False gene and chromosome losses affected by assembly and sequence errors

J, Kim; C, Lee; Bj, Ko; D, Yoo; Won, Sohyoung; Phillippy, Adam M.; Fédrigo, Olivier; Howe, Kerstin; Wood, Jonathan; Durbin, Richard; Formenti, Giulio; Brown, Shan-Estelle; Cantin, Lindsey J.; Mello, Claudio V.; Cho, Soyun; Rhie, Arang; Kim, Ho; Ed, Jarvis

doi:10.1101/2021.04.09.438906

Cited by 20 publications

(20 citation statements)

References 75 publications

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“…Furthermore, we identified seven additional chromosomes (chromosomes [30][31][32][33][34][35][36] in the zebra finch, and eight (chromosomes 8, 9, 14, 15, 17, 19, 21, and X4; Extended Data Fig. 8a, b) in the platypus 26,27 . Relative to the VGP assembly, the earlier short-read Anna's hummingbird assembly was highly fragmented (Extended Data Fig.…”

Section: Curation Is Needed For a High-quality Referencementioning

confidence: 95%

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Towards complete and error-free genome assemblies of all vertebrate species

Rhie

McCarthy

Fédrigo

et al. 2021

Nature

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671

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High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are available for only a few non-microbial species1–4. To address this issue, the international Genome 10K (G10K) consortium5,6 has worked over a five-year period to evaluate and develop cost-effective methods for assembling highly accurate and nearly complete reference genomes. Here we present lessons learned from generating assemblies for 16 species that represent six major vertebrate lineages. We confirm that long-read sequencing technologies are essential for maximizing genome quality, and that unresolved complex repeats and haplotype heterozygosity are major sources of assembly error when not handled correctly. Our assemblies correct substantial errors, add missing sequence in some of the best historical reference genomes, and reveal biological discoveries. These include the identification of many false gene duplications, increases in gene sizes, chromosome rearrangements that are specific to lineages, a repeated independent chromosome breakpoint in bat genomes, and a canonical GC-rich pattern in protein-coding genes and their regulatory regions. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an international effort to generate high-quality, complete reference genomes for all of the roughly 70,000 extant vertebrate species and to help to enable a new era of discovery across the life sciences.

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Section: Curation Is Needed For a High-quality Referencementioning

confidence: 95%

“…Thousands of such false gains and losses in previous reference assemblies have been corrected in our VGP assemblies (more details in refs. 27,44 ), demonstrating that assembly quality has a critical effect on subsequent annotations and functional genomics.…”

Section: Articlementioning

confidence: 99%

Towards complete and error-free genome assemblies of all vertebrate species

Rhie

McCarthy

Fédrigo

et al. 2021

Nature

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1,720

671

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“…The sequencing enzymes used often have difficulty reading through regions with complex structures, such as GC-rich regions often found in promoters that regulate gene expression 9, 10 . It is also now clear that mixing diverse haplotypes in a single assembly, even from the same individual, can introduce many errors with standard assembly tools 8, 10, 11 . These errors include: switch errors where variants from each haplotype are assembled into the same pseudo- haplotype; false duplications and associated gaps where more divergent haplotype homologs are assembled as separate false paralogs; and consensus errors due to collapses between haplotypes.…”

Section: Mainmentioning

confidence: 99%

Automated assembly of high-quality diploid human reference genomes

Jarvis

Formenti

Rhie

et al. 2022

Preprint

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The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has greatly benefited society. However, it still has many gaps and errors, and does not represent a biological human genome since it is a blend of multiple individuals. Recently, a high-quality telomere-to-telomere reference genome, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a duplicate genome, and is thus nearly homozygous. To address these limitations, the Human Pangenome Reference Consortium (HPRC) recently formed with the goal of creating a collection of high-quality, cost-effective, diploid genome assemblies for a pangenome reference that represents human genetic diversity. Here, in our first scientific report, we determined which combination of current genome sequencing and automated assembly approaches yields the most complete, accurate, and cost-effective diploid genome assemblies with minimal manual curation. Approaches that used highly accurate long reads and parent-child data to sort haplotypes during assembly outperformed those that did not. Developing a combination of all the top performing methods, we generated our first high-quality diploid reference assembly, containing only ~4 gaps (range 0-12) per chromosome, most within + 1% of CHM13 length. Nearly 1/4th of protein coding genes have synonymous amino acid changes between haplotypes, and centromeric regions showed the highest density of variation. Our findings serve as a foundation for assembling near-complete diploid human genomes at the scale required for constructing a human pangenome reference that captures all genetic variation from single nucleotides to large structural rearrangements.

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“…Module F, a component in HVC, LMAN, and Area X specializations, was enriched on chromosome 2. In addition to module D, both modules J and K were enriched on "other", a category that includes newly identified zebra finch micro-chromosomes 36 . These findings indicate a remarkable association between the structure of song nuclei gene expression networks, measured in an unbiased way with WGCNA, and the chromosomal structure of the genome.…”

Section: Gene Modules Enriched On Specific Chromosomesmentioning

confidence: 99%

Sex chromosome gene expression associated with vocal learning following hormonal manipulation in female zebra finches

Davenport

Choe²,

Matsunami

et al. 2021

Preprint

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Zebra finches are sexually dimorphic vocal learners. Males learn to sing by imitating mature conspecifics, but females do not. The lack of vocal learning in females is associated with anatomical differences in the neural circuits responsible for vocal learning, including the atrophy of several brain regions during development1. However, this atrophy can be prevented and song learning retained in females after pharmacological estrogen treatment2–4. Little is known about the genetic machinery controlling this sex and estrogen responsive song system development. To screen for drivers, we performed an unbiased analysis of transcriptomes from song control nuclei and surrounding motor regions in zebra finches of either sex treated with 17-β-estradiol or vehicle until sacrifice on day 30, when divergence between the sexes is anatomically apparent. Utilizing the newly assembled autosomes and sex chromosomes from the zebra finch Vertebrate Genomes Project assemblies5, we identified correlated gene modules that were associated to song nuclei in a sex and estradiol dependent manner. Female estradiol treated HVC, in the vocal learning circuit, acquired the smallest of the modular specializations observed in male HVC. This module was enriched for genes governing anatomical development, and it’s specilization was dispraportionately influenced by the expression of Z sex chromosome transcripts in HVC. We propose that vocal learning may be prevented in female zebra finches via the suppression of an estrogen inducible Z chromosome cis-acting regulatory element.

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False gene and chromosome losses affected by assembly and sequence errors

Cited by 20 publications

References 75 publications

Towards complete and error-free genome assemblies of all vertebrate species

Towards complete and error-free genome assemblies of all vertebrate species

Automated assembly of high-quality diploid human reference genomes

Sex chromosome gene expression associated with vocal learning following hormonal manipulation in female zebra finches

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