From telomere to telomere: the transcriptional and epigenetic state of human repeat elements

Abstract

Mobile elements and highly repetitive genomic regions are potent sources of lineage-specific genomic innovation and fingerprint individual genomes. Comprehensive analyses of large, composite or arrayed repeat elements and those found in more complex regions of the genome require a complete, linear genome assembly. Here we present the first de novo repeat discovery and annotation of a complete human reference genome, T2T-CHM13v1.0. We identified novel satellite arrays, expanded the catalog of variants and families for known repeats and mobile elements, characterized new classes of complex, composite repeats, and provided comprehensive annotations of retroelement transduction events. Utilizing PRO-seq to detect nascent transcription and nanopore sequencing to delineate CpG methylation profiles, we defined the structure of transcriptionally active retroelements in humans, including for the first time those found in centromeres. Together, these data provide expanded insight into the diversity, distribution and evolution of repetitive regions that have shaped the human genome.

Satellite DNAs in Health and Disease

“…The level of transcripts detectable within the active human centromere is low and is in contrast with the higher transcriptional levels of pericentromeric satellites [45], which are necessary for heterochromatin maintenance [34]. The predominant factor controlling human α satellite transcription seems to be the presence of centromere-nucleolar contacts and the transcripts are not exported to the cytoplasm, although they are not tightly bound to the centromere [21].…”

“…Tumoral α satellite DNA hypomethylation level was found to be a prognostic parameter in patients with advanced gastric cancer [126]. Human satellite SST1 carries distinctive methylation and transcriptional profiles, including an enhancer embedded in each unit, and this is found only in specific arrays on chromosomes 19 and 4 [45]. These satellite arrays are hypervariable in the human population and alterations in their activity have been linked to cancer [127,129].…”

A critique of the hypothesis that CA repeats are primary targets of neuronal MeCP2

“…The list of genomic locations containing CA and TG repeats was extracted from “Variation and Repeats” group of RepeatMasker track in Mouse (mm9) genome using UCSC table browser functionality [https://genome.ucsc.edu/cgi-bin/hgTables]. For Human (chm13-v1.1), RepeatMasker track was downloaded from processed data (Hoyt et al, 2022). Loci labelled “(CA)n” and “(TG)n” in the RepeatMasker track were used for [CA] n .…”

Advancing genomic technologies and clinical awareness accelerates discovery of disease-associated tandem repeat sequences

“…These efforts are being spearheaded by the Telomere-to-Telomere (T2T) Consortium ( ), which aims to fill in the numerous gaps within the reference genome by conducting complete long-read sequencing gapless assemblies of each individual chromosome. To date, the T2T Consortium has assembled and published complete sequences for several chromosomes and have preprints of assemblies of the whole genome ( Jain et al 2018a ; Miga et al 2020 ; Hoyt et al 2021 ; Logsdon et al 2021 ; Nurk et al 2021 ). The new T2T-CHM13 reference includes gapless assemblies for all 22 autosomes plus Chromosome X.…”

“…A deeper appreciation of satellite repeat tract length variations, and possibly sequence purity, gained by long-read sequencing could reveal associations of disease variation for these and other repeat-rich regions. Another huge advance is the discovery of the huge numbers of previously uncataloged repeats, definitively revealing that the repetitive content in the human genome is 53.9% in CHM13 ( Hoyt et al 2021 ).…”