Abstract
Genetic studies of population isolates have great potential to provide a unique insight into genetic differentiation and phenotypic expressions. Galičnik village is a population isolate located in the northwest region of the Republic of North Macedonia, established around the 10th century. Alport syndrome-linked nephropathy with a complex inheritance pattern has been described historically among individuals in the village. In order to determine the genetic basis of the nephropathies and to characterize the genetic structure of the population, 23 samples were genotyped using a custom-made next generation sequencing panel and 111 samples using population genetic markers. We compared the newly obtained population data with fifteen European population data sets. NGS analysis revealed four different mutations in three different collagen genes in twelve individuals within the Galičnik population. The genetic isolation and small effective population size of Galičnik village have resulted in a high level of genomic homogeneity, with domination of R1a-M458 and R1b-U106* haplogroups. The study explains complex autosomal in cis digenic and X-linked inheritance patterns of nephropathy in the isolated population of Galičnik and describes the first case of Alport syndrome family with three different collagen gene mutations.
Highlights
Studying population isolates in the context of genetic and phenotypic variation can provide a unique insight into genetic differentiation of isolated populations and phenotypic expressions, especially when phenotypically important variants arise either uniquely within that population or begin to exhibit frequency differences across populations
Generation sequencing (NGS) analysis of the collagen genes was performed on affected individuals and their family members to assess the genetic cause of nephropathy
Twenty-three individuals of the Galičnik population were genotyped for collagen gene mutations
Summary
Studying population isolates in the context of genetic and phenotypic variation can provide a unique insight into genetic differentiation of isolated populations and phenotypic expressions, especially when phenotypically important variants arise either uniquely within that population or begin to exhibit frequency differences across populations. The genetic and phenotypic differentiations between and within populations are often complex and can be the result of a combination of various population effects, such as isolation, selection, migration, bottleneck, adaptation, and genetic drift. Over time, all these effects shape the population genetic structure, making it more homogenous internally and more differentiated from neighboring populations [1,2,3,4]. It is one of the two biggest and oldest villages in the region, and was established around the 10th century by a Slavic ethnic group called Mijaks.
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