Information - Concepts In Nutrigenomics - Genetics And Genomics

The Importance of Ancestors

Individual genetic variation results from the inherent error rate of replicating DNA.  No biological process is 100% accurate, so each time the 6 billion bases in our chromosomes (2 of each chromosome and therefore 2 x 3 billion base pairs), errors occur.  Since such processes occur in every living organism, it is not surprising that every human being is genetically unique.

         Migration from Africa

The blue lines indicate the region covered by ice or tundra in the last ice age.  Numbers represent thousands of years before present.  Letters are mitochondrial DNA haplogroups.

  • General European: H, V
  • Southern European: J, K
  • Northern European: T, U, X
  • Near Eastern: J, N
  • African: L, L1, L2, L3, L3*
  • Asian: A, B, C, D, E, F, G (note: M is composed of C,D, E, and G)
  • Native American: A, B, C, D, and sometimes X


Migrations & Environments Produce Genetic Variation

Genetic variation among geographically separate populations results from human migration from east Africa in waves that ultimately led to the peopling of 6 continents.  The successive splitting off of a portion of the gene pool decreased genetic diversity in the migrating group.  Food availability and other factors contributed selective pressures for specific gene variants during migration and dispersal into new environments.  One example of such selection, and a model of gene X environment interactions (see below), is lactose tolerance (see Lactose Intolerance). 

The combination of small founding groups and recent population growth produced geographically distinct populations who share 99.9% of genomic sequences.  SNP and simple tandem repeat (STR) analyses have yielded more detailed information about human relatedness:  on average, there is a 12-14% difference between geographically distinct populations - for example, between Asia and Europe.  Most genetic variation (estimated range of 86-88%) occurs within a geographic population (Asia, for example).  For the foreseeable future, nutrigenomicists will analyze the genetic architecture of individuals since many individuals maintain the preference of mating within like ethnic groups. 

Impact on Personal and Public Health

Where our ancestors came from, and the evolutionary history this implies, determines each individual's chances of inheriting a specific gene variant.  Different gene variants contribute differently to health and disease susceptibility.  Hence, although no perfect genotype exists and diseases are shared among all ethnic groups, different ancestral groups may have different susceptibilities to disease based on the gene variant frequencies in their population. These genetic susceptibilities can influence the frequency, age of onset, severity, mortality and responsive to treatment for many diseases.  For example, epidemiological data indicates that Asian and Hispanic populations seem to have insulin resistance as the predominant mechanism leading to diabetes rather than b-cell dysfunction.  In African-Americans the opposite appears to hold.  Although these are broad generalizations, the results suggest genetic ancestry contributes to the differences in T2DM prevalence and by different mechanisms even though the final disease state looks the same.  Identifying the genes that contribute to T2DM will provide a molecular and genetic understanding of differences among populations.

Ancestral Differences & Epistasis

A recent report showed that a specific haplotype (called HapK) in leukotriene A4 hydrolase (LTA4H) was associated with increased risk of myocardial infarction (MI) in individuals of European descent as well as in African Americans. However, the risk of MI was significantly greater in African-Americans who carried the HapK haplotype.  MI risk is increased by European HapK in both ethnic groups.  However, HapK is present at a very low frequency (if at all) in Nigerian Yorubans (who were genotyped as a part of the HapMap project) indicating that African - Americans inherited this region from European ancestors. The increased risk of MI was NOT associated with the contribution of other portions of European chromosomes. 

The significantly increased risk of MI in African Americans must therefore be due in part to:

  • gene - gene interactions between the LTA4H HapK and other genes derived from Africa (an example of epistatic interactions),
  • environmental influences (leukotrienes are derived from arachidonic acid, an n6 fatty acid obtained from foods, particularly in Western diets where the n6/n3 ratio is very high), and/or
  • interactions among genes and nutrients (through LTA4H or through epistatically-interacting genes regulated by diet). 

This article is important in several spheres:  scientifically, (i) it demonstrates the need to analyze ancestral background in epidemiological studies, (ii) that a SNP or haplotype is "context specific" - that is, a SNP or haplotype may contribute different amounts to disease risk depending on ancestral background because of epistatic (gene-gene) interactions, and (iii) gene - diet interactions (not directly tested in this paper) are important for disease risk in different ancestral backgrounds

Epistatic interactions may also be explained in biochemical terms as biochemical buffering.  The metabolism of all organisms occurs within a fairly narrow window - such that survival depends on systems and networks which are in balance.  If one or more genes (and their proteins) vary too much from the reference, other genes (and their proteins) are likely to also be variant from their references:  life requires a balance among genes and among genes and environmental factors.

Personal and public health implications:  while racism, socioeconomic status, access to health care and other "social factors" contribute to (and may be the dominant factors causing) health disparities, there is likely to an underlying biological difference among ancestral groups for some diseases 

Further reading

Hartman IV, JL.  2006.  Genetic and Molecular Buffering of Phenotypes. In Nutritional Genomics: Discovering the Path to Personalized Nutrition.  Kaput, J and Rodriguz, R (eds). Wiley and Sons, Inc. NY. 2006. pp. 103-133.

Helgadottir, A, Manolescu, A, Helgason A, Thorleifsson, G,  Thorsteinsdottir, U, Gudbjartsson, DF, Gretarsdottir, S, Magnusson, KP,  Gudmundsson, G, Hicks, A, Jonsson, T, Grant, SFA, Sainz, J, O'Brien, SJ, Sveinbjornsdottir, S, Valdimarsson, EM, Matthiasson, SE, Levey, AI, Abramson, JL, Reilly, MP, Vaccarino, V, Wolfe, ML, Gudnason, V, Quyyumi, AA, Topol, EJ, Rader, DJ, Thorgeirsson, G, Gulcher, JR, Hakonarson, H, Kong, A, & Stefansson, K.  (2006) A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction.  Nature Genetics 38, 68 - 74  PMID: 16282974

Jorde, LB and Wooding, SP. 2004. Genetic variation, classification and 'race'.  Nature Genetics 36, S28-33  PMID: 15508000

Tishkoff, SA and Kidd, KK.  2004. Implications of biogeography of human populations for 'race' and medicine. Nature Genetics 36, S21-27.  PMID:15507999