Linear assembly of a human centromere on the Y chromosome

Jain, Miten; Olsen, Hugh E.; Turner, Daniel J.; Stoddart, David; Bulazel, Kira V.; Paten, Benedict; Haussler, David; Willard, Huntington F.; Akeson, Mark; Miga, Karen H.

doi:10.1038/nbt.4109

Cited by 210 publications

(182 citation statements)

References 45 publications

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“…Fourth, the assays could be used to help confirm karyotypes of individuals when performing experimental sex reversal with RNAinterference knock down, or CRISPR/Cas9 modification of sex-determination pathway genes (Li and Handler, 2017;Peng et al, 2015). Finally, the sequences identified here should assist with future B. tryoni Y-chromosome assemblies using long-read sequencing technologies (Jain et al, 2018). All of these future research topics may not be limited just to B. tryoni.…”

Section: Discussionmentioning

confidence: 99%

Identification of Y‐chromosome scaffolds of the Queensland fruit fly reveals a duplicated gyf gene paralogue common to many Bactrocera pest species

Choo

Nguyen

Ward

et al. 2019

Insect Molecular Biology

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Bactrocera tryoni (Queensland fruit fly) are polyphagous horticultural pests of eastern Australia. Heterogametic males contain a sex‐determining Y‐chromosome thought to be gene poor and repetitive. Here, we report 39 Y‐chromosome scaffolds (~700 kb) from B. tryoni identified using genotype‐by‐sequencing data and whole‐genome resequencing. Male diagnostic PCR assays validated eight Y‐scaffolds, and one (Btry4096) contained a novel gene with five exons that encode a predicted 575 amino acid protein. The Y‐gene, referred to as typo‐gyf, is a truncated Y‐chromosome paralogue of X‐chromosome gene gyf (1773 aa). The Y‐chromosome contained ~41 copies of typo‐gyf, and expression occurred in male flies and embryos. Analysis of 13 tephritid transcriptomes confirmed typo‐gyf expression in six additional Bactrocera species, including Bactrocera latifrons, Bactrocera dorsalis and Bactrocera zonata. Molecular dating estimated typo‐gyf evolved within the past 8.02 million years (95% highest posterior density 10.56–5.52 million years), after the split with Bactrocera oleae. Phylogenetic analysis also highlighted complex evolutionary histories among several Bactrocera species, as discordant nuclear (116 genes) and mitochondrial (13 genes) topologies were observed. B. tryoni Y‐sequences may provide useful sites for future transgene insertions, and typo‐gyf could act as a Y‐chromosome diagnostic marker for many Bactrocera species, although its function is unknown.

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Section: Discussionmentioning

confidence: 99%

Identification of Y‐chromosome scaffolds of the Queensland fruit fly reveals a duplicated gyf gene paralogue common to many Bactrocera pest species

Choo

Nguyen

Ward

et al. 2019

Insect Molecular Biology

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“…There is already the chance to get a glimpse into particularly difficult‐to‐assemble gaps such as centromeres in humans (Jain et al., ). For avian genomes, Weissensteiner et al.…”

Section: Quantification Of Missing Dna In 13 Bird Species From Zhangmentioning

confidence: 99%

“…Genome size estimates were converted from C-values into billion basepairs (Gb) assuming 1 pg = 0.978 Gb (Doležel et al, 2003). There is already the chance to get a glimpse into particularly difficult-to-assemble gaps such as centromeres in humans (Jain et al, 2018b). For avian genomes, Weissensteiner et al (2017) recently demonstrated that optical mapping data provide an indirect means to estimate the size and potential sequence content of some assembly gaps.…”

mentioning

confidence: 99%

How complete are “complete” genome assemblies?—An avian perspective

Peona

Weissensteiner

Suh

2018

Molecular Ecology Resources

115

134

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The genomics revolution has led to the sequencing of a large variety of nonmodel organisms often referred to as "whole" or "complete" genome assemblies. But how complete are these, really? Here, we use birds as an example for nonmodel vertebrates and find that, although suitable in principle for genomic studies, the current standard of short-read assemblies misses a significant proportion of the expected genome size (7% to 42%; mean 20 ± 9%). In particular, regions with strongly deviating nucleotide composition (e.g., guanine-cytosine-[GC]-rich) and regions highly enriched in repetitive DNA (e.g., transposable elements and satellite DNA) are usually underrepresented in assemblies. However, long-read sequencing technologies successfully characterize many of these underrepresented GC-rich or repeat-rich regions in several bird genomes. For instance, only ~2% of the expected total base pairs are missing in the last chicken reference (galGal5). These assemblies still contain thousands of gaps (i.e., fragmented sequences) because some chromosomal structures (e.g., centromeres) likely contain arrays of repetitive DNA that are too long to bridge with currently available technologies. We discuss how to minimize the number of assembly gaps by combining the latest available technologies with complementary strengths. At last, we emphasize the importance of knowing the location, size and potential content of assembly gaps when making population genetic inferences about adjacent genomic regions.

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“…Recently, in addition to a complete linear assembly of a human Y centromere, a telomere-to-telomere assembly spanning the whole human X centromere utilizing ultralong ONT reads has been reported, showing, at last, the time is ripe to investigate centromeres in terms of sequencing technology 36,37 . With an increasing number of individual genomes from the same or closely related populations sequenced by long reads, one would be able to precisely observe the processes of diversification and homogenization that occur within human centromeres.…”

Section: Discussionmentioning

confidence: 99%

“…While long-read sequencing was capable of yielding contiguous reference sequences of centromeres for several species 34,35 , reconstruction of whole centromeric sequences for human genomes is still challenging due to their idiosyncratic repeat structures. To date, it has been achieved only for the X and Y chromosomes, which both exist in a haploid state 36,37 . While reference-quality de novo assembly of such repetitive regions remains a demanding task involving substantial manual curation 37-39 , the use of unassembled long reads has promise for investigating centromere variations in a cost-effective manner 40 .Therefore, we exploited a strategy of HOR encoding of unassembled, uncorrected long reads for comprehensive detection and quantification of variant HORs.…”

mentioning

confidence: 99%

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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Linear assembly of a human centromere on the Y chromosome

Cited by 210 publications

References 45 publications

Identification of Y‐chromosome scaffolds of the Queensland fruit fly reveals a duplicated gyf gene paralogue common to many Bactrocera pest species

Identification of Y‐chromosome scaffolds of the Queensland fruit fly reveals a duplicated gyf gene paralogue common to many Bactrocera pest species

How complete are “complete” genome assemblies?—An avian perspective

Long-read Data Revealed Structural Diversity in Human Centromere Sequences

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