Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency |
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Authors: | Rebecca Ott John S Waye P L Chang P Chang |
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Institution: | (1) Department of Biology, McMaster University, Hamilton, Ontario, Canada, CA;(2) Department of Pediatrics, Room 3N18, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada Tel.: +1 905-521-2100, ext. 3716; Fax: +1 905-521-2651; e-mail: changp@fhs.mcmaster.ca, CA;(3) Department of Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada, CA;(4) Department of Pathology, McMaster-University, Hamilton, Ontario, Canada, CA |
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Abstract: | Deficient arylsulfatase A activity causes the neurodegenerative disease metachromatic leukodystrophy. However, some individuals
with deficient enzyme activity appear clinically normal. This “pseudodeficiency” allele commonly found among many reported
populations (frequency ∼ 0.10) is associated with two A→G transitions in cis in the arylsulfatase A gene causing the simultaneous loss of an N-glycosylation and a polyadenylation signal. To understand the evolutionary relationship between such common and tightly linked
mutations, we studied 400 individuals in the African, European, Indian and East Asian populations and found none carrying
the polyadenylation mutation alone. However, the N-glycosylation mutation could occur independently. Its frequency varied from 0.01 in Indians, 0.06 in Europeans, 0.21 in East
Asians to 0.32 in Africans. The frequencies of both mutations occurring together ranged from almost non-existent in the Africans
and East Asians, to 0.075 in the Europeans and 0.125 in the Indians. These frequencies were significantly different among
populations. Haplotype analysis among homozygous pseudodeficiency individuals and eight multi-generation families with six
polymorphic enzymes showed that, of the five haplotypes found in the general population, only one was linked to the double
mutations. Alleles among the four populations with only the N-glycosylation mutation also supported linkage to the same haplotype except in some Europeans whose alleles were discordant.
These results are consistent with the hypothesis that the N-glycosylation mutation may be a recurrent event among the Europeans but first occurred in an ancestral allele before the
emergence of modern Homo sapiens from Africa at ∼100 000–200 000 years ago. Subsequently, the polyadenylation mutation occurred in this ancient allele with
the N-glycosylation mutation, an event that likely took place after the divergence between the European and East Asian lineages.
Received: 23 December 1996 / Accepted: 21 July 1997 |
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