Genetic Epidemiology

Certainly contributing to the amount of attention paid to TSD over the last century is the enigma it (and other deleterious genetic disorders such as sickle-cell anemia) presents: How can a lethal gene get to a high frequency in a population? How can that high frequency be maintained? Why is that gene found at a relatively high level in a particular population? In addressing this problem, one first examines in turn the basic evolutionary forces that change gene frequencies: mutation, gene flow, genetic drift, and natural selection.

Forces of Evolution Affecting Gene Frequencies

Mutations. Mutations are the original source of all genetic variability, occurring at generally very low, but constant, rates. Thus (at least once, but probably more than once) mutation gave rise to each TSD gene variant found among the Ashkenazim and non-Ashkenazim. Mutation alone, however, cannot explain the unusually high frequency of the TSD genes in the Ashkenazim. The reason is simply that there would need to be an unprecedentedly high mutation rate of this gene in Ashkenazi Jews to account for its presently observed frequency in that population. There is no evidence of this being the case.

Gene Flow. Gene flow, the movement of genes from one population to another as individuals move, plays a greater or lesser role in the various explanations of the high TSD gene frequency in the Ashkenazim. Gene flow could have its biggest role if the intriguing scenario proposed by A. Koestler (1976) is correct. He suggests that the Ashkenazim are in large part descended from members of the Khazar Empire. The Khazar Empire existed from the seventh to the tenth century A.D. in an area north of the Caucasus Mountains, and during that time some Khazars converted to Judaism. It is speculated that after the fall of the Khazar Empire, those converts moved northwestward into areas of central Europe where Jews from western Europe were also emigrating. Thus, if those Khazars carried the TSD genes, they delivered them as part and parcel of their contribution to the Ashkenazi gene pool. As was the case with mutation, though, it is unlikely that gene flow in and of itself can account for the high frequency of the TSD genes among Ashkenazi Jews. The reason is that such an explanation would suggest that there was a group (perhaps the Khazars, perhaps some other group) with a high frequency of the TSD gene that provided the Ashkenazi Jewish population with a large number of carriers. There is no evidence of such an occurrence (see Neel 1979), which leaves natural selection and genetic drift as more likely reasons for the high frequency of the TSD genes among Ashkenazi Jews.

Natural Selection. N. C. Myrianthopoulos (1962) and A. G. Knudson and W. D. Kaplan (1962) first suggested that heterozygote carriers of the TSD gene may have a selective advantage over the normal homozygote. Myrianthopoulos and S. M. Aron-son (1966, 1967) calculated that a selective advantage of about 1.25 percent on the part of the heterozygous carrier of the TSD allele would be sufficient to maintain the allele at its present frequency of approximately 1.3 percent among the Ashkenazim, despite the loss of TSD genes through the deaths of recessive homozygotes afflicted with TSD.

They then showed that over the course of 50 generations (roughly from the time of the Diaspora to the present), a heterozygote-selective advantage of about 4.5 percent would increase the TSD allele frequency from 0.13 percent to 1.3 percent, again despite losses of TSD alleles through the deaths of recessive homozygotes. In order to provide support for their hypothesis, they compared sibship sizes of the parents of TSD offspring to the sibship sizes of a control group. They found the former to be slightly larger than the latter. Although the differences were not statistically significant, they indicated a heterozygote advantage sufficient to result in the observed present-day TSD gene frequency in the Ashkenazi population (assuming that the heterozygote advantage had remained more or less constant over time).

Two conditions are essential for a natural selection explanation to hold: (1) a selective agent of sufficient magnitude to affect negatively the reproductive success of individuals, and (2) a physiological basis for the advantage one genotype has over the others. Following up on their earlier work, Myrianthopoulos and Arsonson (1972) suggested that heterozygous carriers of the TSD allele were less susceptible to tuberculosis, a disease especially common in many urban centers of Europe during the nineteenth century. Although they found a negative association between indirect estimates of TSD and tuberculosis prevalence, the association was too small to be statistically significant. Furthermore, no physiological basis was offered to explain why heterozygote carriers of the TSD allele might have a selective advantage with regard to tuberculosis. More recently, J. Zlotogora, M. Zeigler, and Bach (1988) have posited that selection is the reason for the high prevalence of not only TSD in the Ashkenazi population, but also sphingolipid storage disorders in general among all Jews. However, they conclude that the nature of the hypothesized selective forces has yet to be fully elucidated.

Founder Effect and Genetic Drift. G. A. Chase and V. A. McKusick (1972) suggested that founder effect and genetic drift, rather than heterozygote advantage and natural selection, explain better the high TSD gene frequencies in the Ashkenazi Jewish population. D. C. Rao and N. E. Morton (1973) calculated that it was possible that drift could account for the high frequency of the TSD genes in the Ashkenazim, and D. Wagener and colleagues (1978) came to a similar conclusion. T. E. Kelly and colleagues (1975) studied a semi-isolated non-Jewish population with a high frequency of TSD, concluding that founder effect is the most likely cause and suggesting that this case illustrated, in microcosm, how the high frequency of the TSD genes might have occurred. A. L. Fraikor (1977) also favors a genetic drift explanation in a detailed study in which genetic drift (broadened to include founder effect as well as some other population processes) is argued to be the most parsimonious explanation for the high TSD gene frequency among the Ashkenazim.

Genetic drift refers specifically to random changes in gene frequencies from one generation to the next (i.e., "sampling errors"). Sampling error is most pronounced in small populations in which, simply because of the chance combination of a relatively small number of gametes out of millions of genetically different contenders, the offspring generation's gene pool may not contain the same genes in the same frequencies as the parental generation's gene pool. Thus, gene frequencies "drift" up or down through time. Unfortunately, there is no way to tell whether or not genetic drift has occurred in a population. Nonetheless, the probability of genetic drift of a certain magnitude occurring under certain circumstances can be estimated. Population size and changes in population size through time are the most important parameters in these calculations (see Wilson and Bossert 1971). A process related to genetic drift, founder effect, refers to the genetic impact that one or a few individuals may, by chance, have on the genetic structure of a new population after either migration or population decline. It is because of the chance factor that founder effect is usually considered in the context of genetic drift.

Fraikor (1977) chronicles the population history of Ashkenazi Jewry and finds that the conditions most conducive for genetic drift (especially small and semi-isolated local populations and large fluctuations in overall population size) were present throughout much of Europe for hundreds of years. However, A. Chakravarti and R. Chakraborty (1978) calculate that even in some situations highly conducive to genetic drift, the probability of observing the present discrepancies in TSD gene frequencies between the Ashkenazim and non-Ashkenazim is low. They conclude that heterozygote advantage and genetic drift should be considered together as the most probable explanation for the high TSD frequency in the Ashkenazi Jewish population. This conclusion serves as a worthwhile reminder that the forces of evolution are not necessarily mutually exclusive explanations of genetic variation, a point made explicit by S. Wright (1977) in his "shifting balance" theory of evolution.

Up to now the difference between Ashkenazi Jews and non-Ashkenazi Jews (and non-Jews) in TSD prevalence and gene frequencies has been emphasized. Indeed, in the extensive literature on TSD, this difference is often the only one considered. There is, however, evidence of considerable disparity among Ashkenazi Jewish groups in the prevalence of TSD. These differences are also important in assessing the reasons for the overall high frequency of TSD genes among the Ashkenazim. Aronson (1964) found that the ancestors of the majority of Jewish TSD cases in the United States came from the northeastern provinces of Poland and the Baltic States. Myrianthopoulos and Aronson (1967) confirmed this finding, stating that with regard to TSD prevalence in central Europe "some variation, as high as fivefold, existed between Ashkenazi communities of these areas and that this variation is not random but shows a definite geographic trend."

As it happens, these findings can be incorporated into both the natural selection hypothesis and the genetic drift hypothesis. The search for natural selection is made somewhat easier because a selective agent in the environment that might give the hetero-zygote a reproductive advantage no longer needs to exist across Europe, but needs only to be shown to exist in a delimited geographic area. TSD genes spread out from there through gene flow, and it would have been some time before they would have been removed in appreciable numbers through the deaths of the recessive homozygotes; by then the carrier frequency may have become rather high. The case for genetic drift is made somewhat stronger because the Ashkenazim no longer need to be considered a large interbreeding population, but instead can be viewed as a subdivided population made up of a number of smaller semi-isolates in each of which genetic drift is more likely to take place. The TSD genes spread from areas of high frequency to neighboring areas of low frequency through gene flow, thus explaining the geographic distribution observed by Myrianthopoulos and Aronson (1967) of the ancestors of TSD-affected individuals.

A Combination of Factors. In the absence of much substantive data, and the fact that evolutionary forces most often work in concert, the conclusion reached by Chakravarti and Chakraborty (1978), that a combination of heterozygote advantage and genetic drift is the most probable reason for the high TSD gene frequencies in the Ashkenazim, is appeal ing. In a similar vein, although not incorporating heterozygote advantage, Fraikor (1977) does not rely solely on genetic drift, but favors a combination of factors. She writes of Ashkenazi Jewish communities over the last few hundred years:

The combination of polygamy, inbreeding, small effective population size, and large numbers of progeny could have elevated the frequency of the TSD allele in the descendants of these populations. The subsequent period of seminomadism resulted in numerous individual carriers being scattered in many parts of Eastern Europe. Some carriers probably also remained in Germany or Western Europe. During the Golden Age of the sixteenth century, the rapid population expansion and freedom of migration within the territory of Poland greatly enhanced the chances for carriers to marry noncarriers. Such marriages would further increase the number of carriers in the total population, and selection against the gene would be reduced because affected homozygotes were not being produced in significant numbers. (Fraikor 1977)

Alternative Theories

Before leaving this issue, we must consider other explanations for the high frequency of TSD in the Ashkenazi Jewish population. One of these, inbreeding, was mentioned previously. Inbreeding does not change gene frequencies, but because it increases homozygosity generally (dependent on the level of inbreeding), it increases the probability of deleterious alleles coming together in individuals. Inbreeding is, in fact, the likely cause of the high prevalence of other sphingolipid disorders in other Jewish populations (see Zlotogora et al. 1980; Towne 1987; Zlotogora, Zeigler, and Bach 1988), and as Fraikor (1977) hypothesizes, may have played a role in some of the smaller and more isolated Ashkenazi Jewish communities.

Finally, Wagener and Cavalli-Sforza (1975) suggest that either "hitchhiking" or epistasis may have increased TSD gene frequencies in the Ashkenazim. When two genes are in close proximity to each other on a chromosome, they are likely to be inherited together over the generations. Thus, a deleterious allele may "hitch" an evolutionary ride with a selectively favorable allele. With the human genome map becoming more and more detailed, some hitchhiking hypotheses can increasingly be tested. What remains to be seen in this case is whether a highly favorable allele can be found in the Ashkenazim that happens to be on chromosome 15 in the area of q23-q24. Epistasis refers to the interactions between unlinked genes. J. V. Neel (1979) notes the following:

[An] epistasis hypothesis is theoretically possible but difficult to visualize as a general explanation for recessive deleterious genes in high frequencies in defined groups, given what we know about the usual heterozygous effects of these genes. Specifically, in the case of TSD, it is difficult to visualize a genetic interaction that converts half-levels of hex-A into a selective advantage.

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