The influence of Neanderthal alleles on cytotoxic response.

Farida S Akhtari,Tim Wiltshire,Tammy M Havener,John R Jack,Masahide Fukudo,Howard L Mcleod,Alison A Motsinger-Reif

doi:10.7717/peerj.5691

Abstract

Various studies have shown that people of Eurasian origin contain traces of DNA inherited from interbreeding with Neanderthals. Recent studies have demonstrated that these Neanderthal variants influence a range of clinically important traits and diseases. Thus, understanding the genetic factors responsible for the variability in individual response to drug or chemical exposure is a key goal of pharmacogenomics and toxicogenomics, as dose responses are clinically and epidemiologically important traits. It is well established that ethnic and racial differences are important in dose response traits, but to our knowledge the influence of Neanderthal ancestry on response to xenobiotics is unknown. Towards this aim, we examined if Neanderthal ancestry plays a role in cytotoxic response to anti-cancer drugs and toxic environmental chemicals. We identified common Neanderthal variants in lymphoblastoid cell lines (LCLs) derived from the globally diverse 1000 Genomes Project and Caucasian cell lines from the Children’s Hospital of Oakland Research Institute. We analyzed the effects of these Neanderthal alleles on cytotoxic response to 29 anti-cancer drugs and 179 environmental chemicals at varying concentrations using genome-wide data. We identified and replicated single nucleotide polymorphisms (SNPs) from these association results, including a SNP in the SNORD-113 cluster. Our results also show that the Neanderthal alleles cumulatively lead to increased sensitivity to both the anti-cancer drugs and the environmental chemicals. Our results demonstrate the influence of Neanderthal ancestry-informative markers on cytotoxic response. These results could be important in identifying biomarkers for personalized medicine or in dissecting the underlying etiology of dose response traits.

Highlights

Research has revealed that anatomically modern humans and archaic hominins, such as Neanderthals and Denisovans, coexisted and interbred (Green et al, 2010; Higham et al, 2014; Prüfer et al, 2014; Sankararaman et al, 2014)
The dose response profile data from this study consists of the cytotoxic response to 179 environmental chemicals each assayed at 8 different concentrations, with 1.3 million single nucleotide polymorphisms (SNPs) used in the association analysis
A specific small nucleolar RNA profile has been reported in acute promyelocytic leukemia (APL) with ectopic expression of SNORD112, SNORD113 and SNORD114 snoRNA clusters (Valleron et al, 2012)

Summary

Introduction

Research has revealed that anatomically modern humans and archaic hominins, such as Neanderthals and Denisovans, coexisted and interbred (Green et al, 2010; Higham et al, 2014; Prüfer et al, 2014; Sankararaman et al, 2014). Recent studies have shown that Neanderthal haplotypes and alleles are under strong selective pressures, with regions undergoing both positive and negative selection (Abi-Rached et al, 2011; Vernot & Akey, 2014; Sankararaman et al, 2014) These variants have been shown to be strongly associated with a number of clinically important diseases and phenotypes, such as hypercoagulation, depression, actinic keratosis, and urinary tract disorders among others (Simonti et al, 2016). Several of the single nucleotide polymorphisms (SNPs) in the Neanderthal PheWAS catalog are listed as being associated with drug response phenotypes such as ‘Adverse drug events and allergies’, ‘Adverse effects of sedatives or other central nervous system depressants and anesthetics’, ‘Antineoplastic and immunosuppressive drugs causing adverse effects’ and ‘Allergic/adverse effects of penicillin’ This inspired us to investigate the effect of these Neanderthal alleles on drug or chemical response using the Lymphoblastoid Cell Lines (LCL) model

Methods

Results

Discussion

Conclusion