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Detection of Rare Genomic Variants from Pooled Sequencing Using SPLINTER
Published on: June 23, 2012
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Low-coverage sequencing cost-effectively detects known and novel variation in underrepresented populations
Alicia R Martin1, Elizabeth G Atkinson1, Sinéad B Chapman2
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
American Journal of Human Genetics
|March 26, 2021
Summary
Low-coverage sequencing effectively identifies novel genetic variants in underrepresented populations. This cost-effective approach surpasses traditional genotyping arrays for genetic discovery in diverse ancestries.
Area of Science:
- Population Genetics
- Genomic Variation
- Bioinformatics
Background:
- Genetic studies often overlook novel variants in underrepresented populations due to reliance on European-centric genotyping arrays and reference panels.
- Existing genetic research tools may not adequately capture the full spectrum of genetic diversity in diverse ancestral groups.
Purpose of the Study:
- To compare the effectiveness of genotyping arrays versus low-coverage whole-genome sequencing for variant discovery in African populations.
- To evaluate cost-effective data generation strategies for identifying novel genetic associations in underrepresented groups.
Main Methods:
- Whole-genome sequencing of 91 individuals from the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study.
- Downsampling approach to assess concordance between low-coverage sequencing (0.5×–4×) and deep whole-genome sequencing data.
- Comparison of variant imputation accuracy from low-coverage sequencing and Genome-Wide Association Study (GWAS) arrays.
Main Results:
- Low-coverage sequencing at ≥4× depth captures variants across all frequencies more accurately than commonly used GWAS arrays at a comparable cost.
- Sequencing depths of 0.5×–1× showed performance comparable to low-density GWAS arrays.
- 4× low-coverage sequencing detected 45% of singletons and 95% of common variants identified in deep African whole genomes, demonstrating sensitivity to novel variation.
Conclusions:
- Low-coverage sequencing overcomes limitations of ascertainment bias in common genotyping arrays, making it superior for variant discovery in underrepresented populations.
- This strategy enhances the identification of novel genetic variation, crucial for understanding diseases in diverse ancestral groups.
- Low-coverage sequencing offers a cost-effective alternative to traditional methods for expanding genomic discovery in underrepresented populations.
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