scholarly journals A reference-quality, fully annotated genome from a Puerto Rican individual

2021 ◽  
Author(s):  
Aleksey V Zimin ◽  
Alaina Shumate ◽  
Ida Shinder ◽  
Jakob Heinz ◽  
Daniela Puiu ◽  
...  
Keyword(s):  
Puerto Rican ◽  
Human Genome ◽  
Reference Genome ◽  
Individual Genome ◽  
Protein Coding ◽  
Human Reference Genome ◽  
Gene Copies ◽  
Reference Quality ◽  
Assembly Technology ◽  
Individual Human

Until 2019, the human genome was available in only one fully-annotated version, which was the result of 18 years of continuous improvement and revision. Despite dramatic improvements in sequencing technology, no other individual human genome was available as an annotated reference until 2019, when the genome of an Ashkenazi individual was released. In this study, we describe the assembly and annotation of a second individual genome, from a Puerto Rican individual whose DNA was collected as part of the Human Pangenome project. The new genome, called PR1, is the first true reference genome created from an individual of African descent. Due to recent improvements in both sequencing and assembly technology, PR1 is more complete and more contiguous than either the human reference genome (GRCh38) or the Ashkenazi genome. Annotation revealed 42,217 genes (of which 20,168 are protein-coding), including 107 additional gene copies that are present in PR1 and missing from GRCh38. 180 genes have fewer copies in PR1 than in GRCh38, 13 map only partially, and 3 genes (1 protein-coding) from GRCh38 are entirely missing from PR1.

scholarly journals A reference-quality, fully annotated genome from a Puerto Rican individual

Genetics ◽  
2021 ◽  
Author(s):  
Aleksey V Zimin ◽  
Alaina Shumate ◽  
Ida Shinder ◽  
Jakob Heinz ◽  
Daniela Puiu ◽  
...  
Keyword(s):  
Puerto Rican ◽  
Human Genome ◽  
Continuous Improvement ◽  
Reference Genome ◽  
Sequencing Technology ◽  
Individual Genome ◽  
Protein Coding ◽  
Gene Copies ◽  
Reference Quality ◽  
Assembly Technology

Abstract Until 2019, the human genome was available in only one fully-annotated version, GRCh38, which was the result of 18 years of continuous improvement and revision. Despite dramatic improvements in sequencing technology, no other genome was available as an annotated reference until 2019, when the genome of an Ashkenazi individual, Ash1, was released. In this study, we describe the assembly and annotation of a second individual genome, from a Puerto Rican individual whose DNA was collected as part of the Human Pangenome project. The new genome, called PR1, is the first true reference genome created from an individual of African descent. Due to recent improvements in both sequencing and assembly technology, and particularly to the use of the recently completed CHM13 human genome as a guide to assembly, PR1 is more complete and more contiguous than either GRCh38 or Ash1. Annotation revealed 37,755 genes (of which 19,999 are protein-coding), including 12 additional gene copies that are present in PR1 and missing from CHM13. 57 genes have fewer copies in PR1 than in CHM13, 9 map only partially, and 3 genes (all non-coding) from CHM13 are entirely missing from PR1.

scholarly journals Recovery of non-reference sequences missing from the human reference genome

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Ran Li ◽  
Xiaomeng Tian ◽  
Peng Yang ◽  
Yingzhi Fan ◽  
Ming Li ◽  
...  
Keyword(s):  
Human Genome ◽  
Tandem Repeats ◽  
Reference Genome ◽  
De Novo ◽  
Precise Location ◽  
Protein Coding ◽  
Human Reference Genome ◽  
Mhc Haplotype ◽  
Reference Sequences ◽  
Flanking Regions

Abstract Background The non-reference sequences (NRS) represent structure variations in human genome with potential functional significance. However, besides the known insertions, it is currently unknown whether other types of structure variations with NRS exist. Results Here, we compared 31 human de novo assemblies with the current reference genome to identify the NRS and their location. We resolved the precise location of 6113 NRS adding up to 12.8 Mb. Besides 1571 insertions, we detected 3041 alternate alleles, which were defined as having less than 90% (or none) identity with the reference alleles. These alternate alleles overlapped with 1143 protein-coding genes including a putative novel MHC haplotype. Further, we demonstrated that the alternate alleles and their flanking regions had high content of tandem repeats, indicating that their origin was associated with tandem repeats. Conclusions Our study detected a large number of NRS including many alternate alleles which are previously uncharacterized. We suggested that the origin of alternate alleles was associated with tandem repeats. Our results enriched the spectrum of genetic variations in human genome.

scholarly journals Recovery of non-reference sequences missing from the human reference genome

2019 ◽  
Author(s):  
Ran Li ◽  
Xiaomeng Tian ◽  
Peng Yang ◽  
Yingzhi Fan ◽  
Ming Li ◽  
...  
Keyword(s):  
Human Genome ◽  
Tandem Repeats ◽  
Reference Genome ◽  
De Novo ◽  
Precise Location ◽  
Protein Coding ◽  
Human Reference Genome ◽  
Mhc Haplotype ◽  
Reference Sequences ◽  
Flanking Regions

Abstract Background The non-reference sequences (NRS) represent structure variations in human genome with potential functional significance. However, besides the known insertions, it is currently unknown whether other types of structure variations with NRS exist. Results Here, we compared 31 human de novo assemblies with the current reference genome to identify the NRS and their location. We resolved the precise location of 6,113 NRS adding up to 12.8 Mb. Besides 1,571 insertions, we detected 3,041 alternate alleles, which were defined as having less than 90% (or none) identity with the reference alleles. These alternate alleles overlapped with 1,143 protein-coding genes including a putative novel MHC haplotype. Further, we demonstrated that the alternate alleles and their flanking regions had high content of tandem repeats, indicating that their origin was associated with tandem repeats. Conclusions Our study detected a large number of NRS including many alternate alleles which are previously uncharacterized. We suggested that the origin of alternate alleles was associated with tandem repeats. Our results enriched the spectrum of genetic variations in human genome.

scholarly journals Recovery of non-reference sequences missing from the human reference genome

2019 ◽  
Author(s):  
Ran Li ◽  
Xiaomeng Tian ◽  
Peng Yang ◽  
Yingzhi Fan ◽  
Ming Li ◽  
...  
Keyword(s):  
Human Genome ◽  
Tandem Repeats ◽  
Reference Genome ◽  
De Novo ◽  
Precise Location ◽  
Protein Coding ◽  
Human Reference Genome ◽  
Mhc Haplotype ◽  
Reference Sequences ◽  
Flanking Regions

Abstract Background The non-reference sequences (NRS) represent structure variations in human genome with potential functional significance. However, besides the known insertions, it is currently unknown whether other types of structure variations with NRS exist. Results Here, we compared 31 human de novo assemblies with the current reference genome to identify the NRS and their location. We resolved the precise location of 6,113 NRS adding up to 12.8 Mb. Besides 1,571 insertions, we detected 3,041 alternate alleles, which were defined as having less than 90% (or none) identity with the reference alleles. These alternate alleles overlapped with 1,143 protein-coding genes including a putative novel MHC haplotype. Further, we demonstrated that the alternate alleles and their flanking regions had high content of tandem repeats, indicating that their origin was associated with tandem repeats. Conclusions Our study detected a large number of NRS including many alternate alleles which are previously uncharacterized. We suggested that the origin of alternate alleles was associated with tandem repeats. Our results enriched the spectrum of genetic variations in human genome.

scholarly journals Liftoff: accurate mapping of gene annotations

2020 ◽  
Author(s):  
Alaina Shumate ◽  
Steven L Salzberg
Keyword(s):  
Reference Genome ◽  
Supplementary Information ◽  
Closely Related Species ◽  
Protein Coding ◽  
Human Reference Genome ◽  
Sequence Identity ◽  
Gene Annotations ◽  
Genome Assemblies ◽  
Average Sequence Identity ◽  
High Quality Genome

Abstract Motivation Improvements in DNA sequencing technology and computational methods have led to a substantial increase in the creation of high-quality genome assemblies of many species. To understand the biology of these genomes, annotation of gene features and other functional elements is essential; however for most species, only the reference genome is well-annotated. Results One strategy to annotate new or improved genome assemblies is to map or ‘lift over’ the genes from a previously-annotated reference genome. Here we describe Liftoff, a new genome annotation lift-over tool capable of mapping genes between two assemblies of the same or closely-related species. Liftoff aligns genes from a reference genome to a target genome and finds the mapping that maximizes sequence identity while preserving the structure of each exon, transcript, and gene. We show that Liftoff can accurately map 99.9% of genes between two versions of the human reference genome with an average sequence identity >99.9%. We also show that Liftoff can map genes across species by successfully lifting over 98.3% of human protein-coding genes to a chimpanzee genome assembly with 98.2% sequence identity. Availability and Implementation Liftoff can be installed via bioconda and PyPI. Additionally, the source code for Liftoff is available at https://github.com/agshumate/Liftoff Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Assembly and Annotation of an Ashkenazi Human Reference Genome

2020 ◽  
Author(s):  
Alaina Shumate ◽  
Aleksey V. Zimin ◽  
Rachel M. Sherman ◽  
Daniela Puiu ◽  
Justin M. Wagner ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Reference Genome ◽  
Gene Families ◽  
Gene Content ◽  
Specific Reference ◽  
Protein Coding ◽  
Human Reference Genome ◽  
Protein Coding Genes ◽  
Reference Genomes ◽  
Similar Gene

AbstractHere we describe the assembly and annotation of the genome of an Ashkenazi individual and the creation of a new, population-specific human reference genome. This genome is more contiguous and more complete than GRCh38, the latest version of the human reference genome, and is annotated with highly similar gene content. The Ashkenazi reference genome, Ash1, contains 2,973,118,650 nucleotides as compared to 2,937,639,212 in GRCh38. Annotation identified 20,157 protein-coding genes, of which 19,563 are >99% identical to their counterparts on GRCh38. Most of the remaining genes have small differences. 40 of the protein-coding genes in GRCh38 are missing from Ash1; however, all of these genes are members of multi-gene families for which Ash1 contains other copies. 11 genes appear on different chromosomes from their homologs in GRCh38. Alignment of DNA sequences from an unrelated Ashkenazi individual to Ash1 identified ~1 million fewer homozygous SNPs than alignment of those same sequences to the more-distant GRCh38 genome, illustrating one of the benefits of population-specific reference genomes.

scholarly journals Recovery of non-reference sequences missing from the human reference genome

2019 ◽  
Author(s):  
Ran Li ◽  
Xiaomeng Tian ◽  
Peng Yang ◽  
Yingzhi Fan ◽  
Ming Li ◽  
...  
Keyword(s):  
Tandem Repeats ◽  
Reference Genome ◽  
De Novo ◽  
Precise Location ◽  
Protein Coding ◽  
Human Reference Genome ◽  
Protein Coding Genes ◽  
Mhc Haplotype ◽  
Reference Sequences ◽  
Flanking Regions

Abstract The non-reference sequences (NRS) represent structure variations in human genome with potential functional significance. However, besides the known insertions, it is currently unknown whether other types of structure variations with NRS exist. Here, we compared 31 human de novo assemblies with the current reference genome to identify the NRS and their location. We resolved the precise location of 6,113 NRS adding up to 12.8 Mb. Besides 1,571 insertions, we detected 3,041 alternate alleles, which were defined as having less than 90% (or none) identity with the reference alleles. These alternate alleles overlapped with 1,143 protein-coding genes including a putative novel MHC haplotype. Further, we demonstrated that the alternate alleles and their flanking regions had high content of tandem repeats, indicating that their origin was associated with tandem repeats. Our study enriched the spectrum of human genetic variations.

scholarly journals About classical molecular genetics, cytogenetic and molecular cytogenetic data not considered by Genome Reference Consortium and thus not included in genome browsers like UCSC, Ensembl or NCBI

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Thomas Liehr
Keyword(s):  
Human Genome ◽  
Dna Sequences ◽  
Reference Genome ◽  
International System ◽  
Molecular Genetic ◽  
Human Reference Genome ◽  
Molecular Cytogenetic ◽  
Cytogenetic Data ◽  
Human Cytogenetic ◽  
Genome Browsers

Abstract Background The Genome Reference Consortium (GRC) has according to its own statement the “mission to improve the human reference genome assembly, correcting errors and adding sequence to ensure it provides the best representation of the human genome to meet basic and clinical research needs”. Data from GRC is included in genome browsers like UCSC (University of California, Santa Cruz), Ensembl or NCBI (National Center for Biotechnology Information) and are thereby bases for scientific and diagnostically working human genetic community. Method Here long standing knowledge deriving from classical molecular genetic, cytogenetic and molecular cytogenetic data, not being considered yet by GRC was revisited. Results There were three major points identified: (1) GRC missed to including three chromosomal subbands, each, for 1q32.1, 2p21, 5q13.2, 6p22.3 and 6q21, which were defined by International System for Human Cytogenetic Nomenclature (ISCN) already back in 1980s; instead GRC included additional 6 subbands not ever recognized by ISCN. (2) GRC defined 34 chromosomal subbands of 0.1 to 0.9 Mb in size, while it is general agreement of cytogeneticists that it unlikely to detect chromosomal aberrations below 1–2 Mb in size by GTG-banding. And (3): still all sequences used in molecular cytogenetic routine diagnostics to detect heterochromatic and/ or pericentromeric satellite DNA sequences within the human genome are not included yet into human reference genome. For those sequences, localization and approximate sizes have been determined in the 1970s to 1990, and if included at least ~ 100 Mb of the human genome sequence could be added to the genome browsers. Conclusion Overall, taking into account the here mentioned points and correcting and including the data will definitely provide to the still not being completely finished mapping of the human genome.

scholarly journals Progress, Challenges, and Surprises in Annotating the Human Genome

2020 ◽  
Vol 21 (1) ◽  
pp. 55-79 ◽  
Author(s):  
Daniel R. Zerbino ◽  
Adam Frankish ◽  
Paul Flicek
Keyword(s):  
Human Genome ◽  
Reference Genome ◽  
Gene Expression Regulation ◽  
Clinical Applications ◽  
Human Reference Genome ◽  
Complex Knowledge ◽  
Scientific Fields ◽  
Reference Human Genome ◽  
Shed Light

Our understanding of the human genome has continuously expanded since its draft publication in 2001. Over the years, novel assays have allowed us to progressively overlay layers of knowledge above the raw sequence of A's, T's, G's, and C's. The reference human genome sequence is now a complex knowledge base maintained under the shared stewardship of multiple specialist communities. Its complexity stems from the fact that it is simultaneously a template for transcription, a record of evolution, a vehicle for genetics, and a functional molecule. In short, the human genome serves as a frame of reference at the intersection of a diversity of scientific fields. In recent years, the progressive fall in sequencing costs has given increasing importance to the quality of the human reference genome, as hundreds of thousands of individuals are being sequenced yearly, often for clinical applications. Also, novel sequencing-based assays shed light on novel functions of the genome, especially with respect to gene expression regulation. Keeping the human genome annotation up to date and accurate is therefore an ongoing partnership between reference annotation projects and the greater community worldwide.

scholarly journals Loss-of-function tolerance of enhancers in the human genome

2019 ◽  
Author(s):  
Duo Xu ◽  
Omer Gokcumen ◽  
Ekta Khurana
Keyword(s):  
Human Genome ◽  
Gene Interactions ◽  
Loss Of Function ◽  
Structural Variants ◽  
Protein Coding ◽  
Tissue Specific ◽  
Neuronal Stem Cells ◽  
Human Genomes ◽  
Potential Impact ◽  
Individual Human

AbstractPrevious studies have surveyed the potential impact of loss-of-function (LoF) variants and identified LoF-tolerant protein-coding genes. However, the tolerance of human genomes to losing enhancers has not yet been evaluated. Here we present the catalog of LoF-tolerant enhancers using structural variants from whole-genome sequences. Using a conservative approach, we estimate that each individual human genome possesses at least 28 LoF-tolerant enhancers on average. We assessed the properties of LoF-tolerant enhancers in a unified regulatory network constructed by integrating tissue-specific enhancers and gene-gene interactions. We find that LoF-tolerant enhancers are more tissue-specific and regulate fewer and more dispensable genes. They are enriched in immune-related cells while LoF-intolerant enhancers are enriched in kidney and brain/neuronal stem cells. We developed a supervised learning approach to predict the LoF-tolerance of enhancers, which achieved an AUROC of 96%. We predict 5,677 more enhancers would be likely tolerant to LoF and 75 enhancers that would be highly LoF-intolerant. Our predictions are supported by known set of disease enhancers and novel deletions from PacBio sequencing. The LoF-tolerance scores provided here will serve as an important reference for disease studies.

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