The Rh System
One clinically important example of marked differences in allele frequencies is seen with the Rh blood group. The Rh blood group is very important clinically because of its role in hemolytic disease of the newborn and in transfusion incompatibilities. In simplest terms, the population is separated into Rh-positive individuals, who express, on their red blood cells, the antigen Rh D, a polypeptide encoded by the RHD gene, and Rh-negative individuals, who do not express this antigen. Being Rh-negative is therefore inherited as an autosomal recessive trait in which the Rh-negative phenotype occurs in individuals homozygous or compound heterozygous for nonfunctional alleles of the RHD gene. The frequency of Rh-negative individuals varies enormously in different ethnic groups (see Table 9-5).
Hemolytic Disease of the Newborn Caused by Rh Incompatibility
The chief significance of the Rh system is that Rh-negative persons can readily form anti-Rh antibodies after exposure to Rh-positive red blood cells. Normally, during pregnancy, small amounts of fetal blood cross the placental barrier and reach the maternal bloodstream. If the mother is Rh-negative and the fetus Rh-positive, the mother will form antibodies that return to the fetal circulation and damage the fetal red blood cells, causing hemolytic disease of the newborn with consequences that can be severe if not treated.
In pregnant Rh-negative women, the risk for immunization by Rh-positive fetal red blood cells can be minimized with an injection of Rh immune globulin at 28 to 32 weeks of gestation and again after pregnancy. Rh immune globulin serves to clear any Rh-positive fetal cells from the mother’s circulation before she is sensitized. Rh immune globulin is also given after miscarriage, termination of pregnancy, or invasive procedures such as chorionic villus sampling or amniocentesis, in case any Rh-positive cells gained access to the mother’s circulation. The discovery of the Rh system and its role in hemolytic disease of the newborn has been a major contribution of genetics to medicine. At one time ranking as the most common human genetic disease among individuals of European ancestry, hemolytic disease of the newborn caused by Rh incompatibility is now relatively rare, but only because obstetricians remain vigilant, identify at-risk patients, and routinely give them Rh immune globulin to prevent sensitization.
Ethnic Differences in Disease Frequencies
A number of factors discussed earlier in this chapter are thought to explain how differences in alleles and allele frequencies among ethnic groups develop. One is the lack of gene flow due to genetic isolation, so that a mutation in one group would not have an opportunity to be spread through matings to other groups. Other factors are genetic drift, including nonrandom distribution of alleles among the individuals who founded particular subpopulations (founder effect), and heterozygote advantage under environmental conditions that favor the reproductive fitness of carriers of deleterious mutations. Specific examples of these are illustrated in the next section. However, in many cases, we do not have a clear explanation for how these differences developed.
One extreme example of a difference in the incidence of genetic disease among different ethnic groups is the high incidence of Huntington disease (Case 24) among the indigenous inhabitants around Lake Maracaibo, Venezuela, that resulted from the introduction of a Huntington disease mutation into this genetic isolate. There are numerous other examples of founder effect involving other disease alleles in genetic isolates throughout the world, such as the French-Canadian population of Canada, which has high frequencies of certain disorders that are rare elsewhere. For example, hereditary type I tyrosinemia is an autosomal recessive condition that causes hepatic failure and renal tubular dysfunction due to deficiency of fumarylacetoacetase, an enzyme in the degradative pathway of tyrosine. The disease frequency is 1 in 685 in the Saguenay–Lac-Saint-Jean region of Quebec, but only 1 in 100,000 in other populations. As predicted for a founder effect, 100% of the mutant alleles in the Saguenay–Lac-Saint-Jean patients are due to the same mutation.
Thus one of the outcomes of the founder effect and genetic drift is that each population may be characterized by its own particular mutant alleles, as well as by an increase or decrease in specific diseases. The relative mobility of most present-day populations, in comparison with their ancestors of only a few generations ago, may reduce the effect of genetic drift in the future while increasing the effect of gene flow.