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Speaker: Mary-Claire King, American Cancer Society Research Professor of Genetics and Medicine, University of Washington School of Medicine
After briefly reviewing her first lecture, Mary-Claire King explained how genomics could be used to determine one's continent of origin. As a case study, she presented none other than Bill Nye the Science Guy. King tested his DNA for several dozen markers she had around the lab. Nye knows his ancestry to be primarily French and a bit Norwegian. But when asked to guess his ancestry from the unidentified, color-coded pie charts, Nye unwittingly picked Sardinians, Karitania (a rain forest population) and Palestinians, thus showing that a limited sample of twelve markers yields limited data.
Human mitochondrial DNA and the Y-chromosome provide more precise indicators of ancestry. Found in the mitochondria of cells, human mitochondrial DNA is highly variable. As opposed to nuclear DNA, which has over 3 billion base pairs, mitochondrial DNA only has 16,000, and the 1,200 base pairs at its origin of replication (called the D-Loop) constitute the most variable region in the human genome. Because mitochondrial DNA is purely maternally inherited, faithfully transmitted, and highly variable, it can be used to identify the origin of inheritance for almost all families. Mary-Claire King used mitochondrial DNA to identify and reunite the children in Argentina of The Disappeared with their grandparents.
The Y-chromosome offers complementary information for paternal lineage. Since males have migrated less than females across human evolution, a Y can often point to a particular region of origin within the identified continent. For this reason, scientists prefer testing males over females for continent of origin.
King then moved on to address diseases casually associated with "race" in medical practice: diabetes, high blood pressure, and cardiovascular disease. King believes that race can sometimes be a pragmatic means of categorizing patients in so far as "race" is predicative of disease risk. Rather than having any genetic meaning, "race," in this context, is relevant because it is correlated with a set of environmental and economic factors pertaining to a patient's social history.
There are several cases of genes known to be correlated with race. As a result of selection, melanoma varies across continents. In cases of suspected sickle cell anemia, knowing if one is of African inheritance helps in diagnoses because the disease is specific to continent of origin. However, when a trait is specific to subregions of one or more continents possibly due to selection, 'race" is not the best ancestral identifier. The definitions for "ancestry" are both bigger and smaller than the arbitrary term "race."
Multiple Sclerosis (MS) and Systemic Lupus Erythematosis (SLE) are two autoimmune diseases concentrated in specific geographic locations. While MS is a disease of high altitudes, SLE afflicts the Philippines, Africa, South Africa, India, East Asia, and the US. These diseases thrive in specific locations because immune response genes, which are highly variable, are differentially selected in different geographic areas due to differential susceptibility. The rates of MS in Californian Asians, for instance, is four times higher than that found in California Caucasians.
King believes that complex traits are due to a large number of individual mutations, each of which is individually rare. Inherited predisposition to breast cancer is evident on the BRCA1 and BRCA2 genes. There are more than a thousand mutations of BRCA1 and BRCA 2, all of which are individually rare and specific to one region, population, or family. Some examples of mutations include missing two A base pairs, a clipped AAAG, or the insertion of an A.
Five percent of white women and 4% of black women carry a mutation in either BRCA 1 or 2. A woman carrying a mutation in either gene has more than an 80% lifetime risk of breast cancer. Mutations in BRCA1 also correspond to a 50% lifetime risk of ovarian cancer, while mutations in BRCA2 correspond to a 20% lifetime risk of ovarian cancer. It is best for a woman to test for the gene before she gives birth to her first child or before her mid30s. If positive, King recommends prophylactic removal of the ovaries after the birth of her last child. The resulting decrease in estrogen greatly reduces the risk of ovarian cancer as well as, to a lesser extent, breast cancer. Before age forty, colleagues have not seen invasive or primary peritoneal or fallopian tube in situ cancers. But women over forty face a 20-25% risk.
More recently, King has been researching inherited hearing loss. So far, 113 genes having to do with hearing loss have been identified in individual families, and most have multiple mutations in different families. The problem of hearing loss is worldwide due to many local mutations (which, again, are individually rare and numerous). When compared with the mammalian lineage, the human lineage shows an increase in the ratio of amino acid substitutions and silent changes – particularly AA silent substitutions.
Schizophrenia exhibits a roughly similar frequency worldwide (~1%). One’s genetic background in a global sense doesn’t seem to affect one’s risk of schizophrenia. Family history, however, appears to be significant, if in most cases sporadic. The risk of schizophrenia jumps to 6% if one person in your family has the disease. The strange thing about schizophrenia is that it persists despite reduced fertility in schizophrenics (80% fertility reduction in males, 60% in females). King posed the rhetorical question: If there were genes that predisposed one to schizophrenia what kind of mechanism could we suggest that would allow those genes to persist in a population when they are constantly selected out by the people who carry them?
King’s research found a two-fold increase in schizophrenia in adults born during the Dutch Famine. Of those adults who were in gestation during the height of famine (in the spring just before liberation), King discovered a four-fold increase. Looking at the large population born during the China Famine that resulted from the Great Leap Forward (1959-1961), King found the exact same prevalence of schizophrenia. This lead King to suspect that schizophrenia is in some way correlated to folate deficiency. Folate is an essential cofactor for ensuring that DNA replication is faithful. In microorganisms, a lack of folate results in increased mutations. King wonders if a folate deficiency made those conceived during famine more susceptible to mutations in genes affecting brain development. Although each mutation would be a different event, the mutations induced by a folate-deficiency could affect the same gene.
In conclusion, King offered her genomic view of human history: “Everything that can go wrong probably already has somewhere and will again soon.” Most disease-associated mutations are either worldwide and old, or rare and local and recent. It is uncommon for an allele, whether neutral or pathogenic, to be both continent wide and continent specific since most of human history preceded transcontinental migrations and the recent, rapid population expansion. Thus most alleles for disease susceptibility or response to treatment will prove individually rare. While recent ancestry of family is useful in identifying these alleles, “race” will only rarely be useful.
Francesca M. Mari