Machanick, P. | Search bioRxiv

bioRxiv2020

The extent and impact of variation in ADME genes in sub-Saharan African populations

Investigating variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are key to characterising pharmacogenomic (PGx) relationships. ADME gene variation is relatively well characterised in European and Asian populations, but African populations are under-studied - which has implications for safe and effective drug use in Africa. The genetic diversity of ADME genes across sub-Saharan African populations is large. The Southern African population cluster is most distinct from that of far West Africa. PGx strategies based on European variants will be of limited use in African populations. Although established variants are important, PGx must take into account the full range of African variation. This work urges further characterisation of variants in African populations including in vitro and in silico studies, and to consider the unique African ADME landscape when developing precision medicine guidelines and tools for African populations. Author summaryThe ADME genes are a group of genes that play a key role in absorption, distribution, metabolism and excretion of drugs. Variations in these genes can have a significant impact on drug safety and efficacy. Africa has a high level of genetic variation and is under-studied in drug development, which makes study of variations in these genes in African populations very important. Using a new data set of 458 high-coverage genomes from across Africa, we characterise the extent and impact of variation in the ADME genes, looking at both single nucleotide and copy number variations. We identified 343,368 variants, including 40,692 novel variants, and 930 coding variants which are predicted to have high impact on function. Our discovery curves indicate that there will be considerable value in sequencing more African genomes. Moreover, relatively few of these novel variants are captured on common genotyping arrays. We show that there is considerable diversity within Africa in some important genes, and this will have significant consequences for the emerging field of precision medicine in Africa.

genetics↗

bioRxiv2016

MARS: Motif Assessment and Ranking Suite for transcription factor binding motifs

We describe MARS (Motif Assessment and Ranking Suite), a web-based suite of tools used to evaluate and rank PWM-based motifs. The increased number of learned motif models that are spread across databases and in different PWM formats, leading to a choice dilemma among the users, is our motivation. This increase has been driven by the difficulty of modelling transcription factor binding sites and the advance in high-throughput sequencing technologies at a continually reducing cost. Therefore, several experimental techniques have been developed resulting in diverse motif-finding algorithms and databases. We collate a wide variety of available motifs into a benchmark database, including the corresponding experimental ChIP-seq and PBM data obtained from ENCODE and UniPROBE databases, respectively. The implemented tools include: a data-independent consistency-based motif assessment and ranking (CB-MAR), which is based on the idea that correct motifs are more similar to each other while incorrect motifs will differ from each other; and a scoring and classification-based algorithms, which rank binding models by their ability to discriminate sequences known to contain binding sites from those without. The CB-MAR and scoring techniques have a 0.86 and 0.73 median rank correlation using ChIP-seq and PBM respectively. Best motifs selected by CB-MAR achieve a mean AUC of 0.75, comparable to those ranked by held out data at 0.76 - this is based on ChIP-seq motif discovery using five algorithms on 110 transcription factors. We have demonstrated the benefit of this web server in motif choice and ranking, as well as in motif discovery. It can be accessed at http://www.bioinf.ict.ru.ac.za/.

bioinformatics↗