Abstract
The Saguenay–Lac-Saint-Jean (SLSJ) region is located in northeastern Quebec and is known for its unique demographic history and founder effect. As founder populations are enriched with population-specific variants, we characterized the variants distribution in SLSJ and compared it with four European populations (Finnish, Sweden, United Kingdom and France), of which the Finnish population is another founder population. Targeted sequencing of the coding and non-coding immune regulatory regions of the SLSJ asthma familial cohort and the four European populations were performed. Rare and low-frequency coding and non-coding regulatory variants identified in the SLSJ population were then investigated for variant- and gene-level associations with asthma and allergy-related traits (eosinophil percentage, immunoglobulin (Ig) E levels and lung function). Our data showed that (1) rare or deleterious variants were not enriched in the two founder populations as compared with the three non-founder European populations; (2) a larger proportion of founder population-specific variants occurred with higher frequencies; and (3) low-frequency variants appeared to be more deleterious. Furthermore, a rare variant, rs1386931, located in the 3ʹ-UTR of CXCR6 and intron of FYCO1 was found to be associated with eosinophil percentage. Gene-based analyses identified NRP2, MRPL44 and SERPINE2 to be associated with various asthma and allergy-related traits. Our study demonstrated the usefulness of using a founder population to identify new genes associated with asthma and allergy-related traits; thus better understand the genes and pathways implicated in pathophysiology.
Highlights
IntroductionAn advantage of studying founder populations is the possibility to investigate variants, which occurred in higher frequencies as compared with the general population, due to either genetic drift or weaker selection against deleterious alleles [5,6,7,8]
For the first objective of characterizing variants distribution, after removal of related individuals and outliers 76 samples from the SLSJ cohort were paired with 76 samples from each of the four other European populations
We observed a smaller number of variants in both founder populations (total number of variants: 111,669 (SLSJ), 108,485 (FINN), 120,473 (FR), 114,468 (SWE) and 116,937 (UK); Table 2) and was reflected in the mean number of singletons per sample for each population (Supplementary Table 1 and Supplementary Figure 2)
Summary
An advantage of studying founder populations is the possibility to investigate variants, which occurred in higher frequencies as compared with the general population, due to either genetic drift or weaker selection against deleterious alleles [5,6,7,8]. These effects can lead to overcome selection disadvantage and allow alleles to reach higher frequencies in founder populations [9,10,11,12] such as the French-Canadian [13] and Finnish populations [14]. Despite the major contribution of common variants, investigations of rare and low-frequency variants in founder populations would provide additional and insightful information about the underlying biological mechanism of traits development
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