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IPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types.

ABSTRACT: Large-scale collections of induced pluripotent stem cells (iPSCs) could serve as powerful model systems for examining how genetic variation affects biology and disease. Here we describe the iPSCORE resource: a collection of systematically derived and characterized iPSC lines from 222 ethnically diverse individuals that allows for both familial and association-based genetic studies. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic copy-number variants) as determined using high-throughput RNA-sequencing and genotyping arrays, respectively. Using iPSCs from a family of individuals, we show that iPSC-derived cardiomyocytes demonstrate gene expression patterns that cluster by genetic background, and can be used to examine variants associated with physiological and disease phenotypes. The iPSCORE collection contains representative individuals for risk and non-risk alleles for 95% of SNPs associated with human phenotypes through genome-wide association studies. Our study demonstrates the utility of iPSCORE for examining how genetic variants influence molecular and physiological traits in iPSCs and derived cell lines.

SUBMITTER: Panopoulos AD

PROVIDER: S-EPMC5390244 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types.

Panopoulos Athanasia D AD D'Antonio Matteo M Benaglio Paola P Williams Roy R Hashem Sherin I SI Schuldt Bernhard M BM DeBoever Christopher C Arias Angelo D AD Garcia Melvin M Nelson Bradley C BC Harismendy Olivier O Jakubosky David A DA Donovan Margaret K R MKR Greenwald William W WW Farnam KathyJean K Cook Megan M Borja Victor V Miller Carl A CA Grinstein Jonathan D JD Drees Frauke F Okubo Jonathan J Diffenderfer Kenneth E KE Hishida Yuriko Y Modesto Veronica V Dargitz Carl T CT Feiring Rachel R Zhao Chang C Aguirre Aitor A McGarry Thomas J TJ Matsui Hiroko H Li He H Reyna Joaquin J Rao Fangwen F O'Connor Daniel T DT Yeo Gene W GW Evans Sylvia M SM Chi Neil C NC Jepsen Kristen K Nariai Naoki N Müller Franz-Josef FJ Goldstein Lawrence S B LSB Izpisua Belmonte Juan Carlos JC Adler Eric E Loring Jeanne F JF Berggren W Travis WT D'Antonio-Chronowska Agnieszka A Smith Erin N EN Frazer Kelly A KA

Stem cell reports 20170401 4

Large-scale collections of induced pluripotent stem cells (iPSCs) could serve as powerful model systems for examining how genetic variation affects biology and disease. Here we describe the iPSCORE resource: a collection of systematically derived and characterized iPSC lines from 222 ethnically diverse individuals that allows for both familial and association-based genetic studies. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic copy-number variants) as de ...[more]

PMID: 28410642

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Project description:BackgroundIt is expected that functional, mainly missense and loss-of-function (LOF), and regulatory variants are responsible for most phenotypic differences between breeds and genetic lines of livestock species that have undergone diverse selection histories. However, there is still limited knowledge about the existing missense and LOF variation in commercial livestock populations, in particular regarding population-specific variation and how it can affect applications such as across-breed genomic prediction.MethodsWe re-sequenced the whole genome of 7848 individuals from nine commercial pig lines (average sequencing coverage: 4.1×) and imputed whole-genome genotypes for 440,610 pedigree-related individuals. The called variants were categorized according to predicted functional annotation (from LOF to intergenic) and prevalence level (number of lines in which the variant segregated; from private to widespread). Variants in each category were examined in terms of their distribution along the genome, alternative allele frequency, per-site Wright's fixation index (FST), individual load, and association to production traits.ResultsOf the 46 million called variants, 28% were private (called in only one line) and 21% were widespread (called in all nine lines). Genomic regions with a low recombination rate were enriched with private variants. Low-prevalence variants (called in one or a few lines only) were enriched for lower allele frequencies, lower FST, and putatively functional and regulatory roles (including LOF and deleterious missense variants). On average, individuals carried fewer private deleterious missense alleles than expected compared to alleles with other predicted consequences. Only a small subset of the low-prevalence variants had intermediate allele frequencies and explained small fractions of phenotypic variance (up to 3.2%) of production traits. The significant low-prevalence variants had higher per-site FST than the non-significant ones. These associated low-prevalence variants were tagged by other more widespread variants in high linkage disequilibrium, including intergenic variants.ConclusionsMost low-prevalence variants have low minor allele frequencies and only a small subset of low-prevalence variants contributed detectable fractions of phenotypic variance of production traits. Accounting for low-prevalence variants is therefore unlikely to noticeably benefit across-breed analyses, such as the prediction of genomic breeding values in a population using reference populations of a different genetic background.

Project description:Plant structural and biochemical traits are frequently used to characterise the life history of plants. Although some common patterns of trait covariation have been identified, recent studies suggest these patterns of covariation may differ with growing location and/or plant functional type (PFT). Mediterranean forest tree/shrub species are often divided into three PFTs based on their leaf habit and form, being classified as either needleleaf evergreen (Ne), broadleaf evergreen (Be), or broadleaf deciduous (Bd). Working across 61 mountainous Mediterranean forest sites of contrasting climate and soil type, we sampled and analysed 626 individuals in order to evaluate differences in key foliage trait covariation as modulated by growing conditions both within and between the Ne, Be, and Bd functional types. We found significant differences between PFTs for most traits. When considered across PFTs and by ignoring intraspecific variation, three independent functional dimensions supporting the Leaf-Height-Seed framework were identified. Some traits illustrated a common scaling relationship across and within PFTs, but others scaled differently when considered across PFTs or even within PFTs. For most traits much of the observed variation was attributable to PFT identity and not to growing location, although for some traits there was a strong environmental component and considerable intraspecific and residual variation. Nevertheless, environmental conditions as related to water availability during the dry season and to a smaller extend to soil nutrient status and soil texture, clearly influenced trait values. When compared across species, about half of the trait-environment relationships were species-specific. Our study highlights the importance of the ecological scale within which trait covariation is considered and suggests that at regional to local scales, common trait-by-trait scaling relationships should be treated with caution. PFT definitions by themselves can potentially be an important predictor variable when inferring one trait from another. These findings have important implications for local scale dynamic vegetation models.

Dataset Information

IPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types.

Publications

iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types.

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