The dark side of centromeres: types, causes and consequences of structural abnormalities implicating centromeric DNA

Barra, Viviana; Fachinetti, Daniele

doi:10.1038/s41467-018-06545-y

Cited by 218 publications

(206 citation statements)

References 199 publications

(207 reference statements)

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“…Centromere drive theory explained the rapid evolvability of centromeres via genetic conflict during female meiosis I, rendering the centromeres as a crux of the molecular identity of species 43 . Nevertheless, growing evidence suggests that centromeres can be highly variable within a single species 5,10,20,24 , and our findings add another layer of diversification, ultimately challenging the notion of stable human centromeres.…”

Section: Discussionmentioning

confidence: 59%

Long-read Data Revealed Structural Diversity in Human Centromere Sequences

Suzuki

Myers

Morishita

2019

Preprint

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Centromeres invariably serve as the loci of kinetochore assembly in all eukaryotic cells, but their underlying DNA sequences evolve rapidly. Human centromeres are characterized by their extremely repetitive structures, i.e., higher-order repeats, rendering the region one of the most difficult parts of the genome to assess. Consequently, our understanding of centromere sequence variations across human populations is limited. Here, we analyzed chromosomes 11, 17, and X using long sequencing reads of two European and two Asian genomes, and our results show that human centromere sequences exhibit substantial structural diversity, harboring many novel variant higher-order repeats specific to individuals, while frequent single-nucleotide variants are largely conserved. Our findings add another dimension to our knowledge of centromeres, challenging the notion of stable human centromeres. The discovery of such diversity prompts further deep sequencing of human populations to understand the true nature of sequence evolution in human centromeres. MainCentromeres have been one of the most mysterious parts of the human genome since they were characterized, in the 1970s, as large tracts of 171 bp strings called alpha-satellite monomers 1, 2 . With a growing body of evidence suggesting their relevance to human diseases as sources of genomic instability or as repositories of haplotypes containing causative mutations 3-8 , it has become more important to investigate the underlying sequence variations in centromeres 9, 10 .Human centromeres have nested repeat structures. Namely, a series of distinctively divergent alpha-satellite monomers compose a larger unit called higher-order repeat (HOR) unit, and copies of an HOR unit are tandemly arranged thousands of times to form large, homogeneous HOR arrays. While HOR units are chromosome-specific and consist of two to 34 alphasatellite monomers, copies of an HOR unit are almost identical (95 ∼ 100%) within a chromosome (Figure 1a) [11][12][13][14][15][16][17] . The total HOR array length in each chromosome is known to differ dramatically among individuals 7, 18 or across human populations 19,20 . In addition to array length, other types of variation are known to exist within an HOR array, such as structurally variant HORs that consist of different numbers and/or types of alpha-satellite monomers 20-23 and also single-nucleotide variations (SNVs) between the HOR units 20, 24, 25 . One of the major driving forces leading to such centromeric variation has been thought to be structural alterations such as unequal crossovers and/or gene conversions 26,27 .Previous studies have investigated centromeric sequence variations via traditional approaches such as restriction enzymes sensitive to alpha-satellite monomers, Southern blotting, or analysis of k-mers unique to centromeres in short reads obtained in the 1000 Genomes Project 28 , but their observations have remained indirect and were confined to specific types of variations due to technological limitations.Recently, the advent of long-rea...

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Section: Discussionmentioning

confidence: 59%

Long-read Data Revealed Structural Diversity in Human Centromere Sequences

Suzuki

Myers

Morishita

2019

Preprint

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“…Recent advancements in long read sequencing technologies, such as Pacific Biosciences (PB) and Oxford Nanopore Technologies (ONT), led to a substantial increase in the contiguity of genome assemblies (Koren et al, 2017;Kolmogorov et al, 2019;Ruan and Li, 2019;Shafin et al, 2019) and opened a possibility to resolve extra-long tandem repeats ( ETRs ), the problem that was viewed as intractable until recently. Assembling ETRs is important since variations in ETR have been linked to cancer and infertility (Barra and Fachinetti, 2018;Black and Giunta, 2018;Ferreira et al, 2015;Giunta and Funabiki, 2017;Miga et al, 2019;Smurova and De Wulf, 2018;Zhu et al, 2018) . ETR sequencing is also important for addressing open problems about centromere evolution (Alkan et al, 2007;Lower et al, 2018;Shepelev et al, 2009, Henikoff et al, 2015 .…”

Section: Introductionmentioning

confidence: 99%

The String Decomposition Problem and its Applications to Centromere Assembly

Dvorkina

Bzikadze²,

Pevzner

2019

Preprint

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Recent attempts to assemble long tandem repeats (such as multi-megabase long centromeres) faced the challenge of accurate translation of long error-prone reads from the nucleotide alphabet into the alphabet of repeat units . Centromeres represent a particularly complex type of nested tandem repeats , where each unit is itself a repeat formed by chromosome-specific monomers (a repeat within repeat). Given a set of monomers forming a specific centromere, translation of a read into monomers is modeled as the String Decomposition Problem, finding a concatenate of monomers with the highest-scoring sequence alignment to a given read. We developed a StringDecomposer algorithm for solving this problem, benchmarked it on the set of reads generated by the Telomere-to-Telomere consortium, and identified a novel (rare) monomer that extends the set of twelve X-chromosome specific monomers identified more than three decades ago. The accurate translation of each read into a monomer alphabet turns centromere assembly into a more tractable problem than the notoriously difficult problem of assembling centromeres in the nucleotide alphabet. Our identification of a novel monomer emphasizes the importance of careful identification of all (even rare) monomers for follow-up centromere assembly efforts.

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“…This is unfortunate since centromeres play critical roles in chromosome segregation and a large component of genetic disease result from aneuploidies arising during meiosis (Nagaoka et al, 2012). In addition, variations in centromeres are linked to cancer and infertility (Enukashvily et al, 2007, Sahin et al, 2008, Ting et al, 2011, Ferreira et al, 2015, Giunta and Funabiki, 2017, Black et al, 2018, Smurova and De Wulf, 2018, Barra and Fachinetti, 2018, Zhu et al, 2018, Miga 2019. Centromere sequencing is also important for addressing open problems about centromere evolution (Schueler et al, 2001, Alkan et al, 2007, Shepelev et al, 2009, Lower et al, 2018.…”

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confidence: 99%

centroFlye: Assembling Centromeres with Long Error-Prone Reads

Bzikadze¹,

Pevzner

2019

Preprint

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Although variations in centromeres have been linked to cancer and infertility, centromeres still represent the "dark matter of the human genome" and remain an enigma for both biomedical and evolutionary studies. Since centromeres have withstood all previous attempts to develop an automated tool for their assembly and since their assembly using short reads is viewed as intractable, recent efforts attempted to manually assemble centromeres using long error-prone reads. We describe the centroFlye algorithm for centromere assembly using long error-prone reads, apply it for assembling the human X centromere, and use the constructed assembly to gain insights into centromere evolution. Our analysis reveals putative breakpoints in the previous manual reconstruction of the human X centromere and opens a possibility to automatically close the remaining multi-megabase gaps in the reference human genome.

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The dark side of centromeres: types, causes and consequences of structural abnormalities implicating centromeric DNA

Cited by 218 publications

References 199 publications

Long-read Data Revealed Structural Diversity in Human Centromere Sequences

Long-read Data Revealed Structural Diversity in Human Centromere Sequences

The String Decomposition Problem and its Applications to Centromere Assembly

centroFlye: Assembling Centromeres with Long Error-Prone Reads

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