) • Hence the deletion genotypic doesn’t seem to be influenced by “racial” background. • Source: R.S. Cooper (1997).

42. Genetic variation and hypertension • There are at least 33 genetic systems with > 63 loci involved in hypertension predisposition. • In studies on hypertension published between 1997 – 2003, only 2/10 found frequency differences in genetic variants in the direction of the proposed health differential. • In 8/10 studies, genetic variation existed, but it was not in the direction of the hypertension rates seen in America!

43. Hypertension III • Genetic variation in doesn’t explain hypertension differentials: • angiotensin converting enzyme • Angiotensinogen I and II • a- and b- adrenergic receptors • Plasma kallikrein • G protein-b3

44. b2-adrenergic polymorphismsThe gly16 variant has been associated with hypertension in Afro-Caribbean’s and Norwegians, but not African or European Americans. The frequency of the gly16 variant was slightly higher in European Americans it was not significantly different between the normal and hypertensive in either group.

45. Hypertension? • Actually, when hypertension rates are stratified by socioeconomic status, the differential is located amongst African Americans in the higher categories. • This is means that the hypertension difference results from a biological response to social/cultural factors (e.g. control racism, reduce hypertension differential.) • Neser et al. 1986; Broman 1989; Calhoun 1992; Light 1995.

46. Irrational resuscitation of race • Actually Wilson et al. examined population samples from around the world including: Norwegians; Ashkenazi Jews; Armenians; South China; Papua, NG; East and West Africa; and Afro-Carribeans. • They found that 4/6 genetic variants they examined could be formed into four clusters. • This, of course means that 2/6 could not be clustered! (a fact not mentioned by Risch.) • Most importantly, Wilson et al. concluded that the four genetic clusters they discovered, did not match, socially constructed race or ethnicity (again a fact not mentioned by either Risch or Wade.) • Goldstein and Chkhi 2002 interpret Wilson et al.: “races in any meaningful sense of the term do not exist in the human species…”, An. Rev. Genomics and Human Genetics, vol. 3

47. Distribution of Sickle Cell Anemia Allele is discordant with “race.” • The origin of the allele is uncertain. • However it is distributed at high frequency in “Negroids and Caucasoids.” • High altitude Kenyans don’t have any sickle cell. • Seen as “Black” disease in U.S. due to importation of slaves derived from W. Africa were malaria was prevalent. Fig. 5.8, Ridley 1996

48. Polymorphic loci vary in frequency • Polymorphic loci have numerous alleles, with no single allele at a frequency > 99%. • Phenylketonuria, q = 0.01 • Tay Sachs A, q = 0.017 • Cystic Fibrosis, q =0.022 • Sickle Cell Anemia, q = 0.050 Distribution of CF D F-508 allele, Fig. 2.14.10, Cavalli-Sforza, Menozzi, and Piazza, 1994.