Assembly of a pan-genome from deep sequencing of 910 humans of African descent

Sherman, Rachel M.; Forman, Juliet; Antonescu, Valentin; Puiu, Daniela; Daya, Michelle; Rafaels, Nicholas; Boorgula, Meher Preethi; Chavan, Sameer; Vergara, Candelaria; Ortega, Victor E.; Levin, Albert M.; Eng, Celeste; Yazdanbakhsh, Maria; Wilson, James G.; Marrugo, Javier; Lange, Leslie A.; Williams, L. Keoki; Watson, Harold; Ware, Lorraine B.; Olopade, Christopher O.; Olopade, Olufunmilayo; Oliveira, Ricardo Riccio; Ober, Carole; Nicolae, Dan L.; Meyers, Deborah A.; Mayorga, Alvaro; Knight‐Madden, Jennifer; Hartert, Tina V.; Hansel, Nadia N.; Foreman, Marilyn G.; Ford, Jean G.; Faruque, Mezbah U.; Dunston, Georgia M.; Caraballo, Luis; Burchard, Esteban G.; Bleecker, Eugene R.; Araújo, Maria Ilma; Herrera-Paz, Edwin Francisco; Campbell, Monica; Foster, Cassandra; Taub, Margaret A.; Beaty, Terri H.; Ruczinski, Ingo; Mathias, Rasika A.; Barnes, Kathleen C.; Salzberg, Steven L.

doi:10.1038/s41588-018-0273-y

Cited by 302 publications

(341 citation statements)

References 36 publications

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“…Since these insertions are present and homozygous in all 100 genotyped individuals, the reference sequence reflects either rare deletion or errors in GRCh38 36 . Specifically, the 1,638 bp exonic insertion in UBE2QL1 was also reported at high frequency in two previous studies 37,38 .…”

Section: Genotyping In Tandem Repeatssupporting

confidence: 51%

Paragraph: A graph-based structural variant genotyper for short-read sequence data

Chen

Krusche

Dolzhenko

et al. 2019

Preprint

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Accurate detection and genotyping of structural variations (SVs) from short-read data is a long-standing area of development in genomics research and clinical sequencing pipelines. We introduce Paragraph, an accurate genotyper that models SVs using sequence graphs and SV annotations. We demonstrate the accuracy of Paragraph on whole-genome sequence data from three samples using long read SV calls as the truth set, and then apply Paragraph at scale to a cohort of 100 short-read sequenced samples of diverse ancestry. Our analysis shows that Paragraph has better accuracy than other existing genotypers and can be applied to population-scale studies.

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Section: Genotyping In Tandem Repeatssupporting

confidence: 51%

Paragraph: A graph-based structural variant genotyper for short-read sequence data

Chen

Krusche

Dolzhenko

et al. 2019

Preprint

Self Cite

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“…In spite of the growing number of reports of pan-genomes in eukaryotes and the recent extension of such investigations to human populations (32), so far the impact of PAV on the intraspecific diversity of animals has been presumed to be minimal, and sometimes linked to the development of pathologies (38). To the best of our knowledge, PAV has been only marginally explored in bivalves as a phenomenon linked to gene families involved in immune functions, i.e., big defensins in Crassostrea gigas (39) and myticalins in M. galloprovincialis (40).…”

Section: The Mussel Pan-genomementioning

confidence: 99%

Massive gene presence/absence variation in the mussel genome as an adaptive strategy: first evidence of a pan-genome in Metazoa

Gerdol

Moreira

Cruz

et al. 2019

Preprint

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Mussels are ecologically and economically relevant edible marine bivalves, highly invasive and resilient to biotic and abiotic stressors causing recurrent massive mortalities in other species. Here we show that the Mediterranean mussel Mytilus galloprovincialis has a complex pan-genomic architecture, which includes a core set of 45,000 genes shared by all individuals plus a surprisingly high number of dispensable genes (~15,000). The latter are subject to presence/absence variation (PAV), i.e., they may be entirely missing in a given individual and, when present, they are frequently found as a single copy. The enrichment of dispensable genes in survival functions suggests an adaptive value for PAV, which might be the key to explain the extraordinary capabilities of adaptation and invasiveness of this species. Our study underpins a unique metazoan pan-genome architecture only previously described in prokaryotes and in a few nonmetazoan eukaryotes, but that might also characterize other marine invertebrates. Significance statementIn animals, intraspecific genomic diversity is generally thought to derive from relatively small-scale variants, such as single nucleotide polymorphisms, small indels, duplications, inversions and translocations. On the other hand, large-scale structural variations which involve the loss of genomic regions encoding proteincoding genes in some individuals (i.e. presence/absence variation, PAV) have been so far only described in bacteria and, occasionally, in plants and fungi. Here we report the first evidence of a pan-genome in the animal kingdom, revealing that 25% of the genes of the Mediterranean mussel are subject to PAV. We show that this unique feature might have an adaptive value, due to the involvement of dispensable genes in functions related with defense and survival.

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“…Hundreds of thousands of human genomes have been sequenced worldwide and ongoing consortiums and individual projects are sequencing many more 1,2 . The exponential growth of human whole-genome sequencing (WGS) data have already allowed the creation of population or cohort-specific human sequences to catalogue the genomic variation across different populations [3][4][5] . One of the main aims of pan-genome studies is to uncover novel non-reference sequences (NRSs) or variants not represented in the human reference genome (GRCh38).…”

Section: Introductionmentioning

confidence: 99%

Microbial contaminants cataloged as novel human sequences in recent human pan-genomes

Manni

Zdobnov

2020

Preprint

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Human pan-genome studies offer the opportunity to identify human non-reference sequences (NRSs) which are, by definition, not represented in the reference human genome (GRCh38). NRSs serve as useful catalogues of genetic variation for population and disease studies and while the majority consists of repetitive elements, a substantial fraction is made of non-repetitive, non-reference (NRNR) sequences. The presence of non-human sequences in these catalogues can inflate the number of "novel" human sequences, overestimate the genetic differentiation among populations, and jeopardize subsequent analyses that rely on these resources. We uncovered almost 2,000 contaminant sequences of microbial origin in NRNR sequences from recent human pan-genome studies. The contaminant contigs (3,501,302 bp) harbour genes totalling 4,720 predicted proteins (>40 aa). The major sources of contamination are related to Rhyzobiales, Burkholderiales, Pseudomonadales and Lactobacillales, which may have been associated with the original samples or introduced later during sequencing experiments. We additionally observed that the majority of human novel protein-coding genes described in one of the studies entirely overlap repetitive regions and are likely to be false positive predictions.We report here the list of contaminant sequences in three recent human pan-genome catalogues and discuss strategies to increase decontamination efficacy for current and future pan-genome studies.

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Assembly of a pan-genome from deep sequencing of 910 humans of African descent

Cited by 302 publications

References 36 publications

Paragraph: A graph-based structural variant genotyper for short-read sequence data

Paragraph: A graph-based structural variant genotyper for short-read sequence data

Massive gene presence/absence variation in the mussel genome as an adaptive strategy: first evidence of a pan-genome in Metazoa

Microbial contaminants cataloged as novel human sequences in recent human pan-genomes

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