American Journal of Medical Genetics 49:lO-13 (1994)

High Frequencies of Human Genetic Diseases: Founder Effect With Genetic Drift or Selection?

Joel Zlotogora Department of Human Genetics, Hadassah Medical Center, Hebrew University, Jerusalem, Israel

Rare genetic diseases have been reported with high frequency in some populations. The mechanisms which were proposed to explain most of these observations include founder effect, genetic drift or selective advantage. In recent years, many genes have been se- quenced and mutations causing some of these disorders were characterized. According to the analysis of haplotypes and/or mutations, it may be possible to distinguish 3 groups of disorders frequent in isolated populations. In the first group, all the affected patients have only one frequent mutation, suggesting a founder effect with genetic drift. In the sec- ond group, more than one mutation is found among the patients; however, most of the pa- tients are homozygotes for one frequent muta- tion which most probably originated from a common founder; the other patients are com- pound heterozygotes for the common muta- tion and a rare mutation. In the third group, more than one frequent mutation is found re- sponsible for each disease. This may be due to a selective advantage which allows the expan- sion of each new mutation in the particular population or to multiple founder effect with genetic drift in smaller communities which thereafter mixed to form the larger popula- tion. 0 1994 Wiley-Liss, Inc.

KEY WORDS: founder effect, genetic drift, selection, mutations

INTRODUCTION Rare genetic disorders have been reported to be rela-

tively frequent in some populations, for instance, the Old Order Amish people, the Ashkenazi Jews, the Finns, or the French Canadians. These communities

Received for publication November 30, 1992; revision received August 10, 1993.

Address reprint requests to Joel Zlotogora, M.D., Ph.D., Depart- ment of Human Genetics, Hadassah Hospital, P.O. Box 12000, Jerusalem 91120. Israel.

were isolated because of geographical conditions, reli- gion, or by preference and they have been the subject of detailed genetic analysis. In some cases, the genealogi- cal studies demonstrated a common origin of the car- riers, and a founder effect together with genetic drift was proposed to explain the high frequency of the disor- ders [Diamond and Rotter, 19871. However, other expla- nations for these observations have been proposed, in particular, a selective advantage for the heterozygotes [Rotter and Diamond, 19871.

Advances in molecular biology lead to the mapping and cloning of some of the genes involved in these dis- eases. Determination of haplotypes andlor mutations allows analysis of these questions with a new perspec- tive. We reviewed some of the disorders found to be frequent in isolated populations in which molecular data were available. Illustrative examples were chosen according to the author’s interest.

Infantile Form of Neuronal Ceroid Lipofuscinosis (NCL) in Finland

[Vesa et al., 19931 Infantile NCL is an autosomal recessive progressive

encephalopathy with onset before the age of 2 years. The disease is particularly frequent in Finland. The basic defect is unknown but recently the gene was mapped to the short arm of chromosome 1. HY-TM1 and MYCLl are 2 polymorphic markers tightly linked to the gene of infantile NCL and separated physically by 16 kb. Anal- ysis of the haplotype defined by these 2 markers demon- strated a strong linkage disequilibrium in the Finnish patients. This suggests that the disease is caused by one major mutation in Finland which originates from one common ancestor.

Phenylketonuria Among the Yemenite Jews [Avigad et al., 19901

The incidence of phenylketonuria among the Jews originating from Yemen is among the highest reported (1 : 5,000 live births). All of the patients examined are homozygous for the same deletion spanning the third exon of the gene and the genealogical data suggest that a single ancestor living at the end of the seventeenth century in the capital Sa’na, carried the mutation.

0 1994 Wiley-Liss, Inc.

Frequent Human Genetic Diseases 11

distan, 4 different mutations were frequent; in western Iran, one mutation was frequent; the other 4 were rare. In eastern Turkey, 4 mutations were found.

Metachromatic Leukodystrophy in the Habbanite Jews [Zlotogora et al., 19801

Metachromatic leukodystrophy is a neurodegenera- tive disease caused by the deficiency of aryl sulfatase A. In the late infantile form of the disease, the clinical symptoms begin with motor regression after the age of one year. This form of the disease was reported to be frequent (1/75 live births) in a small Jewish isolate that lived for centuries in the town of Habban, Northeast of Aden. The genealogical data pointed to one common ancestor carrier of the mutation who lived at the end of the 18th century. Molecular analysis of the gene coding for aryl sulfatase A demonstrated that all the patients are homozygotes for the same mutation. The common origin of the allele, including this unique metachroma- tic leukodystrophy mutation, is supported by the find- ing that all the carriers have the same intragenic haplo- type defined by 3 restriction sites [Zlotogora et al., submitted].

Gaucher Disease Qpe I11 in the Province of Norrbotten (Sweden) [Dahl et al., 19901

In Gaucher disease type 111, slowly progressive neuro- logical symptoms are present in addition t o the symp- toms due to the storage of the glucocerebrosidase found in the type I of the disease. The disease has been re- ported in high incidence in the province of Norrbotten and 3 common ancestors have been traced back to the 17th century, Analysis of the gene coding for gluco- cerebrosidase demonstrated that all the patients are homozygous for a same mutation L444P. This same mu- tation has also been found in patients with Gaucher disease from other origins often affected with a more severe phenotype (type 11) never seen in patients with the Norrbotten mutation. It is therefore possible that the Norrbotten mutation is linked to another genetic change which causes a milder phenotype.

Aspartylglycosaminuria in Finland [Mononen et al., 19911

Aspartylglycosaminuria is a storage disease with very slowly progressive mental retardation. The disease was first described in Finland and the carrier frequency was found to be 1 : 30 t o 1 :40 in this population. Analysis of the gene coding for aspartylglycosaminidase showed that one mutation C163S (G > C) is responsible for 98% of the mutant alleles in Finns. In this population, this mutation is always linked to another mutation R161Q (G > A) which does not affect the enzyme activity.

Thalassemia in the Jews From Kurdistan [Rund et al., 19911

Jews have lived in the Kurdistan mountains isolated from other Jewish communities for many centuries. They used to live in 3 distinct isolated subgroups; the largest of these was in Northern Iraq, the second in Iran and the smallest in Turkey. Within each group inbreed- ing was very high by preference. Some 20% of the Kur- dish Jews are carriers of thalassemia. Analysis of the mutations disclosed 13 different mutations with almost no overlap between the three groups. In central Kur-

Lysosomal Storage Diseases Among the Ashkenazim [Bach et al., 19921

Lysosomal storage diseases are a group of rare inher- ited disorders caused in most cases by the deficiency of a lysosomal enzyme. Among them, 4 recessive diseases are found with a relatively high incidence in the Ash- kenazi Jews. Tay Sachs disease (TSD) is a neuro- degenerative disease caused by the deficiency of hex- osaminidase A; both the infantile and adult types of the disease are frequent among the Ashkenazim. Gaucher disease type I is caused by the deficiency of gluco- cerebrosidase; the clinical symptoms are variable and some of the affected are asymptomatic. Niemann Pick disease is caused by the deficiency of sphyngomyelinase and 2 major forms are delineated according to the pres- ence or absence of neurological degeneration. Both forms have been reported to be relatively frequent among Ashkenazi Jews. The fourth lysosomal disease frequent in the Ashkenazim is mucolipidosis IV which causes mental retardation and severe ocular symptoms; the basic defect is still unknown.

In infantile TSD among the Ashkenazim two frequent mutant alleles in the gene coding for the chain of hex- osaminidase A have been identified: a G > C transver- sion which abolishes the splice signal at the boundary of exon 12 (18% of the mutant alleles), and a 4 nucleotide insertion within exon 11 (79% of the mutants alleles). In addition, in the same population a third mutation, G269S, is also relatively frequent (3% of the alleles). This latter mutation causes the adult type of the disease either in the homozygotes, or more frequently in com- pound heterozygotes when found together with one of the mutations causing the infantile type of TSD [Triggs- Raine et al., 19901. Two mutations in the gene coding for glucocerebrosidase, N370S (A > G) (71.6%) and 84GG (11.6%), have been found to be frequent among the Ash- kenazim affected with Gaucher disease. Another 3 mu- tations are found in the Ashkenazim with a frequency of 1% or more [Sibille et al., 19931. Since the recent cloning of the gene for sphyngomyelinase, 3 different mutations were found which account for 65% of the mutant alleles in the Ashkenazi patients with Niemann Pick disease [Levran et al., 19931.

Tay Sachs Disease Among the French Canadian [Hechtman et al., 19921

TSD is relatively frequent among the French Cana- dians. Analysis of the hexosaminidase A gene uncovered a 7.6 Kb deletion including the first exon in most of the patients (75% of the alleles). It seems that the center of origin of this mutation is the Gasp6 region in Canada, Most of the other French Canadian patients were com- pound heterozygotes for the deletion and an intron 7 splice site mutation (G > A). This second mutation has a different geographic center of diffusion and the founder seems to have originated from Charlevoix in Canada. Neither mutation was detected in France, the ancestral

12 Zlotogora

homeland of the French Canadians, and therefore they are both probably relatively recent events.

Tay Sachs Disease in a Cajun Population [McDowell et al., 19921

Infantile TSD is relatively frequent in Cajun families in southwest Louisiana. The Cajun community was founded in the 18th century by French Acadians with the addition of other emigrants, and remained isolated till the 19th century. In this population almost all the patients with TSD tested were found to be homozygote for an exon 11 insertion mutation which is also present in some 70% of the Ashkenazi TSD carriers. A single ancestral couple from France was found to be common to most carriers of this mutation. One affected child was a compound heterozygote for the common mutation and a single base transition (G > A) in the donor splice site of intron g.

Gyrate Atrophy of the Choroid and Retina in Finns [Mitchell et al., 19891

Gyrate atrophy is an autosomal recessive disorder caused by the deficiency of the mitochondria1 enzyme, ornithine aminotransferase. The major symptoms of the disease are related to vision; some patients also present with mental retardation and speech defects. The disease is frequent in Finland and most of the patients are either homozygous for a mutation R180T (G > C) or for another mutation L402P (T > C); each is found with similar frequency, and there are very few compound heterozygotes [Aula P, personal communication].

DISCUSSION Analysis of the data accumulated in various diseases

relatively frequent in some populations documented 3 types of observations. In the first group of disorders, the data are compatible with a founder effect with genetic drift: all the patients are homozygotes for .a same muta- tion. The examples which were presented here are: phe- nylketonuria in the Yemenite Jews, metachromatic leu- kodystrophy in the Habbanite Jews, and Gaucher disease in Norrbotten county. Analysis of the haplo- types in diseases such as infantile NCL in Finns or metachromatic leukodystrophy in the Habbanite Jews demonstrated a common origin of each of the mutations. These observations confirm the genealogical data ob- tained in each of these disorders. All of these disorders occurred in communities which were relatively small and had been isolated until recently. Even though selec- tion eliminates the homozygotes of these lethal diseases, the frequency of the mutant alleles was augmented by the large size of the families.

In the second group of diseases, more than one muta- tion was found in each population. However, the distri- bution of the mutations among the patients still sug- gests a founder effect with genetic drift. In the Finns, one mutation always linked to another polymorphic mu- tation accounts for 98% of mutant alleles in the patients with aspartylglycosaminuria. In the Cajun population in which most affected children are homozygous for an identical mutation originating from one ancestral cou- ple, only one patient was found to be a compound hetero-

zygote for this mutation and another mutation. The presence of rare mutations in addition to the frequent mutation is most probably due to the fact that nowadays these populations are relatively large and not com- pletely isolated. The mutations may have occurred as a random event or may have been introduced by a carrier from outside. In both cases, the rare mutation is seen because of the high frequency of the other mutation and affected patients are compound heterozygotes [Zlotogora, 19931.

In the third group of diseases, more than one frequent mutation is found. Examples given here are thalasse- mia among the Kurdish Jews, lysosomal storage dis- eases among the Ashkenazim, Tay Sachs disease in French Canadians, and gyrate atrophy in Finns. A pos- sible explanation for these observations is the existence of a selective advantage for the heterozygotes. While mutations occur in all populations at a similar rate, some of them may become frequent because of a selective advantage in a particular environment. As already dis- cussed, more than one mutation may be found among patients in apopulation where a disease is frequent. The rare mutation is then only apparent because of the high frequency of another mutation in the population. If the carriers of the new mutation have some selective advan- tage, then the new mutation will also become frequent. A selective advantage has been postulated for thalassemia which, similar to sickle cell anemia, seems to protect the heterozygotes against malaria. A high incidence of the disease was reported in various parts of the world; for instance, in the Mediterranean basin many different mutations were found to be frequent [Orkin and Kazazian, 19841. A selective advantage for the carriers of lysosomal storage diseases has also been suggested [Zlotogora et al., 19881. It may be that even though carriers of lysosomal diseases are healthy, the partial enzyme deficiency leads to a subtle storage of similar type of substances in the lysosome. This storage may be advantageous to the cell in some particular environmental conditions. For instance, it may confer in the cell resistance to some infectious agents. In a popu- lation such as the Ashkenazim, such a selective advan- tage may explain that not only one disease is caused by more than one frequent mutation, but also that more than one lysosomal storage disease is found in high frequency. It has been suggested that the advantage may have been resistance to pulmonary diseases, in particular tuberculosis, which were prevalent in the regions from which the Ashkenazi Jews originated [Rot- ter and Diamond, 19871.

Another possible explanation for the finding of more than one frequent mutation in a population where a disease is frequent, may be that while nowadays the population seems to be homogenous, in fact it is com- posed of smaller communities which, in the past, were isolated one from the other. For instance, the Ash- kenazim were dispersed in small communities in East- ern Europe and only recently are considered as one ethnic group. The French Canadians and the Finns in- clude also many smaller communities which were geo- graphically isolated one from the other. The occurrence of mutations in some of the smaller communities may

Frequent Human Genetic Diseases 13

have been followed later by the spread of each mutation within the community. The spread may have been be- cause of a selective advantage as already discussed; however, another possibility is a founder effect and ge- netic drift in each of the smaller communities. Among the French Canadians two relatively frequent muta- tions cause infantile TSD. Each mutation was shown to originate from a different geographic region in Canada. These observations are consistent with the possibility of two subpopulations in which TSD mutation expanded from one founder and which later mixed. In Finland, two frequent mutations cause gyrate atrophy; however, most of the patients reported up to now are homozygous for one of the mutations and compound heterozygotes are rare. This finding supports the possibility that the mu- tations first occurred in two smaller isolated commu- nities. With the expansion of the Finnish population and its mixing, it may be expected that the 2 mutations will spread at random and that the 3 different genotypes including the compound heterozygote will be common if there is no disadvantage to the compound heterozygote.

From the data presented here, it is evident that mo- lecular studies of haplotypes and mutations are useful to try to understand the mechanisms which lead to the high frequency of genetic disorders in some populations. However, i t is still difficult in some cases to determine whether the principal cause was genetic drift or selec- tion. Nowadays, there are many isolated populations in which the analysis of mutations and their diffusion will help us to understand what were the mechanisms which lead to the high frequencies of genetic diseases in iso- lated populations. This knowledge should also be useful for understanding the cause of the high frequency of diseases such as cystic fibrosis or phenylketonuria in larger populations.

REFERENCES Avigad S, Cohen BE, Bauer S, Schwartz G, Frydman M, Woo SLC, Niny

Y, Shiloh Y (1990): A single origin of phenylketonuria in Yemenite Jews. Nature 334:168-170.

Bach G, Zlotogora J, Ziegler M 11992): Lysosomal storage disorders among Jews. In Bonne-Tamir B, Adam A (eds): “Genetic Diversity Among Jews: Diseases and Markers a t the DNA Level.” NY and Oxford: Oxford University Press, pp 301-303.

Dahl N, Lagerstrom hl. Erikson A, Pettersson U (1990): Gaucher dis- ease type I11 (Norrbottnian type) is caused by a single mutation in exon 10 of the glucocerebrosidase gene. Am J Hum Genet 47: 275-278.

Diamond JM, Rotter JI (1987): Observing the founder effect in human evolution. Nature 3!!9:105-106.

Hechtman P, Boulay B, DeBraekeleer M, Andermann E, MelanCon S, Larochelle J , Prevost C, Kaplan F (1992): The intron 7 donor splice transition: A second Tay-Sachs disease mutation in French Canada. Hum Genet 90:402-406.

Levran 0, Desnick W, Schuchman EH (1993): Type A Niemann-Pick disease: A frameshift mutation in the acid sphingomyelinase gene (fsp330) occurs in Ashkenazi Jewish patients. Human Mutation 2:317-319.

McDowell GA, Mules EH, Fabacher P, Shapira E, Blitzer MG (1992): The presence of two different infantile Tay-Sachs disease mutations in a Cajun population. Am J Hum Genet 51:1071-1077.

Mitchell GA, Brody LC, Sipila I, Looney JE, Wong C, Engelhardt JF, Pate1 AS, Steel G, Obie C, Kaiser-Kupfer M (1989): At least two mutant alleles of ornithine aminotransferase cause gyrate atrophy of the choroid and retina in Finns. Roc Nat Acad Sci USA 86: 197-201.

Mononen I, Heisterkamp N, Kaartinen V, Williams JC, Yates JR, Griffin PR, Hood LE, Groffen J (1991): Aspartylglycosaminuria in the Finnish population: Identification of two point mutations in the heavy chain of glycoasparaginase. Proc Nat Acad Sci USA 88: 2941-2945.

Orkin SH, KazazianHH (1984): Themutation andpolymorphismofthe human-globin gene and its surrounding DNA. An Rev Genet 18: 131-171.

Rotter JI, Diamond JM (1987): What maintains the frequencies of human genetic diseases? Nature 329:289-290.

Rund D, Cohen T, Filon D, Dowling CE, Warren T, Barak I, Rachmile- witz E, Kazazian HH, Oppenheim A (1991): Evolution of a genetic disease in a genetic ethnic isolate: P-Thalassemia in the Jews of Kurdistan. Proc Nat Acad Sci USA 88:310-314.

Sibille A, Eng CM, Kim SJ, Pastores G, Grabowski GA (1993): Phe- notypeigenotype correlations in Gaucher disease type I: Clinical and therapeutic implications. Am J Hum Genet 52:1094-1101.

Eggs-Raine BI, Feigenbaum ASJ, Natowicz M, Skomorowski MA, Schuster SM, Clarke JTR, Mahuran DJ, Kolodny EH, Gravel RA (1990): Screening for carriers of Tay Sachs disease among Ash- kenazi Jews. A comparison of DNA based and enzyme based tests. N Engl J Med 323:6-12.

Vesa J, Hellsten E, Makela TP, Jarvela I, Airaksinen T, Santavuori P, Peltonen L (1993): A single PCR marker in strongallelic association with the infantile form of neuronal ceroid lipofuscinosis facilitates reliable prenatal diagnostics and disease carrier identification. Eur J Hum Genet 1:125-132.

Zlotogora J (1993): Is the presence of two different Tay-Sachs mutations in a Cajun population a n unexpected observation? Am J Hum Genet 521014- 1015.

Zlotogora J, Bach G, Barak Y, Elian E (1980): Metachromatic leuko- dystrophy in the Habbanite Jews: High frequency in a genetic isolate and screening for heterozygotes. Am J Hum Genet 32: 663-669.

Zlotogora J, Ziegler M, Bach G (1988): Selection in favor of lysosomal storage disorders? Am J Hum Genet 42271-273.