Dataset Information

Whole Genome Sequencing and Progress Toward Full Inbreeding of the Mouse Collaborative Cross Population.

ABSTRACT: Two key features of recombinant inbred panels are well-characterized genomes and reproducibility. Here we report on the sequenced genomes of six additional Collaborative Cross (CC) strains and on inbreeding progress of 72 CC strains. We have previously reported on the sequences of 69 CC strains that were publicly available, bringing the total of CC strains with whole genome sequence up to 75. The sequencing of these six CC strains updates the efforts toward inbreeding undertaken by the UNC Systems Genetics Core. The timing reflects our competing mandates to release to the public as many CC strains as possible while achieving an acceptable level of inbreeding. The new six strains have a higher than average founder contribution from non-domesticus strains than the previously released CC strains. Five of the six strains also have high residual heterozygosity (>14%), which may be related to non-domesticus founder contributions. Finally, we report on updated estimates on residual heterozygosity across the entire CC population using a novel, simple and cost effective genotyping platform on three mice from each strain. We observe a reduction in residual heterozygosity across all previously released CC strains. We discuss the optimal use of different genetic resources available for the CC population.

SUBMITTER: Shorter JR

PROVIDER: S-EPMC6505143 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Whole Genome Sequencing and Progress Toward Full Inbreeding of the Mouse Collaborative Cross Population.

Shorter John R JR Najarian Maya L ML Bell Timothy A TA Blanchard Matthew M Ferris Martin T MT Hock Pablo P Kashfeen Anwica A Kirchoff Kathryn E KE Linnertz Colton L CL Sigmon J Sebastian JS Miller Darla R DR McMillan Leonard L Pardo-Manuel de Villena Fernando F

G3 (Bethesda, Md.) 20190507 5

Two key features of recombinant inbred panels are well-characterized genomes and reproducibility. Here we report on the sequenced genomes of six additional Collaborative Cross (CC) strains and on inbreeding progress of 72 CC strains. We have previously reported on the sequences of 69 CC strains that were publicly available, bringing the total of CC strains with whole genome sequence up to 75. The sequencing of these six CC strains updates the efforts toward inbreeding undertaken by the UNC Syste ...[more]

PMID: 30858237

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Project description:The Collaborative Cross Consortium reports here on the development of a unique genetic resource population. The Collaborative Cross (CC) is a multiparental recombinant inbred panel derived from eight laboratory mouse inbred strains. Breeding of the CC lines was initiated at multiple international sites using mice from The Jackson Laboratory. Currently, this innovative project is breeding independent CC lines at the University of North Carolina (UNC), at Tel Aviv University (TAU), and at Geniad in Western Australia (GND). These institutions aim to make publicly available the completed CC lines and their genotypes and sequence information. We genotyped, and report here, results from 458 extant lines from UNC, TAU, and GND using a custom genotyping array with 7500 SNPs designed to be maximally informative in the CC and used a novel algorithm to infer inherited haplotypes directly from hybridization intensity patterns. We identified lines with breeding errors and cousin lines generated by splitting incipient lines into two or more cousin lines at early generations of inbreeding. We then characterized the genome architecture of 350 genetically independent CC lines. Results showed that founder haplotypes are inherited at the expected frequency, although we also consistently observed highly significant transmission ratio distortion at specific loci across all three populations. On chromosome 2, there is significant overrepresentation of WSB/EiJ alleles, and on chromosome X, there is a large deficit of CC lines with CAST/EiJ alleles. Linkage disequilibrium decays as expected and we saw no evidence of gametic disequilibrium in the CC population as a whole or in random subsets of the population. Gametic equilibrium in the CC population is in marked contrast to the gametic disequilibrium present in a large panel of classical inbred strains. Finally, we discuss access to the CC population and to the associated raw data describing the genetic structure of individual lines. Integration of rich phenotypic and genomic data over time and across a wide variety of fields will be vital to delivering on one of the key attributes of the CC, a common genetic reference platform for identifying causative variants and genetic networks determining traits in mammals.

Project description:The Collaborative Cross (CC) is a multiparent panel of recombinant inbred (RI) mouse strains derived from eight founder laboratory strains. RI panels are popular because of their long-term genetic stability, which enhances reproducibility and integration of data collected across time and conditions. Characterization of their genomes can be a community effort, reducing the burden on individual users. Here we present the genomes of the CC strains using two complementary approaches as a resource to improve power and interpretation of genetic experiments. Our study also provides a cautionary tale regarding the limitations imposed by such basic biological processes as mutation and selection. A distinct advantage of inbred panels is that genotyping only needs to be performed on the panel, not on each individual mouse. The initial CC genome data were haplotype reconstructions based on dense genotyping of the most recent common ancestors (MRCAs) of each strain followed by imputation from the genome sequence of the corresponding founder inbred strain. The MRCA resource captured segregating regions in strains that were not fully inbred, but it had limited resolution in the transition regions between founder haplotypes, and there was uncertainty about founder assignment in regions of limited diversity. Here we report the whole genome sequence of 69 CC strains generated by paired-end short reads at 30× coverage of a single male per strain. Sequencing leads to a substantial improvement in the fine structure and completeness of the genomes of the CC. Both MRCAs and sequenced samples show a significant reduction in the genome-wide haplotype frequencies from two wild-derived strains, CAST/EiJ and PWK/PhJ. In addition, analysis of the evolution of the patterns of heterozygosity indicates that selection against three wild-derived founder strains played a significant role in shaping the genomes of the CC. The sequencing resource provides the first description of tens of thousands of new genetic variants introduced by mutation and drift in the CC genomes. We estimate that new SNP mutations are accumulating in each CC strain at a rate of 2.4 ± 0.4 per gigabase per generation. The fixation of new mutations by genetic drift has introduced thousands of new variants into the CC strains. The majority of these mutations are novel compared to currently sequenced laboratory stocks and wild mice, and some are predicted to alter gene function. Approximately one-third of the CC inbred strains have acquired large deletions (>10 kb) many of which overlap known coding genes and functional elements. The sequence of these mice is a critical resource to CC users, increases threefold the number of mouse inbred strain genomes available publicly, and provides insight into the effect of mutation and drift on common resources.

Project description:BackgroundPublic health surveillance data are critical to understanding the current state of the HIV and AIDS epidemics. Surveillance data provide significant insight into patterns within and progress toward achieving targets for each of the steps in the HIV care continuum. Such targets include those outlined in the National HIV/AIDS Strategy (NHAS) goals. If these data are disseminated, they can be used to prioritize certain steps in the continuum, geographic locations, and groups of people.ObjectiveWe sought to develop and report indicators of progress toward the NHAS goals for US cities and to characterize progress toward those goals with categorical metrics.MethodsHealth departments used standardized SAS code to calculate care continuum indicators from their HIV surveillance data to ensure comparability across jurisdictions. We report 2018 descriptive statistics for continuum steps (timely diagnosis, linkage to medical care, receipt of medical care, and HIV viral load suppression) for 36 US cities and their progress toward 2020 NHAS goals as of 2018. Indicators are reported categorically as met or surpassed the goal, within 25% of attaining the goal, or further than 25% from achieving the goal.ResultsCities were closest to meeting NHAS goals for timely diagnosis compared to the goals for linkage to care, receipt of care, and viral load suppression, with all cities (n=36, 100%) within 25% of meeting the goal for timely diagnosis. Only 8% (n=3) of cities were >25% from achieving the goal for receipt of care, but 69% (n=25) of cities were >25% from achieving the goal for viral suppression.ConclusionsDisplay of progress with graphical indicators enables communication of progress to stakeholders. AIDSVu analyses of HIV surveillance data facilitate cities' ability to benchmark their progress against that of other cities with similar characteristics. By identifying peer cities (eg, cities with analogous populations or similar NHAS goal concerns), the public display of indicators can promote dialogue between cities with comparable challenges and opportunities.

Dataset Information

Whole Genome Sequencing and Progress Toward Full Inbreeding of the Mouse Collaborative Cross Population.

Publications

Whole Genome Sequencing and Progress Toward Full Inbreeding of the Mouse Collaborative Cross Population.

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