An ancient autosomal haplotype bearing a rare achromatopsia-causing founder mutation is shared among Arab Muslims and Oriental Jews

Abstract

Numerous cultural aspects, mainly based on historical records, suggest a common origin of the Middle-Eastern Arab Muslim and Jewish populations. This is supported, to some extent, by Y-chromosome haplogroup analysis of Middle-Eastern and European samples. Up to date, no genomic regions that are shared among Arab Muslim and Jewish chromosomes and are unique to these populations have been reported. Here, we report of a rare achromatopsia-causing CNGA3 mutation (c.1585G>A) presents in both Arab Muslim and Oriental Jewish patients. A haplotype analysis of c.1585G>A-bearing chromosomes from Middle Eastern and European origins revealed a shared Muslim-Jewish haplotype, which is different from those detected in European patients, indicating a recurrent mutation stratified by a Jewish-Muslim founder effect. Comprehensive whole-genome haplotype analysis using 250 K single nucleotide polymorphism arrays revealed a large homozygous region of ~11 Mbp shared by both Arab Muslim and Oriental Jewish chromosomes. A subsequent microsatellite analysis of a 21.5 cM interval including CNGA3 and the adjacent chromosome 2 centromere revealed a unique and extremely rare haplotype associated with the c.1585G>A mutation. The age of the shared c.1585G>A mutation was calculated using the microsatellite genotyping data to be about 200 generations ago. A similar analysis of mutation age based on the Arab Muslim data alone showed that the mutation was unlikely to be the product of a recent gene flow event. The data present here demonstrate a large (11 Mbp) genomic region that is likely to originate from an ancient common ancestor of Middle-Eastern Arab Muslims and Jews who lived approximately 5,000 years ago.

Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities

“…Before 1 AD the annual population growth rate was potentially less than ~1% [18,19]. Thus, for the growth rate a range of values (1-3%) was used for the calculations in part based on the growth rates by Zelinger and colleagues [20]. …”

Genetics and Disease Expression in the CNGA3 Form of Achromatopsia

“…A detailed analysis of the c.1585G>A CNGA3 founder mutation was reported by us previously, and interestingly was found to be a part of an ancient shared haplotype between Oriental Jewish and Muslim patients. 18 The 2 most common mutations identified in our cohort of patients were found in CNGA3, as shown in Table 2 (available at www.aaojournal.org): c.1585G>A (p.V529M in 16 families and 39 patients) and c.940_942delATC (in 12 families and 32 patients). The most common ACHM mutation in the Western population (c.1148delC in CNGB3 9 ) was the cause of disease in only 4 families of North African Jewish origin in our cohort.…”

“…15 We reported previously genetic findings in a number of ACHM patients from the United States 16,17 and identified a founder mutation in the CNGA3 gene causing ACHM in Muslim and Jewish populations representing 10 families living in Israel. 18 That observation prompted this study, which shows that ACHM is a relatively common retinal phenotype in the Israeli and Palestinian populations. A comprehensive genetic and clinical analysis revealed the identification of 21 disease-causing mutations in the CNGA3 and CNGB3 genes in 49 families (including 130 patients).…”

Carrier frequency analysis of mutations causing autosomal-recessive-inherited retinal diseases in the Israeli population

“…Similarly, the founder mutation CNGA3-p.(Ile314del) was found only in Arab Muslims of the vicinity of Jerusalem (AMJ) with a carrier frequency of 1.6%. On the other hand, some variants appear in multiple ethnic groups: the CNGA3-p.(Val529Met) founder mutation [17] that appears in both Oriental Jews (OJ) and AMJ ( Fig. 4a) and the pan-ethnic variant ABCA4c.5882G>A that is common in all Israeli subpopulations (ranging from 2.6 to 5%, Fig.…”