Lipkin, E. | Search bioRxiv

bioRxiv2025

Is it chaotic? Chicken Linkage Disequilibrium and quantitative trait loci

Linkage disequilibrium (LD) underpins genome-wide association studies (GWAS) to map Quantitative Trait Loci Regions (QTLRs). A common yet misled assumption is that the closest sites to a significant marker are the prime candidates as the causative mutation. However, LD blocks are typically fragmented and intermingled. We studied chicken LD of mapped QTLRs for Mareks Disease in numerous chicken populations. We estimated background LD by random sampling of non-syntenic or syntenic marker pairs from different or same chromosomes. We defined LD blocks as a group of markers located on the same chromosome having significant moderate (0.15 [≥] r2 < 0.7) or high (r2 [≥] 0.7) LD, regardless of distance and the number of mixed markers with no LD. Next, we studied QTLR LD by all SNP markers within the QTLRs. We found very complex, nearly chaotic, LD patterns, with fragmented and interdigitated LD blocks. Exceptional LD was found between QTLRs 4-5. LD blocks and protein networks shared by the two QTLRs suggest possible functional relationships. Thus, potential causative candidates could be found beyond non-LD sites, occasionally at a very large distance from a significant marker, and even in another QTLR. Multiple effects might make LD intrinsically chaotic, thus limiting GWAS informativity and repeatability. Chaotic complexity challenges the practical use of LD across populations, and must be accounted for while interpreting genetic mapping studies.

genetics↗

bioRxiv2021

Complex and long-range linkage disequilibrium and its relationship with QTL for Marek's Disease resistance in chicken populations

Chicken long-range linkage disequilibrium (LRLD) and LD blocks, and their relationship with previously described Mareks Disease (MD) quantitative trait loci regions (QTLRs), were studied in an F6 population from a full-sib advanced intercross line (FSAIL), and in eight commercial pure layer lines. Genome wide LRLD was studied in the F6 population by random samples of non-syntenic and syntenic marker pairs genotyped by Affymetrix HD 600K SNP array. To illustrate the relationship with QTLRs, LRLD and LD blocks in and between the MD QTLRs were studied by all possible marker pairs of all array markers in the QTLRs, using the same F6 QTLR genotypes and genotypes of the QTLR elements markers in the eight lines used in the MD mapping study. LRLD was defined as r2 [≥] 0.7 over a distance [≥] 1 Mb, and 1.5% of all syntenic marker pairs were classified as LRLD. Complex fragmented and interdigitated LD blocks were found, over distances ranging from a few hundred to a few million bases. Vast high, long-range, and complex LD was found between two of the MD QTLRs. Cross QTLRs STRING networks and gene interactions suggested possible origins of this exceptional QTLRs LD. Thus, causative mutations can be located at a much larger distance from a significant marker than previously appreciated. LRLD range and LD block complexity may be used to identify mapping errors, and should be accounted for while interpreting genetic mapping studies. All sites with high LD with a significant marker should be considered as candidate for the causative mutation.

genomics↗

bioRxiv2020

Mapping QTL associated with resistance to avian oncogenic Mareks Disease Virus (MDV) reveals major candidate genes and variants

Mareks Disease (MD) represents a significant global economic and animal welfare issue. Mareks Disease Virus (MDV) is a highly contagious oncogenic and highly immune-suppressive alpha-herpes virus, which infects chickens, causing neurological effects and tumour formation. Though partially controlled by vaccination, MD continues to have a profound impact on animal health and on the poultry industry. Genetic selection provides an alternative and complementary method to vaccination. However, even after years of study, the genetic mechanisms underlying resistance to MDV remain poorly understood. The MHC is known to play a role in disease resistance, along with a handful of other. In this study, one of the largest to date, we used a multi-facetted approach to identify QTL regions (QTLR) influencing resistance to MDV, including an F6 population from a full-sib advanced intercross line (FSIL) between two elite commercial layer lines differing in resistance to MDV, RNA-seq information from virus challenged chicks, and genome wide association study (GWAS) from multiple commercial lines. Candidate genomic elements residing in the QTLR were further tested for association with offspring mortality in the face of MDV challenge in 8 pure lines of elite egg-layer birds. Thirty-eight QTLR were found on 19 chicken chromosomes. Candidate genes, miRNAs, lncRNAs and potentially functional mutations were identified in these regions. Association tests were carried out in 26 of the QTLR, using 8 pure lines of elite egg-layer birds. Numerous candidate genomic elements were strongly associated with MD resistance. Genomic regions significantly associated with resistance to MDV were mapped, and candidate genes identified. Various QTLR elements were shown to have strong genetic association with resistance. These results provide a large number of significant targets for mitigating the effects of MDV infection on both poultry health and the economy - whether by means of selective breeding, improved vaccine design or gene-editing technologies. Author summaryMareks Disease has a huge impact on the global poultry industry in terms of both animal welfare and economic cost. For many years, researchers have sought to identify the genes underlying resistance to Mareks Disease Virus (MDV). However, this is a complex trait with each genetic locus having a small effect, so identifying causal genes and variants is no easy task. To date, it is known that the MHC confers differing susceptibility/resistance. A few other non-MHC genes have also been implicated in disease resistance, although based on experimental inbred lines and not representing real world commercial poultry. Using an F6 intercross population of birds with differences in MDV survival, we have identified many regions of the genome involved in resistance and highlighted candidate genes, miRNAs and lncRNA. Access to DNA from phenotyped birds spanning 15 generations of 8 elite commercial lines has provided a unique opportunity for us to show genetic association of markers in these transcripts with MDV survival. This genetic study, the largest to date, provides novel targets for mitigation of Mareks Disease within the poultry industry. This could be through selective breeding strategies, improved vaccine design or future gene editing technologies.

genomics↗