Banos, Georgios

Coffey, M.

Ilska, Joanna

Nussey, Daniel

Psifidi, Androniki

Seeker, Luise

Whitelaw, Christopher

Involuntary culling is a major cause of economic loss in dairy cows. Here we examine the genetic background of telomere length (TL) and its association with dairy cow longevity, using the largest dataset of TL measurement in livestock species. Heritability of TL at birth (TLB) was moderate and significant. A genome-wide association study (GWAS) revealed three suggestive genome-wide significant SNPs on chromosomes 1 and 23 affecting TLB. Significant phenotypic correlations of TLB with a range of longevity traits and a significant genetic correlation with survival to 48 months of age were also estimated. Keywords: longevity, dairy, telomere length, biomarker, GWA

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     Edinburgh Research Explorer                                      Genetic background of early life telomere length and associationwith dairy cow longevityCitation for published version:Ilska, J, Psifidi, A, Seeker, L, Whitelaw, C, Coffey, M, Nussey, D & Banos, G 2018, Genetic background ofearly life telomere length and association with dairy cow longevity. in Proceedings of the 11th Congress onGenetics Applied to Livestock Production:  Volume Technologies - Novel Phenotypes. Auckland, NewZealand, 11th World Congress on Genetics Applied to Livestock Production, Auckland, New Zealand,11/02/18.Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:Proceedings of the 11th Congress on Genetics Applied to Livestock ProductionGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 09. May. 2019Proceedings of the World Congress on Genetics Applied to Livestock Production, 11.498Genetic background of early life telomere length and association with dairycow longevityJ. J. Ilska1, A. Psifidi2,3, L. A. Seeker1,2, B.Whitelaw2, M. Coffey1, D. Nussey4, G. Banos1,21Animal & Veterinary Sciences, SRUC, Roslin Institute Building, Easter Bush, MidlothianEH25 9RG, Georgios.Banos@sruc.ac.uk (Corresponding Author)2The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh,Easter Bush, Midlothian, UK3Royal Veterinary College, London, UK4 Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh,Edinburgh, Midlothian, UKSummaryInvoluntary culling is a major cause of economic loss in dairy cows. Here we examine thegenetic background of telomere length (TL) and its association with dairy cow longevity,using the largest dataset of TL measurement in livestock species. Heritability of TL at birth(TLB) was moderate and significant. A genome-wide association study (GWAS) revealedthree suggestive genome-wide significant SNPs on chromosomes 1 and 23 affecting TLB.Significant phenotypic correlations of TLB with a range of longevity traits and a significantgenetic correlation with survival to 48 months of age were also estimated.Keywords: longevity, dairy, telomere length, biomarker, GWASIntroductionTelomeres are tandem repeated DNA sequences capping chromosome ends. In vitro studiesshow that they are truncated during each mitotic cycle; once a critical length is reached, theirprotective function is lost and cells enter a stage of replicative senescence. The link betweenTL and cell age has thus led to a hypothesis that it could be used as a predictor of theorganism’s longevity; this was later confirmed in some studies on humans and wild animals(e.g. Cawthon et al. 2003), however the results have not been consistent.In dairy cows, involuntary culling is a major source of economic loss, with geneticprogress limited by low heritability and difficulties in measuring longevity. Therefore, a traitmeasured early in life, which could predict the lifespan of a cow could improve returns. TL isproving to be a likely candidate, with preliminary results showing its significant and positiveassociations with dairy cow longevity (Brown et al. 2012).Estimates of TL heritability vary between studies and species, from 0.2 to 0.8 (e.g.Reichert et al. 2015). Recent GWAS studies in humans identified several single nucleotidepolymorphisms (SNPs) and genes associated with TL in humans (e.g. Codd et al. 2013).However, the genetic background of TL in cattle remains largely unknown.The objective of this study was to investigate the genetic architecture of leukocyte TLat birth using pedigree and genomic data, and test its associations with longevity in dairycattle.Material and methodsDataData included 662 female Holstein Friesian cattle from the SRUC Dairy Research Centre atCrichton Royal Farm, Scotland. The Langhill cows in this experimental herd are split intotwo genetic merit groups, randomly assigned to high or low forage feed groups. The pedigreeincluded 11,598 individuals over 27 generations, of which 71 sires and 478 dams hadoffspring with TL records. Leukocyte TLB was measured from whole blood samplescollected through venepuncture within the first 14 days after birth. DNA was extracted fromthe blood samples and TLB was measured by qPCR as described before (Seeker et al. 2016).The raw TLB measures were log-transformed to ensure normal distribution.Sources of variance in TLBThe sources of variance in TLB were examined by mixed linear models with the directadditive effect of the animal, and either maternal genetic or maternal permanent environmenteffects fitted as random. Their significance was tested individually through log-likelihoodratio test (LRT). Based on preliminary analyses including 21 fixed effects and covariates,fixed effects fitted were qPCR row and plate, binary lameness status of the calf’s dam inlactation preceding the calf’s birth, genetic group of the calf and the feed group of the calf’sdam.TLB and longevityLongevity measures were herd life (HL – days between birth and cull date), productive life(PL – days between first calving and cull date) and binary survival to 12, 24, 36, 48, 60 and72 months of age. The association between TLB and longevity was tested in three ways: 1)fitting TLB as a covariate in models fitted to longevity traits, 2) fitting a bivariate phenotypicanalysis with longevity traits corrected for pertaining fixed effects and, 3) fitting a bivariateanimal model with both traits corrected for the fixed effects. For binary survival traits,generalised linear mixed models logit link function were used. Significance of the residualand genetic correlations for HL and PL was tested with a LRT. Significance of phenotypicgenetic and residual correlations between TLB and binary traits was tested using two-tailed t-test. Significance of TLB as a covariate was established from conditional Wald F statistic.Significance threshold was corrected for multiple testing using a Holm-Bonferroni test,assuming four independent hypotheses.Genome-wide association studyFor 246 animals Illumina Bovine SNP50 BeadChip array genotypes were available.Multidimensional scaling analysis confirmed the clustering of the individuals into the twoknown genetic groups. SNPs exceeding the minor allele frequency of 0.05, with p-value ofHardy-Weinberg Equilibrium test being £10-6 and proportion of individuals and markers withmissing genotypes<0.05 were removed. After quality control 38,522 SNPs remained forfurther analysis. GEMMA software was used to run the GWAS based on a mixed model thatincluded the genomic relationship matrix among individuals as a random effect, andyear/season of birth, genetic group and qPCR row as fixed effects. A genome-widesignificance threshold was set at p=0.05 and a suggestive significance threshold of one falsediscovery per genome scan was applied. Bonferroni correction was used to account formultiple testing. Furthermore, using Ensembl, significant SNPs were mapped on the referencegenome (Bos_taurus_UMD3.1) and a search for annotated genes within 0.5 MB windowsaround the significant SNP was performed. A pathway analysis was also performed using theIPA software.Results and DiscussionTLB was moderately heritable (0.36±0.09). In the studied dataset maternal variances were notfound to be significant, although a subset of the data indicated a significant maternalenvironment effect (0.33±0.10) (Ilska et al. 2017). The inconsistency of the estimates formaternal effects is common in studies of TL and exceeds the expectation of the heterogeneityof results caused by random error alone (Eisenberg 2014). Possible explanations includegenuine differences between populations or an epigenetic inheritance of telomere sequencesfrom particular germ cells. The significant effect of the lameness status of the dam on heroffspring’s TLB (offspring of lame cows in the preceding lactation had shorter TLB thanthose whose dams were not lame) supports the findings of associations between intra-uterinestress, hormone exposure and TL in offspring. Lameness is a major cause of chronic stress incattle, and has been shown to affect the hormonal cascade, particularly cortisol and oestradiollevels.The GWAS revealed three suggestive SNPs, on chromosomes 1 and 23 (Figure 1). The twosignificant markers on chromosome 23 were located within NEDD9, a gene involved in cellcycle progression and cytoskeletal regulation and has been previously associated with TL inhumans. IPA analysis revealed the presence of significant pathways related with positiveregulation of DNA metabolic process and response to hormones, positive regulation of cellcycle process, positive regulation to leukocyte chemotaxis, stress, immune response, cytokinesignalling and cell proliferation.Figure 1. Manhattan plot for TLB; x-axis is chromosome number; y-axis is -log10(p value);horizontal lines show the genome-wide (red) and suggestive genome-wide (blue) significancethresholds.Associations with longevityTLB showed significant associations with several measures of longevity (Table 1). Thephenotypic correlation between TLB and survival was positive across all age groups andsignificant for ages 12, 24 and 36 months. Due to the relatively low number of records, theanalyses for ages 48 and older failed to converge; thus more research is needed to examinethese associations. The results of analyses of lifespan were significant for HL but not PL. Asingle significant estimate of genetic correlation at 0.76 (±0.23) was found between TLB andST_M48 (heritability of 0.15±0.06), suggesting that animals with genetic propensity forlonger TLB have a higher probability to survive to four years of age. A significant negativeresidual correlation was also estimated, which could potentially explain the relatively lowestimates of the phenotypic correlations. In the literature, associations of TL with longevityare inconclusive and depend on the population studied, as well as on the period of longevityto be predicted. The associations between longevity and TL in dairy cows are likely to bedifferent to those detected in humans and wild animals, as the longevity of a dairy cow doesnot represent her biological limits but depends on productivity, disease resistance and fertility.Table 1.Regression coefficient (β) of TLB fitted as a covariate on longevity traits; correlationestimates from bivariate analyses of TL and longevity, from fixed effect and mixed animalmodel analyses. Standard errors in brackets. ST_M12 to ST_M48 – survival to age in months,HL – herd life. RA, RE and RP – genetic, residual and phenotypic correlations respectively.Longevitytraitβ Fixed effectmodel RPMixed animal modelRA RE RPST_M12 2.55 (0.85) * 0.09 (0.02) * 0.52 (0.30) -0.04 (0.04) 0.11 (0.07)ST_M24 2.14 (0.75) 0.10 (0.02) * 0.87 (0.44) -0.08 (0.04) * 0.12 (0.06)ST_M36 -1.18 (1.28) 0.07 (0.02) * -0.06 (0.26) 0.08 (0.04) 0.05 (0.04)ST_M48 1.01 (0.99) 0.21 (0.02) ¥ 0.76 (0.23) * -0.21 (0.07) * 0.13 (0.06)HL 531.4 (224.3) 0.12 (0.05) * -0.40 (0.24) 0.15 (0.09) 0.01 (0.06)* Estimate significant after Holm-Bonferroni correction¥ Analysis failed to converge.List of ReferencesBrown, D.E. et al., 2012. Hot topic : Association of telomere length with age, herd , andculling in lactating Holsteins. Journal of Dairy Science, 95(11), pp.6384–6387.Cawthon, R.M. et al., 2003. Association between telomere length in blood and mortality inblood and mortality in people aged 60 years or older. The Lancet, 361(9355), pp.393–395.Codd, V. et al., 2013. Identification of seven loci affecting mean telomere length and theirassociation with disease. Nature Genetics, 45(4), pp.422–427.Eisenberg, D.T. a, 2014. Inconsistent inheritance of telomere length (TL): is offspring TLmore strongly correlated with maternal or paternal TL? European Journal of HumanGenetics, 22(1), pp.8–9.Ilska, J.J. et al., 2017. Genetic Parameters of Telomere Length in Cattle. In British Society ofAnimal Science. Chester.Reichert, S. et al., 2015. Maternal telomere length inheritance in the king penguin. Heredity,114(1), pp.10–16.Seeker, L.A. et al., 2016. Method specific calibration corrects for DNA extraction methodeffects on relative telomere length measurements by quantitative PCR. PLoS ONE,11(10), pp.1–15.

Genetic background of early life telomere length and association with dairy cow longevity

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Genetic background of early life telomere length and association with dairy cow longevity

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