Age and founder effect of SOD1 A4V mutation causing ALS

Area of Science:

• Genetics
• Neuroscience
• Population Genetics

Background:

• The alanine to valine mutation at codon 4 (A4V) in the SOD1 gene is a significant cause of familial amyotrophic lateral sclerosis (ALS), particularly in North America.
• This mutation leads to a rapidly progressive form of ALS affecting lower motor neurons and accounts for half of SOD1-related familial ALS cases in North America.
• While prevalent in North America, the A4V mutation is infrequently observed in European populations.

Purpose of the Study:

• To investigate the geographical and temporal origins of the SOD1 A4V mutation.
• To determine the ancestral source and age of the A4V mutation in different populations.

Main Methods:

• Genotyping of multiple cohorts, including North American and European A4V patients, ALS patients with other SOD1 mutations, sporadic ALS patients, and diverse ethnic control groups.
• High-throughput SNP genotyping using Taqman assay and genotyping of a novel biallelic CA repeat in SOD1 exon 5.
• Statistical association analysis using Haploview and age estimation using methods based on r(2) degeneration and Bayesian approaches (DMLE+).

Main Results:

• A specific haplotype of 10 polymorphisms was strongly associated with the A4V mutation in white controls, suggesting a founder effect.
• The strength of this haplotype association decreased with non-white control groups, indicating distinct founder effects.
• Two distinct founder effects for A4V were identified: one Amerindian and one European, with the European haplotype differing from the North American one.
• The estimated age of the A4V mutation ranged from 458 +/- 59 years (r(2) degeneration) to 554-734 years (Bayesian method).

Conclusions:

• The SOD1 A4V mutation in North America originates from two distinct founder events.
• These founder events are estimated to have occurred 400-500 years ago, involving Amerindian and European ancestral sources.
• This research provides crucial insights into the population genetics and historical origins of a specific genetic cause of ALS.