There are many differences between the curses in the tochechah (“rebuke”) in Vayikra (26:14-41) from those in Devarim (28:15-68).  Aside from Devarim listing twice as many curses than are listed in Vayikra, a major difference is that in Vayirka the curses were addressed to the community, whereas in Devarim they were directed to the individual. There is an opinion that the curses in Vayikra referred to the period of the destruction of the First Beis HaMikdash, whereas the curses in Devarim referred to the period of the destruction of the Second Beis HaMikdash and thereafter (Nachshoni, 1991).

“All these curses will come upon you and pursue you and overtake you, until you are destroyed because you will not have listened to the voice of Hashem, your God, to observe that He commanded you “ (Devarim, 28:45). The thought continues, “They will be in you as a sign and as a wonder, and in your offspring, forever” (Devarim, 28:46).  Focus on the two key words, “in” and “forever.” Noting that the curses will be in, rather than upon an individual (e.g., such as a skin blemish), implies that the curses are an inherent part of the individual. And, the verse could have ended with the phrase “in your offspring,” the extra word, forever, implies that the curses are within the individual and are transmitted from one generation to the next generation. In my understanding, the implication is that these verses are referring to genetic diseases, which are carried in the mutated DNA of genes and which potentially can be transmitted from generation-to-generation, forever.  Random gene mutations, or alternations in DNA, are a type of genetic damage that can be repaired or eliminated at birth and may not be transmitted to the subsequent generation. However, the pasuk seems to be referring to the type of gene mutation termed a “founder mutation,” which is a germ-line mutation transmitted in the gametes and passed from generation-to-generation (Drayna, 2005).

Inherited genetic diseases, which follow germ-line transmission, follow two general patterns. Many germ-line transmitted genetic diseases are caused by different de novo mutations that have occurred at various locations within the same gene and cause the identical genetic disease. Thus, unrelated families affected by the same genetic disease usually have different gene mutations responsible for that disease.  Most de novo disease-causing mutations occur at a frequency of one in a few thousands to one in a few millions. For example, the blood clotting disease, hemophilia a, is caused by a gene mutation encoding blood factor VIII.  Each new case of hemophilia a is caused by a discrete mutation in the gene encoding factor VIII, with hundreds of mutations being identified. Conversely, for other transmitted genetic diseases, the same unchanged mutation is repeated over and over again. This category of this later gene mutation is termed a founder mutation, as the mutation is identical in all people who have the genetic disease. Everyone with a founder mutation has a common ancestor – the founder – in which the gene mutation appeared initially (Drayna, 2005).  For example, the HEXA gene, when defective, is the founder mutation for Tay-Sachs disease and is thought to have arisen in the 8-9th century, corresponding with the demographic expansion of Ashkenazi Jews in Central Europe in the early Middle Ages (Frisch et al., 2004). The overall heterozygote frequency of the most common form of this mutation in the Ashkenazim is 3-4% (Motulsky, 1995)

The wild-type, functional HEXA gene, located on chromosome #15, encodes for the synthesis of hexosaminidase A, an enzyme which controls the accumulation of gangliosides, fatty-like substances. An individual having one chromosome #15 with the functional HEXA gene and having the other chromosome #15 with the defective HEXA gene is 100% normal, as one dosage of the functional gene encodes for a sufficient quantity of hexosaminidase A to control the metabolism of the gangliosides. However, a baby born with both chromosomes #15 carrying the defective HEXA gene will develop Tay-Sachs disease. Without hexosaminidase A, harmful quantities of gangliosides accumulate in lysosomes within the brain’s neurons, eventually leading to the premature death of the cells. This results in the progressive deterioration of brain neurons, causing mental and physical disabilities and death of the child by the age of four years (Wikipedia, n.d.).

As the readership of this article is predominantly Jewish, attention will focus on founder mutations in the Jewish community, particularly among the Ashkenazim. However, initially two points must be stressed. First, deleterious founder mutations are not unique to Ashkenazim, but are also noted in the Sephardic (e.g., North African, Lebanese, and Syrian) and the Mizrachi (e.g., Persian and Iraqi) Jewish communities. Many of my Sephardic and Persian students are usually surprised to learn that genetic diseases also occur in their communities and are not limited to the Ashkenazi population. The Israeli Ministry of Health has recommended genetic screening for reproductive purposes for thalassemia, which occurs at an elevated frequency in Jews from Iraq, Iran, Kurdistan, and North Africa, and for metachromatic leukodystrophy, which is at an elevated frequency in Jews from Yemen (Zlotogora, 2009). The need to develop genetic screening programs for the Sephardic (Bloch, 2009) and Persian (Kaback et al., 2010) Jewish communities has been noted. 

Second, it should not be thought that deleterious founder mutations are unique to the Jewish community. For any given founder mutation, every ethnic or national group has its own unique version of that specific mutation. For example, consider the founder mutation, BRCA1, which has been linked to a predisposition of breast cancer. The version of this mutated gene that occurs in the Jewish community is designated BRCA1 185delAG. There are at least 27 other versions of this mutation (Fackenthal and Olopade, 2007).  Different versions of a defective  BRCA1 founder mutation have been noted in several non-Jewish communities, including those in Scotland (Liede et al., 2000), Russia (Krylova et al., 2006), Poland (Gorski et al., 2004),Finland (Sarantaus et al., 2000), Norway (Rudkin et al., 2006), Sweden (Bergman et al., 2005), Greece (Armaou et al., 2009), Iceland (Barkardottir et al., 2001), Greenland (Harboe et al., 2009), Korea (Seo et al., 2004), Japan (Hirasawa et al., 2014), India (Kadalmani et al., 2007), Mexico (Villarreal-Garza et al., 2015), Chile (Gallardo et al., 2006), and Canada (Chappuis et al., 2001).

The wild-type, functional  BRCA1 gene, located on chromosome #17, is a tumor suppressor gene, as it encodes for the BRCA1 protein which is responsible for repairing damaged DNA or for destroying cells in which the extent of damaged DNA is so severe that it cannot be repaired. Suppose a zygote is formed through fusion of one gamete carrying the functional BRCA1 gene and the other gamete with the mutated non-functional BRCA1 gene. This heterozygous unicellular zygote will progress into a healthy multicellular adult with cells that are heterozygous for the BRCA1 gene. One dosage of the functional BRCA1 gene produces sufficient BRCA1 protein to initiate the process of repairing damaged DNA. This heterozygous adult, whether male or female, is said to have a predisposition for cancer. In cells of breast tissue of this heterozygous individual, if the lone functional BRCA1 gene is damaged so that the cell has no functional BRCA1 genes, then that cell has lost its ability to repair damaged DNA, which may eventual lead to a malignancy (Brooker, 2015).

The version of the mutant BRCA1 gene designated 185delAG is largely found in Ashkenazim, occurring in 1% of Ashkenazi Jewry (Struewing et al., 1995), but it has also identified, albeit at a lower frequency, in Sephardic and Mizrachi Jewry. Interestingly, the same founder BRCA1 185delAG mutation arose independently in two non-Jewish populations, one in Malaysia and the other in the United Kingdom (Laitman et al., 2013). However, as the BRCA1 185delAG is relatively unique to the Jewish community, it is used as a genetic archeological tool to trace population migrations. The mutated BRCA1 185delAG gene apparently originated before the destruction of the second Beis HaMikdash; the founder was most probably a Jew who lived in Yerushalayim. Before the destruction of the second Beis HaMikdash the Jewish population was not, as yet, split into Ashkenazi and Sephardic communities. Thus, it was not surprising to researchers when this mutated gene was found in Jews of different backgrounds. In addition to be noted in Ashkenazim, researchers found the BRCA1 185delAG gene present in Iraqi and Iranian Jews, who belong to the oldest Jewish community outside of Israel.  As the identical copy of this founder mutation was identified in Ashkenazim and Sephardim, the thought was that this mutation arose prior to the dispersion of the Jewish people, after the destruction of the second Beis HaMikdash (Bar-Sade et al., 1997, 1998). Today, however, the occurrence of the defective BRCA1 gene is greater within the Ashkenazi population, with a frequency of 0.8-1% (Fackenthal and Olopade, 2007).

During the Spanish Inquisition of 1492 many Sephardic Jews were given the choice of (forced) conversion to Roman Catholicism or to leave Spain. To avoid persecution, many Jews pretended to convert to Christianity, but secretly practiced Jewish rituals and remained as Jews. Over time, many of these Spanish Jews, or Marranos, assimilated into Spanish society. Today, it is not unusual that the BRCA1 185delAG mutation, a marker of Jewish ancestry, was identified in non-Jewish Spanish breast cancer patients (Diez et al., 1999).

Mullineaux et al. (2003) identified the BRCA1 185delAG mutation in a group of non-Jewish Americans of Spanish ancestry from the San Luis Valley, Colorado.  Long (2003) suggested that these Latinos were Conversos, or Sephardic Jews who, during the Spanish Inquisition, openly converted to Christianity but clandestinely practiced Judaism. Several thousand of the Conversos joined the Conquistadors in settling in Nueva Espana (a Spanish colony in the New World, north of the Isthmus of Panama) and in Nueva Leon (a region in Mexico).When the Inquisition reached these regions, many Conversos moved into the territories that became California, Arizona, New Mexico, Texas, and Colorado.  Some Conversos intermingled with native American Indian tribes, as the BRCA1 gene was identified in a Colorado Indian tribe (JTA, 2012). Conversos apparently fled to South America, as the BRCA1 185delAG mutation was identified in Chilean (Gallardo et al., 2006; Mew et al., 2002) and Ecuadorian (Velez et al., 2012) families.   

“Jewish genetic diseases”

Unfortunately, the phrase, “Jewish genetic disease,” is prevalent in the scientific and lay literature and portrays the Jewish population as a community of genetically inferior individuals with an overabundance of mutant genes. HaShem is an “equal opportunity employer” and deleterious founder mutations are present in all non-Jewish communities, with each specific mutation occurring at an elevated frequency in that particular community.  For example, familial Mediterranean fever (FMF) is an autosomal recessive disease manifested by recurrent fevers, rashes, and painful inflammation of joints, abdomen, and lungs. FMF is most common in people of the Mediterranean region, including in North African Jewry but also in individuals of Armenia, Turkey, and various Arab countries, with a frequency of 1 in 5 to 1 in 200 individuals (Counsyl, n.d.).  FMF, is thought to be an ancient founder mutation, traced to the sons of Shem, the son of Noach (Migdal et al., 1997). Similarly, Tay-Sachs disease is not limited to Ashkenazim, but is seen in French Canadians of southeastern Quebec, occurring at a carrier frequency similar to that in Ashkenazim but caused by a different mutated version of the HEXA gene. Cajuns of southern Louisiana, however, carry the same mutated HEXA gene as in Ashkenazim (Wikipedia, n.d.). As noted above, familial breast cancer is caused by different versions of the mutated BRCA 1 and is evident in populations world-wide; familial breast cancer should not be viewed as a uniquely Jewish health issue. Interestingly, the same BRCA1 185delAG founder mutation noted in Ashkenazim apparently arose independently in two non-Jewish populations, one in Malaysia and the other in the United Kingdom (Laitman et al., 2013).

The phrase “Jewish genetic diseases” that permeates the literature is both incorrect and offensive. The repeated juxtaposition of the word “Jewish” with “genetic diseases” has derogatory connotations among lay persons and may gradually influence the self-perception and public image of Jews. It should be stressed that HaShem did not single out the Jewish people to be carriers of genetic diseases. What is the source of, or reason for, this derogatory phrase? Carmeli (2004), based on a search of the PubMed database, performed a systematic comparison of genetic research to Jews and to other population groups. She noted that Jews were over-represented in human genetic literature, particularly in mutation-related contexts. She suggested possible reasons for the pervasiveness of Jews in mutation-related genetics studies: (a) Jewish communities are comparatively endogamous, yet sizeable; (b) easy access of geneticists to a variety of different Jewish communities (e.g., in the State of Israel, a geneticist can conveniently study several different isolated populations that migrated to Israel from all over the world); (c) many of the researchers are Jewish scientists, which alleviates any ethical concerns that may arise; and (d) the largest Jewish communities are in geographical proximity to major research centers.

The phrase “Jewish genetic diseases” implies that Jews, presumably burdened by a defective genome, would have a reduced life span. However, the opposite is true. Using data from the Health and Retirement Study (HRS), which was directed to Americans above 50 years of age, Sullivan (2010) examined the relationship between adult mortality and religious affiliation. Fifty years of age was selected for the baseline, as health risks for developing chronic disease and of dying start to increase after 50 years of age. Sullivan’s analysis focused on Jewish, Catholic, three Protestant groups (Mainline, Evangelical, and Black) and those with no religious preference. She noted mortality differentials with Jews having the lowest rate of mortality of any religious group.

Data compiled by the World Health Organization (World Health Statistics, 2015) showed that for 2013,  the life expectancy for Israelis was 81 years for males and 84 years for females, a year short of the top values.

Heterozygote advantage

If founder mutations are harmful, why do they persist to be transmitted from generation-to-generation.  The carrier of a founder mutation has one copy of the mutant gene and usually, as in Tay-Sachs disease, does not display the disease. The founder mutation for Tay-Sachs disease and for a predisposition to breast cancer have survived the environmental selection pressure for their elimination. Apparently, these mutations provide some positive advantage to compensate for their deleterious effects on life expectancy. Studies have indicated that a single copy of a founder mutation gives the carrier an advantage in the struggle for survival; this has been termed the “heterozygote advantage” (Drayna, 2005). Apparently, there is a balancing selection of competing forces that lead to a stable level of the BRCA1 and HEXA defective genes within the population.  Whereas the BRCA genes predispose a carrier to malignancy, the BRCA mutation improves fertility both in male and female heterozygous carriers. Increased fertility in carrier males is seen as a lower first and mean age at paternity and in carrier females as a lower rate of miscarriage (Kwiatkowski et al. 2016). Female BRCA1 carriers, analyzed within the Utah Population Database, had significantly more children, shorter birth intervals, and excess post-reproductive mortality risks than non-carrier controls (Smith et al., 2012). 

Three theories were proposed for identifying the heterozygote advantage responsible for the prevalence of Tay-Sachs mutant gene within the Jewish community.  The first hypothesis focused on resistance to tuberculosis. Being crammed into tuberculosis-ridden urban ghettos may have placed eastern European Jews under much stronger selection for resistance to tuberculosis than their rural non-Jewish neighbors. “An unexpectedly low frequency of deaths from tuberculosis among Tay-Sachs heterozygotes has in fact been reported, but the evidence remains inconclusive.” Two other thoughts were presented. “A second hypothesis is selection in Jews for the intelligence putatively required to survive recurrent persecution, and also to make a living by commerce, because Jews were barred from the agricultural jobs available to the non-Jewish population. A related third possibility is sexual selection for increased reproductive success, because men with the qualities required to become rabbis were prized as husbands and would have tended to marry wealthy women capable of nourishing many children” (Diamond, 1994).

Eliminating the transmission of founder mutations

Tay-Sachs disease occurred (note the use of the past tense) at a relatively high frequency in the Ashkenazi Jewish population, with an incidence of 1:3,6000  vs. 1:360,000 in the general non-Jewish population. The key verb in the preceding sentence is “occurred.” In 1983 a not-for profit organization, Dor Yeshorim, was established by Rabbi Eckstein, himself a parent of Tay-Sachs children. This organization provided confidential and anonymous genetic screening for carriers of Tay-Sach disease (as well as for other genetic diseases), specifically addressing the needs the charedi/chassidic ultra-Orthodox Jewish communities. Because abortion is generally not an acceptable option of this community, the Dor Yeshorim screening is a premarital program for individuals before their engagement or earlier in a relationship. Initially, the genetic screening was done using a biochemical assay to detect for hexosaminidase A, but subsequently it progressed to DNA analysis (Bach et al., 2001). The premarital screening program developed by Dor Yeshorim virtually eliminated the birth of Jewish Tay-Sachs babies worldwide (Gross, 2005).

Dor Yeshorim does not test for BRCA genes. Rabbi Eckstein reasoned, “What is the advantage of screening for a condition, a mutation, that has no treatment. It is just making more tragedy. For the rest of her life and her future generations, she will be burdened with worry” (Wheelwright, 2011). An alternative approach is available to avoid transmission of the BRCA genes. Preimplantation genetic diagnosis (PGD) is a reproductive option for BRCA mutation carriers, especially for those who already require in vitro fertilization (IVF) due to fertility problems. In this procedure, ova are fertilized outside of the human body, the embryos are tested for the presence of BRCA mutations, and only BRCA-free embryos are transferred to the uterus for implantation (Derks-Smeets et al., 2014; Sagi et al., 2009). PGD is also an option to avoid Tay-Sachs offspring in a couple for which both the husband and wife are carriers.

Concluding remarks

Not everyone may agree with the suggestion that a pasuk within the tochechah in Devarim refers to founder mutations, which is okay. If so, what relevance does this article convey? The important aspects of this article are: (a) as many founder mutations are deleterious, premarital genetic screening should be a serious consideration; (b) if both members of a couple are known carriers of a potential deleterious founder mutation and want to ensure that it is not transmitted to their offspring, then IVF and PGD are options, and (c) usage of the phrase “Jewish genetic diseases” should be avoided and eliminated from one’s vocabulary, as genetic diseases occur in all populations.

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