Tracing the Origin of the RSPO2 Long-Hair Allele and Epistatic Interaction between FGF5 and RSPO2 in Sapsaree Dog

Genetic analysis of the hair-length of Sapsaree dogs, a Korean native dog breed, showed a dominant mode of inheritance for long hair. Genome-Wide Association Study (GWAS) analysis and subsequent Mendelian segregation analysis revealed an association between OXR1, RSPO2, and PKHD1L1 on chromosome 13 (CFA13). We identified the previously reported 167 bp insertion in RSPO2 3’ untranslated region as a causative mutation for hair length variations. The analysis of 118 dog breeds and wolves revealed the selection signature on CFA13 in long-haired breeds. Haplotype analysis showed the association of only a few specific haplotypes to the breeds carrying the 167 bp insertion. The genetic diversity in the neighboring region linked to the insertion was higher in Sapsarees than in other Asian and European dog breeds carrying the same variation, suggesting an older history of its insertion in the Sapsaree genome than in that of the other breeds analyzed in this study. Our results show that the RSPO2 3’ UTR insertion is responsible for not only the furnishing phenotype but also determining the hair length of the entire body depending on the genetic background, suggesting an epistatic interaction between FGF5 and RSPO2 influencing the hair-length phenotype in dogs.

Epistatic Interaction Effect Between Chromosome 1BL (Yr29) and A Novel Locus on 2AL Facilitating Resistance to Stripe Rust in Chinese Wheat Changwu 357-9

Stripe rust (yellow rust) is a serious disease of bread wheat ( Triticum aestivum L.) worldwide. Genetic resistance is considered the most economical, effective and environmentally friendly method to control the disease. The current study focused on characterizing the components of stripe rust resistance and understanding the interactions in Changwu 357-9 (CW357-9)/Avocet S RIL population. A genetic linkage map constructed using a new GenoBaits Wheat 16K Panel and the 660K SNP array had 5,104 polymorphic SNP markers spanning 3,533.11 cM. Four stable QTL were detected on chromosome arms 1BL, 2AL, 3DS, and 6BS across all environments in Chngwu357-9. The most effective QTL Q YrCW357-1BL was Yr29 and the 6BS QTL was identified as Yr78 . The novel QTL on 2AL with moderate effect showed significant epistatic interaction with Yr29 . The QTL on 3DL should be same as QYrsn.nwafu-3DL and enriches the overall stripe rust resistance gene pool for breeding. Polymorphisms of flanking AQP markers AX-110020417 (for QYrCW357-1BL ), AX-110020417 (for QYrCW357 -2AL ), AX-109466386 (for QYrCW357 -3DL ), and AX-109995005 (for QYrCW357 -6BS ), were evaluated in a diversity panel including 225 wheat cultivars and breeding lines. The results suggested that these high-throughput markers could be used to introduce QYrCW357-1BL ( Yr29 ), QYrCW357-2AL , QYrCW357 -3DL , and QYrCW357 -6BS into commercial wheat cultivars. Combinations of these genes with other APR QTL should lead to higher levels of stripe rust resistance along with the beneficial effects of multi-disease resistance gene Yr29 on improving resistance to other diseases.

A sex-specific evolutionary interaction between ADCY9 and CETP

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3,400 Peruvians. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues, which also differs between males and females. We also detected interaction effects of the two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. We propose that ADCY9 and CETP coevolved during recent human evolution due to sex-specific selection, which points towards a biological link between dalcetrapib’s pharmacogene ADCY9 and its therapeutic target CETP.

A sex-specific evolutionary interaction between ADCY9 and CETP

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of natural selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3400 Peruvians. We further detected interaction effects of these two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues. We propose that ADCY9 and CETP coevolved during recent human evolution, which points towards a biological link between dalcetrapib's pharmacogene ADCY9 and its therapeutic target CETP.

Molecular Mechanisms of Genetic Interaction (Epistasis) in the Evolution and Management of Antibiotic Resistance Tuberculosis: Current Consequence and Future Perspectives

Tuberculosis (TB) is an infectious chronic human disease caused by Mycobacterium tuberculosis (MTB) bacteria. M. tuberculosis has a great capability of resistance with plentiful natural and acquired mechanisms in their genome that contribute to the spread of highly drug resistance strains and became major public health concern. The majority of drug resistance in M. tuberculosis strains has been resulted from a numbers of chromosomal mutation events most of which are due to the mechanisms of epistasis that leads to the creation of resistance genes to anti-TB drugs. Epistasis can occur when two or more mutations interact with each other to express new phenotypic traits to modify their fitness cost. Thus, the objective of this review was to assessed the molecular mechanisms of epistasis and its consequences in the evolution and managements of antibiotic resistance-TB. The epistatic interactions within and between resistance gene mutations in M. tuberculosis could be detected by co-culture competitive fitness experimental assay under optimal growth conditions that showed either significantly negative or improving deleterious positive fitness effect. Molecular mechanisms of epistatic interaction could have important practical consequences in the trajectory of drug resistance, evolution of antimicrobial resistance and management of antibiotic resistance-TB. Understanding the evolution of M. tuberculosis under antibiotic treatments is a burning issue today. Unlike the deleterious positive epistasis, the beneficial negative epistatic interaction of resistance gene mutations under multidrug therapy method and/or collateral drug sensitivity approaches based on the knowledge of drug combinations help to mitigate the spread of drug-resistant strains, reduce treatment duration, minimize adverse drug effects on evolution of MDR/XDR-TB and improve treatment outcomes of TB patients.

Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction

Background: The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. Methods: Eight kindreds with familial AF and slow conduction, including a family affected by early onset AF, heart block and incompletely penetrant non-ischemic cardiomyopathy (NICM) underwent whole exome sequencing. Results: A known pathogenic mutation in the desmin (DES) gene resulting in S13F substitution at a PKC phosphorylation site was identified in all four members of the kindred with early-onset AF and heart block, while only two developed NICM. Higher penetrance of the mutation for AF and heart block prompted the screening for DES modifier(s). A second deleterious mutation in the phosphodiesterase 4D interacting-protein (PDE4DIP) gene resulting in A123T substitution segregated with early onset AF, heart block and the DES mutation. Three additional novel deleterious PDE4DIP mutations were identified in four other unrelated kindreds. Characterization of PDE4DIP in vitro suggested impaired compartmentalization of PKA and PDE4D characterized by reduced colocalization with PDE4D, increased cAMP activation leading to higher PKA phosphorylation of the β2-adrenergic-receptor, and decreased PKA phosphorylation of Desmin in response to isoproterenol stimulation compared to wildtype PDE4DIP. Conclusion: Our findings identify an epistatic interaction between DES and PDE4DIP variants, increasing the penetrance for conduction disease and arrhythmia.