We used 15 genetic variants spanning chromosome 21 from the SOD1 gene to the SCAF4 gene, comparing them with the population reference panels. We determined all the inferred SOD1 haplotypes for these 14 SNPs in the IBS, European, Asian, African and Mixed American populations, using all available 1K Genomes Project subjects as a control group.

A conserved haplotype block, in high linkage disequilibrium, was detected between the start of intron 1 and the end of SOD1, including the SCAF4 gene. The founder p.A5V-SOD1 haplotype in our patients is identical to the Swedish population. This European haplotype (p.A5V-EUR) was the most common in all populations. The American haplotype (p.A5V-USA) was the second most common worldwide. However, both haplotypes have similar frequencies in the Asian population (0.386 for p.A5V-EUR, 0.385 for p.A5V-USA).

These genetic studies suggest that the first inhabitants of the Americas came from a single Siberian population, which migrated using the Bering Land Bridge around 16,500 years ago. We propose a Eurasian origin for the p.A5V mutation in the haplotype p.A5V-EU. A Eurasian individual could have introduced the haplotype p.A5V-EU in America, and the mutation could have recombined in their descendants to produce the p.A5V-USA haplotype linked to the p.A5V mutation. A genetic drift in America could therefore explain the founder effect of p.A5V in the haplotype p.A5V-USA being the most frequent ALS1 mutation in USA. A similar genetic phenomenon was described for the p.D91A variant.