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Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility.

ABSTRACT: The rhesus macaque (Macaca mulatta) is the most widely studied nonhuman primate (NHP) in biomedical research. We present an updated reference genome assembly (Mmul_10, contig N50 = 46 Mbp) that increases the sequence contiguity 120-fold and annotate it using 6.5 million full-length transcripts, thus improving our understanding of gene content, isoform diversity, and repeat organization. With the improved assembly of segmental duplications, we discovered new lineage-specific genes and expanded gene families that are potentially informative in studies of evolution and disease susceptibility. Whole-genome sequencing (WGS) data from 853 rhesus macaques identified 85.7 million single-nucleotide variants (SNVs) and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay, providing a framework for developing noninvasive NHP models of human disease.

SUBMITTER: Warren WC

PROVIDER: S-EPMC7818670 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility.

Warren Wesley C WC Harris R Alan RA Haukness Marina M Fiddes Ian T IT Murali Shwetha C SC Fernandes Jason J Fernandes Jason J Dishuck Philip C PC Storer Jessica M JM Raveendran Muthuswamy M Hillier LaDeana W LW Porubsky David D Mao Yafei Y Gordon David D Vollger Mitchell R MR Lewis Alexandra P AP Munson Katherine M KM DeVogelaere Elizabeth E Armstrong Joel J Diekhans Mark M Walker Jerilyn A JA Tomlinson Chad C Graves-Lindsay Tina A TA Kremitzki Milinn M Salama Sofie R SR Audano Peter A PA Escalona Merly M Maurer Nicholas W NW Antonacci Francesca F Mercuri Ludovica L Maggiolini Flavia A M FAM Catacchio Claudia Rita CR Underwood Jason G JG O'Connor David H DH Sanders Ashley D AD Korbel Jan O JO Ferguson Betsy B Kubisch H Michael HM Picker Louis L Kalin Ned H NH Rosene Douglas D Levine Jon J Abbott David H DH Gray Stanton B SB Sanchez Mar M MM Kovacs-Balint Zsofia A ZA Kemnitz Joseph W JW Thomasy Sara M SM Roberts Jeffrey A JA Kinnally Erin L EL Capitanio John P JP Skene J H Pate JHP Platt Michael M Cole Shelley A SA Green Richard E RE Ventura Mario M Wiseman Roger W RW Paten Benedict B Batzer Mark A MA Rogers Jeffrey J Eichler Evan E EE

Science (New York, N.Y.) 20201201 6523

The rhesus macaque (<i>Macaca mulatta</i>) is the most widely studied nonhuman primate (NHP) in biomedical research. We present an updated reference genome assembly (Mmul_10, contig N50 = 46 Mbp) that increases the sequence contiguity 120-fold and annotate it using 6.5 million full-length transcripts, thus improving our understanding of gene content, isoform diversity, and repeat organization. With the improved assembly of segmental duplications, we discovered new lineage-specific genes and expa ...[more]

PMID: 33335035

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Project description:BackgroundUntil recently, few genomic reagents specific for non-human primate research have been available. To address this need, we have constructed a macaque-specific high-density oligonucleotide microarray by using highly fragmented low-pass sequence contigs from the rhesus genome project together with the detailed sequence and exon structure of the human genome. Using this method, we designed oligonucleotide probes to over 17,000 distinct rhesus/human gene orthologs and increased by four-fold the number of available genes relative to our first-generation expressed sequence tag (EST)-derived array.ResultsWe constructed a database containing 248,000 exon sequences from 23,000 human RefSeq genes and compared each human exon with its best matching sequence in the January 2005 version of the rhesus genome project list of 486,000 DNA contigs. Best matching rhesus exon sequences for each of the 23,000 human genes were then concatenated in the proper order and orientation to produce a rhesus "virtual transcriptome." Microarray probes were designed, one per gene, to the region closest to the 3' untranslated region (UTR) of each rhesus virtual transcript. Each probe was compared to a composite rhesus/human transcript database to test for cross-hybridization potential yielding a final probe set representing 18,296 rhesus/human gene orthologs, including transcript variants, and over 17,000 distinct genes. We hybridized mRNA from rhesus brain and spleen to both the EST- and genome-derived microarrays. Besides four-fold greater gene coverage, the genome-derived array also showed greater mean signal intensities for genes present on both arrays. Genome-derived probes showed 99.4% identity when compared to 4,767 rhesus GenBank sequence tag site (STS) sequences indicating that early stage low-pass versions of complex genomes are of sufficient quality to yield valuable functional genomic information when combined with finished genome information from a closely related species.ConclusionThe number of different genes represented on microarrays for unfinished genomes can be greatly increased by matching known gene transcript annotations from a closely related species with sequence data from the unfinished genome. Signal intensity on both EST- and genome-derived arrays was highly correlated with probe distance from the 3' UTR, information often missing from ESTs yet present in early-stage genome projects.

Project description:The rhesus macaque (Macaca mulatta) is a key species for advancing biomedical research. Like all draft mammalian genomes, the draft rhesus assembly (rheMac2) has gaps, sequencing errors and misassemblies that have prevented automated annotation pipelines from functioning correctly. Another rhesus macaque assembly, CR_1.0, is also available but is substantially more fragmented than rheMac2 with smaller contigs and scaffolds. Annotations for these two assemblies are limited in completeness and accuracy. High quality assembly and annotation files are required for a wide range of studies including expression, genetic and evolutionary analyses.We report a new de novo assembly of the rhesus macaque genome (MacaM) that incorporates both the original Sanger sequences used to assemble rheMac2 and new Illumina sequences from the same animal. MacaM has a weighted average (N50) contig size of 64 kilobases, more than twice the size of the rheMac2 assembly and almost five times the size of the CR_1.0 assembly. The MacaM chromosome assembly incorporates information from previously unutilized mapping data and preliminary annotation of scaffolds. Independent assessment of the assemblies using Ion Torrent read alignments indicates that MacaM is more complete and accurate than rheMac2 and CR_1.0. We assembled messenger RNA sequences from several rhesus tissues into transcripts which allowed us to identify a total of 11,712 complete proteins representing 9,524 distinct genes. Using a combination of our assembled rhesus macaque transcripts and human transcripts, we annotated 18,757 transcripts and 16,050 genes with complete coding sequences in the MacaM assembly. Further, we demonstrate that the new annotations provide greatly improved accuracy as compared to the current annotations of rheMac2. Finally, we show that the MacaM genome provides an accurate resource for alignment of reads produced by RNA sequence expression studies.The MacaM assembly and annotation files provide a substantially more complete and accurate representation of the rhesus macaque genome than rheMac2 or CR_1.0 and will serve as an important resource for investigators conducting next-generation sequencing studies with nonhuman primates.This article was reviewed by Dr. Lutz Walter, Dr. Soojin Yi and Dr. Kateryna Makova.

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Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility.

Publications

Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility.

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