Human Genetics

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Human Genetics









Whether or not race is a useful construct in biology, medicine, and society has been debated for more than a century. Despite this attention, even the most elementary questions about race persist. What is a race? How many human races are there? What determines membership in a race? Is race a useful proxy for health or behavior?

Scientific interest in the relationship between race and human biological variation has intensified recently with advances in genomics. There is hope that an increased knowledge of the human DNA sequence and the discovery of DNA sequence variations within and among individuals will provide definitive answers to the long-standing questions about the biological aspects, and indeed the biological validity, of the idea of race. Genomic data have revealed the patterns of human genetic diversity in exquisite detail. However, it is still a challenge to understand how these patterns relate to the biological processes that generated them, and to discover the implications of these patterns for broader issues related to health and disease. While the purpose here is to focus on contemporary issues of race in genetics and disease research, it must also be remembered that race is not simply a biological topic; it is part of human social and political fabric as well.


A basic familiarity with terms and concepts in genetics is essential to understanding human genetic variation. To begin, all hereditary information is encoded in DNA (deoxyribonucleic acid). Each DNA molecule is composed of two strands of basic building blocks called nucleotides. There are four different kinds of nucleotides, denoted by the letters A, C, G, and T. The letter designations for nucleotides are used as a shorthand for the chemical bases that give the four kinds of nucleotides their distinctive properties. The two strands of a DNA molecule are wound together lengthwise forming a double helix shape. At each position along the double helix, the nucleotide from one strand is paired with a nucleotide from the other, according to a basic rule: A with T and C with G. In essence, each DNA molecule exists as a long string of nucleotide pairs. The information in genes is encoded in the sequence of A, T, C, and G nucleotides (see Figure 1).

The DNA double helix is super-coiled and bundled with proteins into structures called chromosomes. Every person has twenty-three pairs of chromosomes, with one member of each pair inherited from their mother and the other member inherited from their father. One of the twenty-three chromosome pairs is special because it determines the person’s chromosomal sex. The two members of this pair are different in males (they are denoted X and Y); while females carry two X chromosomes. The other twenty-two pairs of chromosomes are called autosomes. The autosomes are alike in males and females. Chromosomes are contained inside the nuclei of cells. Interestingly, humans and other life forms carry a small DNA molecule outside of the cell nucleus. This DNA molecule occurs in many copies in a

cell component called the mitochondrion. Mitochondrial DNA (mtDNA) is easy to work with in the laboratory and has been studied extensively.

In the early twenty-first century, geneticists speak of the genome, which is a complete copy of the DNA for a species. The term locus refers to a specific physical location on a genome. Loci (plural of locus) vary in length: They can be small and hold only a single nucleotide, or they can be large and hold stretches of thousands or millions of nucleotides. Alleles are alternative nucleotide sequences that occupy the same locus. New alleles are created by the chemical process of mutation. The differences between alleles are usually minor; at some places one base is substituted for another, or a small number of nucleotides is inserted or deleted from the DNA sequence.

A gene is a nucleotide sequence that encodes the information for a specific product such as a protein. Every gene resides at a locus and there are often allelic forms of genes. Surprisingly, the genome contains far more DNA than is required to encode all of the information in human genes. In fact, only about 2 percent of the genome encodes genes, and about half of the genome consists of repeated nucleotide sequences with no known function.


Genetic diversity is measured from DNA sequence differences between alleles. There are many methods for estimating genetic diversity. However, all of the methods reveal three major features that typify a unique pattern of human genetic diversity. The first feature is that the amount of diversity at the DNA level is only a fraction of what would be expected for a species that consists of billions of members. The second feature is that the genetic diversity in people living outside of sub-Saharan Africa is mostly a subset of the genetic diversity in populations within sub-Saharan Africa. The third feature is that, at most genetic loci, a variant allele that is common in one human population is common in the entire species. These three features have been reproduced by many independent studies and in many regions of the genome.

The three basic properties of human genetic variation are seen in patterns of nucleotide diversity, which is defined as the probability that a nucleotide at a random position in the genome will differ between two randomly chosen copies of the genome (Nei 1987). The first property, that humans have low diversity, is apparent when comparing humans and chimpanzees. Humans and chimps are each others’ closest relatives and, in comparison to other animals, are remarkably similar genetically and behaviorally. In a study of mtDNA, nucleotide diversity in chimpanzees was 4.32 percent, which was more than seven times the value observed in humans, which is 0.609 percent. It would normally be expected that the human population, with more than six billion members, would harbor more diversity than the chimpanzee population, with only 100,000 to 200,000 members. Figure 2, modified from Gagneux et al. (1999), provides a further illustration of this finding. Each terminal branch on the trees represents a group of closely related mtDNA sequences, and the branch lengths represent the numbers of nucleotide changes among these sequence groups. Notice that the chimpanzee tree is bushier than the human tree.

The second and third basic properties of human genetic variation are illustrated by a study of DNA sequences from widely dispersed populations in Africa, Asia, and Europe (Yu, Chen, Ota, et al. 2002) that estimated nucleotide diversity at different levels of population structure; for example, the nucleotide diversity between two copies of the genome that were sampled from the same population (within group) or from different populations (between groups).

As shown in Figure 3, nucleotide diversity is lower if both copies of the genome are drawn from Europe or from Asia, than if both copies of the genome are drawn from Africa. That is, Africa has more within-group nucleotide diversity than Europeor Asia. However, what is even more interesting is that if one copy of the genome is drawn from Asia and the other

copy is drawn from Europe, the nucleotide diversity is nearly the same as when both copies are drawn from Europe or both copies are drawn from Asia. On the other hand, if one copy of the genome is drawn from Africa and the other from Asia, the nucleotide diversity is higher than if both pairs were drawn from Asia. The result is the same for African-European pairs in comparison to European-European pairs. By contrast, if both copies of the genome are drawn from Africa, nucleotide diversity is higher than either the African-Asian or African-European pairs. This unexpected result comes from the fact that diversity in non-Africans is mostly a subset of the diversity in Africans. In other words, there is widespread diversity in Africans that is not found in non-Africans, but most of the widespread diversity in non-Africans is found in Africans.

Repeated DNA sequences further support the three primary features of genetic variation. In a study that included 4,199 alleles from 377 loci in different populations from around the world, about half of the alleles (46.7%) were widely represented in populations across major geographic regions, and only 7.4 percent were exclusive to populations in a single region (Rosenberg et al. 2002). These region-specific alleles tended to be rare, even within their region of occurrence. This finding is consistent with a theory in population genetics that holds that common alleles are usually old and expected to be shared across populations either by descent from a common ancestor or because they have spread by migrations, whereas new alleles are rare and localized to the geographic region in which they arose because they have not had time to spread.

The low nucleotide diversity and nested subset pattern of genetic diversity is consistent with a model that postulates a succession of ancient founder events that occurred as the human species expanded its range and occupied new continents. In this view, the origin of the species was in Africa about 200,000 years ago, and the species expanded out of Africa beginning only 100,000 years ago (Rogers and Jorde 1995; Harpending and Rogers 2000; Rogers 2001). While the present data agree with the recent African-origin scenario, it must be recognized that there are active debates on the timing of human origin and the global expansion of the species (Wolpoff et al. 2001).

A final word of caution is that the patterns described above represent averages over many different loci. The variation at any single locus can deviate from the overall average. One reason for different patterns of variation across loci is that the order and timing of evolutionary change is a complex stochastic process. While each locus is potentially an outcome of the same process, no two outcomes are alike (Harpending and Rogers 2000). Another reason for different patterns at different loci is that natural selection can create deviations from the otherwise common patterns of genetic variation (Ruiz-Pesini et al. 2004). For instance, alleles that bestow a resistance to malaria are primarily found in regions with a history of malaria and reflect localized adaptations. Because natural selection can present a bias, DNA sequences that do not encode functional products are the most useful for understanding patterns of population history and relationships.


The word race should be used carefully because different meanings have been affixed to it in scientific, social, and historical contexts. Population geneticists typically define race as a group of individuals in a species showing closer genetic relationships within the group than to members of other such groups (Hartl and Clark 1997, p. 121). However, race defined in this way is not a very useful description for the overall pattern of DNA variation in humans. Figure 4 illustrates some of its shortcomings.

Panel 4A represents three hypothetical groups. Within each of the three groups, the members are, on average, more similar to each other than they are to the members of the other two groups. If one focuses on a pair of the groups, say A and B, a member of A is less similar compared with a member of B than with another member of A. The same is true the other way around: A member of B is less similar compared with a member of A than with another member of B. The relationship is symmetrical: A is a race when compared with B and B is a race when compared with A. The same pattern is evident when members of A are compared with members of C and when members of B are compared with members of

C. Panel 4B shows that the actual pattern of variation in human DNA sequences lacks symmetry between populations. For example, the genetic variation found in Europeans and Asians is a subset of the variation found in Africa.

Genes from African populations are, on average, less similar to each other than they are to genes from European and Asian populations. Thus, Africans cannot be considered a race by the population genetics definition. Conversely, Europeans can be considered a race relative to Africans because the similarity between a pair of genomes drawn from Europe is greater than the similarity between a pair from Europe and Africa. The same sort of asymmetry holds in comparing genomes from Asia with genomes from Africa. However, one would be hard-pressed to argue that Europeans and Asians are races with respect to each other, because European-European pairs, Asian-Asian pairs, and European-Asian pairs are all similar to nearly the same degree. Thus, whether or not a particular group is a race, or how many races a group belongs to, is relative to whom that group is being compared.


Several studies have successfully used sets of highly variable DNA markers from nonfunctional regions of the genome to reveal clusters of genetically similar individuals. Notably, the resulting genetic clusters tend to contain people sampled from the same region of the world (Pritchard et al. 2000; Rosenberg et al. 2002; Bamshad et al. 2003). It is now estimated that only a modest number of highly variable loci are required to correctly assign an individual to a continental cluster (Bamshad et al. 2003; Rosenberg et al. 2003). While only nonfunctional markers have been used for finding genetic clusters, one study has shown that the frequencies for alleles of drug metabolizing enzymes differ among clusters (Wilson et al. 2001).

To many scientists and nonscientists, these results seem to affirm the validity of race. After all, the correct assignment of individuals to populations has been traditionally viewed as a gold standard in validating races (Mayr 1969). Nevertheless, the ability to assign individuals to groups is unlikely to resolve the major issues surrounding race. The ability to classify individuals is ambiguous with respect to the pattern of variation among groups. Both of the patterns of variation illustrated in Panel 4A permit classification of individuals, but the asymmetrical pattern of actual human variation (Panel 4B) challenges conventional intuition about what race means.


Though it is often possible to use genetic information to assign an individual to the geographical region from

which he or she came, the inference is not as strong in the reverse direction. An individual’s ancestry conveys only a small amount of information about the specific genetic markers that they carry. This is true even when the occur-rence of a particular marker is restricted to a localized geographicregion. Aprime example is the ALDH2-2 alleleat the acetaldehydrogenase 2 locus (ALDH2). This allele encodes a dominant-acting deficiency that prevents formation of the active ALDH2 enzyme. A consequence of ALDH2 inactivity is the accumulation of the noxious metabolic intermediate acetaldehyde (Inoue et al. 1984). Elevated blood acetaldehyde is associated with alcohol sensitivity and symptoms such as increased blood flow, dizziness, accelerated heart rate, sweating, and nausea (Wolff 1972; Agarwal and Goedde 1990; Agarwal et al. 1991). These symptoms in combination define the “flushing response.” The ALDH2-2 allele affects human health in an interesting way. Individuals who carry the ALDH2-2 are protected from heavy drinking and ultimately alcoholism by the unpleasantness of flushing.

Figure 5 presents data on the frequencies of four major allele complexes at the ALDH2 locus (Peterson et al. 1999; Mulligan et al. 2003). The ALDH2-2 allele is carried on H4. Notice that H4 is found only in Asian populations, where it is relatively common. Because ALDH2-2 is found only in Asians, it is a perfect indicator of Asian ancestry. Nonetheless, the converse cannot be claimed, because most Asians do not carry the ALDH2-2 allele. As a result, while the ALDH2-2 allele is a good indicator that an individual will not drink alcohol or become alcoholic, most Asians do not carry ALDH2-2, and some Asians do drink alcohol and become alcoholic.

Population membership, therefore, may not be a precise indicator of genetic susceptibility to, or treatment of, diseases. While many marker alleles can be used to accurately infer ancestry, ancestry will allow only a weak inference about whether an individual carries a particular disease-risk allele.


Health researchers are actively debating the value of race and ethnicity in the diagnosis and treatment of chronic diseases such as diabetes, high blood pressure, and cancers (Burchard et al. 2003; Cooper et al. 2003). It is well known that chronic diseases are unevenly distributed in the general population. Depending on the disease, some groups are more or less prone than others. However, chronic conditions are difficult to analyze because they are caused by a combination of many factors, including both genes and environment. This complexity makes it likely that people presenting the same diagnosis vary widely with respect to the underlying causes that led to their problem. The chief argument for using race in medicine is that it can serve as a proxy for the total mix of genes and environments experienced by the patient. As such, it will better enable doctors to tailor diagnoses and treatments to the patient. However, there are several arguments against using race in the practice of medicine. First, racial groups are often too poorly defined to serve as useful proxies for genetic populations or specific environments. Second, the known genetic differences among populations are too small for population membership to be a strong indicator of the genes carried by individuals. Third, analyses suggest that although disease-predisposing

alleles can vary in frequencies across population, the disease-predisposing alleles appear to have similar effects in people in different groups (Ioannidis et al. 2004). Fourth, a race-specific approach to medicine easily lends itself to misuses such as justifying unequal opportunity for health care. Despite these caveats, the U.S. Food and Drug Administration has recently approved the marketing of BiDil, a congestive heart failure medication, for a specific racial group: African Americans.


The genetic diversity in our species has three defining features. First, the level of diversity in humans is consistent with a much smaller population than is living in the early twenty-first century. Second, the geographic pattern of genetic diversity forms nested subsets. Third, at most genetic loci, an allele that is common in one human population is common throughout the species. The architecture of human genetic variation is ultimately explained by the evolutionary history of our species and best understood in that context.

These findings complicate genetic scholars’ notions of human race by contradicting the intuitive expectation that a race classification is symmetrical (i.e., if A is a race with respect to B, then B is a race with respect to A). For example, non-African people are more homogeneous than the species as a whole, but there is nearly as much genetic diversity in African people as there is in the species as a whole. Despite the inadequacy of race concepts for describing patterns of genetic variation, genetic differences among human populations do exist, and one of the most striking ways that populations differ is in the overall level of variation. African populations harbor the greatest diversity. On average, non-African populations harbor less diversity.

A major question is: Do disease susceptibility alleles have the same distribution as the more-or-less neutral variations in the DNA sequence? The answer to this question is not yet known. Some speculation has led to the common disease–common variant hypothesis (Reich and Lander 2001), which holds that the alleles that contribute to common diseases will have population distributions much like neutral variants because they are only disadvantageous in the post-reproductive phase of life, and are therefore undetected by natural selection. To the extent that this is true, the susceptibility alleles for common diseases should be widely shared. In general, the findings from one population should be relevant to others. However, two important caveats must be raised. The first is that because Africans harbor more allelic variation than do non-Africans, studying non-Africans will not identify important genetic variants related to the health of people of African descent. The second is that effects of major genes may be modified by the rare variants that are specific to local populations or geographic regions.

Race is clearly a poor descriptor of the patterns of genetic variation. However, breaking the tradition of using it will be difficult. A major barrier to breaking this tradition is that lay people and scientists alike use what is known as the implicit definition of race. In this view, races represent a pattern of variation that is difficult to pinpoint but clear to most people. This position is imprecise and irrefutable because it is based on an article of faith: that races display a pattern of variation that is already clear to most people. It is easy for users of the implicit definition to talk past each other, and for them to unwittingly fall back on prejudices or use typological thinking that is inconsistent with biological processes. The utility and internal consistency of race concepts can only be validated or rejected to the extent that they are explicitly stated. It must also be remembered that race is as much a social phenomenon as it is a biological one. The ancestry of individuals and groups is hopelessly confounded with environment and social standing. Therefore, it is unlikely that one line of evidence, such as genetics or genomics, will clarify all of the important health issues surrounding race.

SEE ALSO Clusters; Eugenics, History of; Forensic Anthropology and Race; Gene Pool; Genes and Genealogies; Genetic Distance; Genetic Marker; Genetic Variation Among Populations; Genetics, History of; Genetics and Athletic Performance; Human and Primate Evolution.


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Jeffrey C. Long
Nicole Scott
Cecil M. Lewis Jr.

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