Asian origin for the worldwide-spread mutational event in Machado-Joseph disease.
BACKGROUND
Machado-Joseph disease is the most frequent dominant ataxia worldwide. Despite its frequency and presence in many populations, only 2 founder mutations have been suggested to explain its current geographic distribution.


OBJECTIVE
To trace back in history the main mutational events in Machado-Joseph disease, we aimed to assess ancestral haplotypes and population backgrounds, to date the mutations, and to trace the routes and time of introduction of the founder haplotypes in different populations.


METHODS
We studied 264 families with Machado-Joseph disease from 20 different populations. Six intragenic single-nucleotide polymorphisms were used to determine ancestral mutational events; 4 flanking short tandem repeats were used to construct extended haplotypes and measure accumulation of genetic diversity over time within each lineage.


RESULTS
The worldwide-spread lineage, TTACAC, had its highest diversity in the Japanese population, where we identified the ancestral short tandem repeat-based haplotype. Accumulated variability suggested a postneolithic mutation, about 5774 +/- 1116 years old, with more recent introductions in North America, Germany, France, Portugal, and Brazil. As to the second mutational event, in the GTGGCA lineage, only 7 families (of 71 families) did not have Portuguese ancestry, although gene diversity was again smaller in Portuguese families (0.44) than in non-Portuguese families (0.93).


CONCLUSIONS
The worldwide-spread mutation may have first occurred in Asia and later been diffused throughout Europe, with a founder effect accounting for its high prevalence in Portugal; the other Machado-Joseph disease lineage is more recent, about 1416 +/- 434 years old, and its dispersion may be explained mainly by recent Portuguese emigration.
Martins
Sandra
S
Instituto de Patologia e Imunologia Molecular da Universidade do Porto and Faculdade de Ciências, University of Porto, Porto, Portugal.
Calafell
Francesc
F
Gaspar
Claudia
C
Wong
Virginia C N
VC
Silveira
Isabel
I
Nicholson
Garth A
GA
Brunt
Ewout R
ER
Tranebjaerg
Lisbeth
L
Stevanin
Giovanni
G
Hsieh
Mingli
M
Soong
Bing-Wen
BW
Loureiro
Leal
L
Dürr
Alexandra
A
Tsuji
Shoji
S
Watanabe
Mitsunori
M
Jardim
Laura B
LB
Giunti
Paola
P
Riess
Olaf
O
Ranum
Laura P W
LP
Brice
Alexis
A
Rouleau
Guy A
GA
Coutinho
Paula
P
Amorim
António
A
Sequeiros
Jorge
J
D001208:Asia / Q000453:epidemiology; D004641:Emigration and Immigration; D005060:Europe / Q000453:epidemiology; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D007564:Japan / Q000453:epidemiology; D017827:Machado-Joseph Disease / Q000453:epidemiology* / Q000235:genetics*; D009154:Mutation / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011153:Population; D011174:Portugal / Q000453:epidemiology; D020080:Tandem Repeat Sequences / Q000235:genetics