Multiple mutations in a specific gene in a small population

0 Academic C&Gtique

des sciences / Elsevier, Paris I Genetics

Multiple mutations population

in a specific gene in a small

Mutations mdtiples d ‘un mbne g&e aims lespetites popuhtions Josu6 Feingold Unite de recherches d’epid6miologie 75251 Paris cedex 05, France

genetique,

lnserm

U155,

(Received 27 April 1998, accepted after revision 8 June

1998)

universite Paris-VII, case 7041, 2, place Jussieu,

Abstract - Hereditary diseases have been reported with relatively high frequency in some small populations. Founder effect and genetic drift, associated or not with selective advantage of heterozygotes in case of recessive diseases, are the main explanations. Therefore, if we consider one population and one particular disease, only one deleterious allele should be observed. Determination of mutations has shown that in most cases the situation is more complex; more than one mutation is found among the patients. This finding can be explained by a multiple founder effect, with genetic drift and new mutations. (0 Academic des sciences / Elsevier, Paris.) multiple

mutations

/small

populations/founder

effect

/ genetic

drift

R&urn6 - De nombreuses maladies htreditaires ont une frequence elevee dam des petites populations. L’explication classique de ce phenomene est l’existence dun effet fondateur suivi d’une derive genetique. Un avantage selectif des heterozygotes en cas de maladie recessive autosomique peut &tre associe aux deux facteurs precedents. De ce fait, si l’on considere un gene particulier et une population, une seule mutation deletere doit Ctre observee. L’etude des mutations pathologiques a I’echelle moleculaire a montre que, dans la majorite des cas, la situation etait plus complexe. En effet on observe t&s souvent plusieurs mutations d’un mCme gene dam une petite population. Des effets fondateurs multiples, la fusion de petites populations, de nouvelles mutations expliquent ces observations qui sont apparemment paradoxales. (0 Academic des sciences / Elsevier, Paris.) mutations

multiples

Version

I p&es

populations

/ &et

fondateur

I d&k

gLnCtique

abrCg&e

Dans de nombreuses petites populations ou qui l’etaient B leur origine, la frequence de certaines maladies hereditaires est relativement tlevee. On explique ce fait par un effet fondateur suivi d’une derive genetique. A ce mecanisme peut s’associer, pour les maladies recessives autosomiques, un avantage selectif des heterozygotes. La consequence de ces hypotheses est que, pour un gene particulier, on ne doit observer qu’une mutation dtktere dam une petite popula-

Communicated E-mail:

by Jean Rosa

[email protected]

C. R. Acad. 1998.321,553-555

Sci.

Paris,

Sciences

de

la vie

/ Life

WenCes

tion. L’analyse moleculaire des mutations a montre que les faits sont en realitt beaucoup plus complexes. Trois situations d&rites par J. Zlotogora peuvent s’observer. - Dam une premiere situation, on n’observe qu’une seule mutation deletere. C’est par exemple le cas de la phenylcetonurie chez les juifs du Yemen. - Dans la seconde, plusieurs mutations sont decrites mais l’une est predominante. C’est ainsi que plusieurs mutations du gene de la calpaine 3 sont a I’origine de la dystrophie mus-

J. Feingold

culaire des ceintures dans Pile de la Rkunion, mais une des mutations d&Pres est prkdominante. Une situation analogue est observCe au Quebec dans la tyrosirkmie de type 1 : la frequence relative de la mutation prhdominante est de 90 %. - Dans la troisikme situation, plusieurs mutations d&Sres relativement frkquentes sont observkes. C’est le cas par exemple de la mucoviscidose dans la population de la RCunion ou

Hereditary

disorders

have

been

reported

to be relatively

nished such examples [l-7]. The most often suggested genetic hypothesis to explain such observations is a founder effect together with genetic drift. This explanation does not exclude a selective advantage for heterozygotes in case of recessive diseases. Therefore, if we consider and one be observed.

types

of situations

there is only with a founder

one

mutation effect with

and the genetic

of

homozygotes for the deleterious gene, the frequency of the mutant alleles was increased by genetic drift. Using simulation studies in closed populations having an average of 4.0 offspring per generation, F.B. Livingston showed that the frequency of a deleterious gene occurring in one of the founders can reach polymorphic frequencies in over 50 % of the populations after the doubled

in

size

for

several

generations

[121. In the particular

second situation, genetic disease

more than one mutation is found in a specific

for a popu-

lation. However, one mutation is predominant fact still suggests a founder effect with genetic observed mutations, in addition to the frequent

and this drift. Rare one, are

new tion.

by migramost chil-

mutations and/or mutations For instance, in the Cajun

introduced population,

dren affected by Tay-Sachs disease are homozygous for the same mutation, an exon 11 insertion, and only one affected child was found to be a compound heterozygote [13, 141. In the population of Reunion Island,

554

observed

the

presence

of at least

six

of the calpain gene in limb-girdle type 2A. One of these mutations As pointed out by Zlotogora [B],

is in

this case, observation of rare mutations is due to the high frequency of the ‘major’ mutation, affected patients being compound heterozygotes with rare mutations involved. In this situation, if we exclude the major deleterious allele, the frequency of the rare alleles is about

disease, is a good example. This disease is rare in most populations, with a prevalence at birth lower than l/l 00 000 [I 61. In the region of Saguenay Lac Saint Jean (Quebec, Canada) the prevalence at birth is l/l 800, and

disorders occurred in populations which were relatively small and had been isolated. Despite the elimination

had

[15]

mutations dystrophy predominant.

of

drift. Zlotogora has presented some examples concerning autosomal recessive diseases: phenylketonuria in the Yemenite Jews [9], metachromatic leucodystrophy in the Habbanite Jews [I 01 and Gaucher type 3 disease in Norbotten county in Sweden [I I]. As pointed out, these

population

et al.

of haplotypes associated more complex situations [B]. concerning various relatively populations, has noted three

single deleterious determination

[B].

In the first situation, data are compatible

different muscular clearly

the same as that observed in populations where the disease is rare. In such populations we consider all the deleterious alleles. Hereditary tyrosinemia, a recessive

locus, only one Nevertheless,

mutations and/or identification with mutations have shown J. Zlotogora, analysing data frequent diseases in some

dans des villages arabes de

Pour expliquer ces faits, il faut admettre que plusieurs effets fondateurs peuvent 6tre g l’origine d’une population, celle-ci peut en outre rksulter de la fusion de plusieurs populations. On ne peut exclure l’apparition de nko-mutations dont la survenue est rkente.

Richard

frequent in small populations and in populations which were small at their origin. The Amish people, the Ashkenazi, Sepharadi or Oriental Jews, the Finns, the French Canadians and many Arab communities have fur-

one population allele should

de certaines maladies hkriditaires Galike.

the gene mutation, population prevalence which tions.

frequency is about l/40. One mutation, a splice represents 90 % of the mutations [I 71. In this the frequency of the rare alleles is l/400. The of the disease is consequently l/l60 000 is the

frequency

observed

in

the

other

In the third situation, more than one frequent is found and the case of cystic fibrosis (CF), Island, is a good example. The disease involves so-called ‘petits birth is about

l/l

blancs’ 000.

popula-

mutation in Reunion mainly the

inhabitants, and prevalence Three frequent mutations

at have

been observed: AF508, the major mutation in Europe and North America, Y122X, clearly a ‘Reunion mutation’, and the 2120+1 G 8 A mutation, an African one. These three mutations account, respectively, for 39, 29 and 12 % of the CF alleles [IB-201. A similar situation was observed in Israel, in the small non-Jewish population of Galilee, concerning three other recessive diseases, namely Hurler disease, metachromatic leucodystrophy (MLD) and non-syndromic recessive deafness [21-231. Molecular analysis of the iduronidase gene of arylsulfatase A gene and connexin five and two mutations of respectively. One possible explanation

three,

26 genes revealed similar frequencies, for such findings,

more than one frequent mutation for a frequent disease in a specific population, is the multiple origin of an apparently homogeneous population. But Carrasquillo et al. have shown that the two connexin 26 very recent origin. They have estimated mutations to be 3-5 generations [21]. C. R. Acad.

Sci. Paris, Sciences

mutations have a the age of these Similar examples

de la vie / Life Sciences 1998.32 1,553~555

Multiple

have

been

observed

concerning

p thalassaemia

additional

comments

-The

difference

between

are

1 and

situations

2 can

be the

References Jl 1 McKusick kins University

Genetic Studies PA, 1978.

[21 Bonne-Tamir B., Adam A., Genetic and Markers at the DNA Level, Oxford [31 Motulsky (1995) 99-100.

A.G.,

Jewish

diseases

of the Amish,

Diversity University and

among Press,

origins,

Nat.

Johns

Jews: Oxford, Genet.

Diseases 1992.

[41 Norio R., Nevalinna H.R., Perheentupa J., Hereditary diseases land: rare flora in rare soil, Ann. Clin. Res. 5 (1973) 109-l 41, [51 de la Chapelle tions: the example

A.J., Disease of Finland,

gene mapping J. Med. Cenet.

I61 Bouchard G, De Braekeleer M, Histoire versite du Quebec, Ville !, 1990.

d’un

in isolated 30 (1993)

human 857-868.

genome,

Presse

[7) Teebi A.S., Farag T.I., Genetic disorders among Oxford monographs in Medical Genetics 30, Oxford Oxford, 1997. ISI Zlotogora J., High frequencies effect with genetic drift or selection,

Hop-

1995

(9)

in Finpopulade I’uni-

Arab populations, University Press,

of human genetic diseases: Founder Am. J. Med. Genet. 49 (1994) 1 O-l 3.

191 Avigad S., Cohen B.E., Bauer S., Schwartz C., Frydman M., Woo S.L.C., Niny Y., Shiloh Y., A single origin of phenylketonuria in Yemenite Jews, Nature 334 (1990) 168-l 70. [lo] Zlotogora J., Bach C., Barak Y., Elian E., Metachromatic phy in the Habbanite Jews: High frequency in a genetic screening for heterozygotes, Am. J. Hum. Genet. 32 (1980)

leukodystroisolate and 663-669.

[ill Dahl N., Lagerstrom M., Erikson A., Pettersson U., Gaucher disease type III (Norrbottnian type) is caused by a single mutation in exon 10 of the glucocerebrosidase gene, Am. J. Hum. Genet. 47 (1990) 275-278. J121 Livingstone F.G., Simulation determination of the polymorphic human populations, Hum. Biol.

of the founder effect and its role in the frequencies of deleterious genes in 59 (1987) 59-75.

[13] McDowell G.A., Mules E.H., Fabacher P., Shapira E., Blitzer The presence of two different infantile Tay-Sachs disease mutations Cajun population, Am. J. Hum. Cenet. 51 (1992) 1071-1077. I141 Zlotogora J., Is the presence a Cajun population an unexpected (1993) 1014-1015.

of two different observation?,

[15] Richard I., Broux O., Allamand V., Fougerousse N., Bourg N., Brenguier L., Mutations in the proteolytic 3 cause limb-girdle muscular dystrophy type 2A, Cell [161 Mitchell Striver C.R.,

G.A., Beaudet

C. R. Acad. 1998.321,553-555

Sci. Paris,

de

la vie

in 52

!., Chiannikulchai enzyme calpain 81 (1995) 27-40.

Lambert M.A., Tangay R.M., Hypertyrosinemia, A.L., Sly W.S., Valle D. (eds), The Metabolic

Sciences

M.G., in a

Tay-Sachs mutations Am. J. Hum. Cenet.

/ Life Sciences

in a small

population

- Even in a small inbred population homozygosity (autozygosity) mapping must concern only affected individuals born to closely related parents (i.e. first cousins). It is impossible to assume a priori the existence of a unique deleterious mutation small population.

of Inherited 1077-l 106.

V.A. (ed), Medical Press, Baltimore,

gene

In the same population the situation can differ from one disease to another: in Reunion Island, situation two concerns limb-girdle muscular dystrophy (LGMD 2A) and situation three cystic fibrosis.

necessary.

simply the consequence of the sample size studied: discovery of rare mutations needs a large sample.

in a specific

-

among

Kurdish Jews [241, lysosomal storage diseases among Ashkenazi Jew 1251 and Tay-Sachs disease in French Canadians 1261. A selective advantage for heterozygotes can also explain such a situation [27]. Some

mutations

in: Basis

Diseases,

for a particular

7th edition,

McGraw-Hill,

recessive

New

disease

York,

in a

1994,

pp.

1171 Grompe M., St Louis M., Demers S.I., Al-Dhalimy M., Leclerc B., Tangay R.M., A single mutation of the fumarylacetoacetate hydroxylase gene in most French Canadians with hereditary tyrosinemia type 1, N. Engl. J. Med. 331 (1994) 353-357. [181 Hillaire D., Chomel J.C., Lesur F., Renouil M., Musenger C., Pierson F., Berthelon M., Lenoir G., Gerard C., Bois E., Kitzis A., Munnich A., Kaplan J.C., Feingold I., Cystic fibrosis in the population of Reunion Island, Ann. Genet. 34 (1991) 5-7. 1191 Chevalier-Porst F., Chomel J.C., Hillaire D., Kitzis A., Kaplan J.C., Goutaland R.. Mathier M., Bozon D., A non sense mutation in exon 4 of the cystic fibrosis gene frequent among the population of reunion Island, Hum. Mol. Genet. 1 (1992) 647-648. I201 Bienvenu T., Cartault F., Lesure F., Renouil M., Beldjord C., Kaplan J.C., A splicing mutation in intron 16 of the cystic Fibrosis Transmembrane conductance regulator gene, associated with severe disease is common on Reunion Island, Hum. Hered. 46 (1996) 168-l 71, J211 Heinisch U., Zlotogora J., Kafert S., Gieselmann V., Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area, Am. J. Hum. Genet. 56 11995) 51-57. J221 Bach G., Moskowitz S.M., Tieu ular anlysis of Hurler syndrome in Israel: multiple allelic mutations of area, Am. J. Hum. Genet. 53 (1993)

PT., Matynia A., Neufeld E.F., MolecDruze and Muslim Arab patients in the IDUA gene in a small geographic 330-338.

1231 Carrasquillo M.M., Zlotogora J., BarRes S., Chakravarti A., Two different con&in 26 mutation& an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations, Hum. Mol. Genet: 12 (1997) 2163-2172. [24J Rund D., Cohen T., Filon D., Dowling C.E., Warren T., Barak I., Rachmilewitr E., Kazazian H.H., Oppenheim A., Evolution of a genetic disease in a genetic ethnic isolate: b-Thalassemia in the Jews of Kurdistan, Proc. Nat. Acad. Sci. USA 88 (1991) 310-314. [251 Bach G., Zlotogora J., Ziegler M., Lysosomal among Jews, in: Bon&Tamir B., Adam A. (eds), Among Jews: Diseases and Markers at the DNA Level, Press, Oxford, 1992, pp. 301-303.

storage Genetic Oxford

disorders Diversity University

J261 Hechtman P., Boulay B., DeBraekeleer M., Andermann E., Melancon S., Larochelle J., Prevost C., Kaplan F., The intron 7 donor splice transition: A second Tay-Sachs disease mutation in French Canada, Hum. Genet. 90 (1992) 402-406. J271 Zlotogora J., Ziegler M., Bach storage disorders?, Am. Hum. Genet.

G., Selection in favor 42 (1998) 271-273.

of lysosomal

555