Abstract
BackgroundPolymorphic human Alu elements are excellent tools for assessing population structure, and new retrotransposition events can contribute to disease. Next-generation sequencing has greatly increased the potential to discover Alu elements in human populations, and various sequencing and bioinformatics methods have been designed to tackle the problem of detecting these highly repetitive elements. However, current techniques for Alu discovery may miss rare, polymorphic Alu elements. Combining multiple discovery approaches may provide a better profile of the polymorphic Alu mobilome. AluYb8/9 elements have been a focus of our recent studies as they are young subfamilies (~2.3 million years old) that contribute ~30% of recent polymorphic Alu retrotransposition events. Here, we update our ME-Scan methods for detecting Alu elements and apply these methods to discover new insertions in a large set of individuals with diverse ancestral backgrounds.ResultsWe identified 5,288 putative Alu insertion events, including several hundred novel AluYb8/9 elements from 213 individuals from 18 diverse human populations. Hundreds of these loci were specific to continental populations, and 23 non-reference population-specific loci were validated by PCR. We provide high-quality sequence information for 68 rare AluYb8/9 elements, of which 11 have hallmarks of an active source element. Our subfamily distribution of rare AluYb8/9 elements is consistent with previous datasets, and may be representative of rare loci. We also find that while ME-Scan and low-coverage, whole-genome sequencing (WGS) detect different Alu elements in 41 1000 Genomes individuals, the two methods yield similar population structure results.ConclusionCurrent in-silico methods for Alu discovery may miss rare, polymorphic Alu elements. Therefore, using multiple techniques can provide a more accurate profile of Alu elements in individuals and populations. We improved our false-negative rate as an indicator of sample quality for future ME-Scan experiments. In conclusion, we demonstrate that ME-Scan is a good supplement for next-generation sequencing methods and is well-suited for population-level analyses.
Highlights
Polymorphic human Alu elements are excellent tools for assessing population structure, and new retrotransposition events can contribute to disease
Eight single-replicate insertions and two insertions with low read counts within SVA_D (SINE/VNTR/ Alu) elements did not have an Alu element when detected by PCR
We tested nine insertions found in AFP20 and in one other individual, and all nine insertions were confirmed by PCR (Additional file 1: Tables S2, S3)
Summary
Polymorphic human Alu elements are excellent tools for assessing population structure, and new retrotransposition events can contribute to disease. AluYb8/9 elements have been a focus of our recent studies as they are young subfamilies (~2.3 million years old) that contribute ~30% of recent polymorphic Alu retrotransposition events. Alu elements are members of the SINE family of elements and utilize the LINE-1 endonuclease and reverse-transcriptase for retrotransposition [4] This process inserts the Alu element, including its constitutive poly(A) tail and a target site duplication (TSD) sequence, into the genome [4, 5]. These hallmarks provide evidence of a retrotransposition event rather than a duplication or rearrangement. Alu elements contribute to the variation and regulation of the human genome [16, 18, 21,22,23], highlighting the importance of characterizing rare, ancestrally informative loci
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