Characterisation of telomere length dynamics in dairy cattle and association with productive lifespan

Telomeres form protective caps at the ends of linear chromosomes. They consist of repetitive DNA nucleotides and associated proteins of the shelterin complex. In vitro telomeres become shorter during cell division and when a critical shortness is reached they trigger a DNA damage response that leads to replicative senescence or apoptosis. Telomere shortening is a recognised hallmark of cellular ageing and seems to be also associated with organismal ageing. Telomere length (TL) and the rate of shortening vary across individuals and several studies have found that short telomeres and fast telomere depletion are associated with poor survival and early onset of age related diseases. However, longitudinal studies are needed to better understand the relationship of TL and TL dynamics with longevity measures. Relevant studies on livestock species are largely missing from the literature. In the dairy industry, farmers are forced to cull a considerable percentage of their heifers and cows at a young age due to fertility problems or diseases. As a consequence many replacement heifers have to be reared to maintain a specific herd size. This results in increased costs, consumption of resources, and damage to the environment. Breeding for an improved productive lifespan is difficult because longevity measures are recorded at the end of life and are known to have a low heritability. Therefore, the expected genetic improvement is generally slow, but could be considerably accelerated if an early life heritable biomarker was identified that is predictive of productive lifespan and could be used for animal selection. The question is if TL could be used as such a biomarker. The objectives of this thesis were to 1) develop robust methods to measure average relative leukocyte TL (RLTL) in cattle, 2) examine RLTL dynamics with age at a population as well as at an individual level, 3) estimate genetic parameters and 4) assess the association of RLTL and RLTL dynamics with productive lifespan. A quantitative polymerase chain reaction (qPCR) based assay developed for human studies was adapted to cattle and delivered robust results (repeatability > 80%, coefficient of variation=0.05). Different DNA extraction methods were tested for their effect on RLTL measurements and it was demonstrated that fast silica based DNA extraction methods are suitable for telomere projects which can improve the sample throughput and enable large-scale projects. Subsequently, RLTL in 1328 whole blood samples of 308 Holstein Friesian dairy cows and additionally in 284 whole blood samples of 38 female calves was measured. Repeatability and random regression models were used for the statistical analysis of telomere data. RLTL decreased considerably within the first year of life, but remained relatively stable afterwards at population level. Animals varied significantly in their amount and direction of telomere change. The genetic correlation between consecutive measurements in the same individual weakened with increasing sample interval from r=1 to r=0.69 which indicates that TL in the beginning of life might be under a different genetic control than TL later in life. For the first time in a livestock species we calculated heritability estimates for RLTL which were high (0.32-0.38) and remained constant over life. Long telomeres at birth were not predictive of better productive lifespan. However, animals with long RLTL at the ages of one and five years had a survival advantage. Also, animals that showed less average RLTL attrition over their lives remained in production for longer. TL dynamics differed among individuals and a considerable subset of individuals demonstrated telomere lengthening between consecutive measurements. On average, telomeres tend to shorten early in life and then remain relatively constant. While TL is a heritable trait throughout lifetime, telomere change is not heritable. Short TL at specific ages and telomere attrition over life were associated with poorer productive lifespan