Sequence Analysis and Characterization of Active HumanAlusubfamilies Based on the 1000 Genomes Pilot Project

Abstract

The goal of the 1000 Genomes Consortium is to characterize human genome structural variation (SV), including forms of copy number variations such as deletions, duplications, and insertions. Mobile element insertions, particularly Alu elements, are major contributors to genomic SV among humans. During the pilot phase of the project we experimentally validated 645 (611 intergenic and 34 exon targeted) polymorphic “young” Alu insertion events, absent from the human reference genome. Here, we report high resolution sequencing of 343 (322 unique) recent Alu insertion events, along with their respective target site duplications, precise genomic breakpoint coordinates, subfamily assignment, percent divergence, and estimated A-rich tail lengths. All the sequenced Alu loci were derived from the AluY lineage with no evidence of retrotransposition activity involving older Alu families (e.g., AluJ and AluS). AluYa5 is currently the most active Alu subfamily in the human lineage, followed by AluYb8, and many others including three newly identified subfamilies we have termed AluYb7a3, AluYb8b1, and AluYa4a1. This report provides the structural details of 322 unique Alu variants from individual human genomes collectively adding about 100 kb of genomic variation. Many Alu subfamilies are currently active in human populations, including a surprising level of AluY retrotransposition. Human Alu subfamilies exhibit continuous evolution with potential drivers sprouting new Alu lineages.

The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology

“…These mutations (and patterns of mutations) have been useful for determining whether a given MEI belongs to a lineage that is known to be active in humans (Boissinot et al 2000;Batzer and Deininger 2002;Wang et al 2005;Konkel et al 2015). Thus, we developed new MELT tools to identify interior mutations in MEIs and assign MEIs to lineages (or subfamilies).…”

“…Likewise, interior mutations frequently are introduced into Alu, L1, and SVA copies by the error-prone L1 reverse transcriptase that replicates all three of these element classes (Gilbert et al 2005). Interior mutations have been useful for identifying and tracking active subfamilies of Alu, L1, and SVA elements (Boissinot et al 2000;Batzer and Deininger 2002;Wang et al 2005;Konkel et al 2015) and for tracking relationships between source elements and their offspring (Scott et al 2016). Several additional hallmark features of human MEIs include (1) 3 ′ transductions that are caused by alternative, downstream poly(A) signals (Moran et al 1999), (2) 5 ′ inversions that are caused by twin priming (Ostertag and Kazazian 2001), and (3) 5 ′ truncations that are caused by incomplete replication (Beck et al 2011).…”

Genome-wide analysis of polymerase III–transcribed Alu elements suggests cell-type–specific enhancer function

“…They belong to the primate-specific short interspersed nuclear element (SINE) family of retrotransposons; comparison of primate genomes revealed that the rapid expansion of Alu elements during primate evolution has contributed to wide-ranging genetic diversity in humans, including genetic defects owing to disruption of coding regions and splicing events (Deininger and Batzer 1999;Kazazian 2004;Ade et al 2013). Although more active during the earlier stage of primate evolution, Alu elements continue to be transcribed (Conti et al 2015) and inserted into modern human genomes (Konkel et al 2015), potentially making a profound impact on human biology.…”

The Developmental Gene Hypothesis for Punctuated Equilibrium: Combined Roles of Developmental Regulatory Genes and Transposable Elements

“…Alu Y eventually became the leading family in catarrhines prior to the radiation of old world monkeys and apes . Finally, Alu Ya5 and Alu Yb8—the two main Alu Y subfamilies currently active in humans—arose a few million years ago during the emergence of our own lineage, the hominins . Given the timing of events and the fact that Alu elements are associated with regulatory functions, such as transcription factor binding sites, adenosine‐to‐inosine (A‐to‐I) editing, and circular RNA, it is likely that this family of retrotransposons has played an integral role in the evolution of primate morphology, including our own …”