Biology subjects

Lappalainen, T.

Publications and source records attributed to Lappalainen, T..

3 recordsLinked to original sources

bioRxiv2018

RecNW: A fast pairwise aligner for targeted sequencing

MotivationTargeted sequencing aims at in-depth analysis of specific genomic loci through high-throughput sequencing for applications such as resequencing or CRISPR gene editing. These applications require exact pairwise alignment algorithms to fully characterize large amounts of reads by comparison to the targeted locus, or reference. Optimal solutions to this alignment problem are provided by classic implementations of the global and semi-global versions of Needleman-Wunsch algorithms, but they remain computationally expensive due to their quadratic complexity in time and space.\n\nImplementationIn this paper we present RecNW, an open source C++ exact aligner packaged for Python that implements the semi-global version of the Needleman-Wunsch algorithm with affine gap penalty. RecNW utilizes low complexity of targeted sequencing libraries by aligning only unique reads, and recurrently using blocs of the alignment matrix between reads based on their similarities. Through this, RecNW performs exact alignment on average more than four times faster than gold standard comparable software.\n\nSoftwarehttps://github.com/AYahi/recNW

bioinformatics↗

bioRxiv2017

Modified penetrance of coding variants by cis-regulatory variation shapes human traits

Coding variants represent many of the strongest associations between genotype and phenotype, however they exhibit inter-individual differences in effect, known as variable penetrance. In this work, we study how cis-regulatory variation modifies the penetrance of coding variants in their target gene. Using functional genomic and genetic data from GTEx, we observed that in the general population, purifying selection has depleted haplotype combinations that lead to higher penetrance of pathogenic coding variants. Conversely, in cancer and autism patients, we observed an enrichment of haplotype combinations that lead to higher penetrance of pathogenic coding variants in disease implicated genes, which provides direct evidence that regulatory haplotype configuration of causal coding variants affects disease risk. Finally, we experimentally demonstrated that a regulatory variant can modify the penetrance of a coding variant by introducing a Mendelian SNP using CRISPR/Cas9 on distinct expression haplotypes and using the transcriptome as a phenotypic readout. Our results demonstrate that joint effects of regulatory and coding variants are an important part of the genetic architecture of human traits, and contribute to modified penetrance of disease-causing variants.

genetics↗

bioRxiv2017

Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations

The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. We isolated monocytes from 134 genotyped individuals, stimulated the cells with three defined microbe-associated molecular patterns (LPS, MDP, and ppp-dsRNA), and profiled the transcriptome at three time points. After mapping expression quantitative trait loci (eQTL), we identified 417 response eQTLs (reQTLs) with differing effect between the conditions. We characterized the dynamics of genetic regulation on early and late immune response, and observed an enrichment of reQTLs in distal cis-regulatory elements. Response eQTLs are also enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover novel reQTL effects in multiple GWAS loci, and show a stronger enrichment of response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli modifying genetic predisposition to disease.

genetics↗