Extensive impact of low-frequency variants on the phenotypic landscape at population-scale, bioRxiv, 2019-04-16

AbstractGenome-wide association studies (GWAS) allows to dissect the genetic basis of complex traits at the population level1. However, despite the extensive number of trait-associated loci found, they often fail to explain a large part of the observed phenotypic variance2–4. One potential source of this discrepancy could be the preponderance of undetected low-frequency genetic variants in natural populations5,6. To increase the allele frequency of those variants and assess their phenotypic effects at the population level, we generated a diallel panel consisting of 3,025 hybrids, derived from pairwise crosses between a subset of natural isolates from a completely sequenced 1,011 Saccharomyces cerevisiae population. We examined each hybrid across a large number of growth traits, resulting in a total of 148,225 crosstrait combinations. Parental versus hybrid regression analysis showed that while most phenotypic variance is explained by additivity, a significant proportion (29%) is governed by non-additive effects. This is confirmed by the fact that a majority of complete dominance is observed in 25% of the traits. By performing GWAS on the diallel panel, we detected 1,723 significantly associated genetic variants, with 16.3% of them being low-frequency variants in the initial population. These variants, which would not be detected using classical GWAS, explain 21% of the phenotypic variance on average. Altogether, our results demonstrate that low-frequency variants should be accounted for as they contribute to a large part of the phenotypic variation observed in a population.

biorxiv genomics 100-200-users 2019

High accuracy DNA sequencing on a small, scalable platform via electrical detection of single base incorporations, bioRxiv, 2019-04-16

AbstractHigh throughput DNA sequencing technologies have undergone tremendous development over the past decade. Although optical detection-based sequencing has constituted the majority of data output, it requires a large capital investment and aggregation of samples to achieve optimal cost per sample. We have developed a novel electronic detection-based platform capable of accurately detecting single base incorporations. The GenapSys technology with its electronic detection modality allows the system to be compact, accessible, and affordable. We demonstrate the performance of the system by sequencing several different microbial genomes with varying GC content. The platform is capable of generating 1.5 Gb of high-quality nucleic acid sequence in a single run. We routinely generate sequence data that exceeds 99% raw accuracy with read lengths of up to 175 bp. The utility of the platform is highlighted by targeted sequencing of the human genome. We show high concordance of SNP detection on the human NA12878 HapMap cell line with data generated on the Illumina sequencing platform. In addition, we sequenced a targeted panel of cancer-associated genes in a well characterized reference standard. With multiple library preparation approaches on this sample, we were able to identify low frequency mutations at expected allele frequencies.

biorxiv genomics 100-200-users 2019

 

Created with the audiences framework by Jedidiah Carlson

Powered by Hugo