USOS DE PRENDAS Y HERRAMIENTAS

Telomere length measurement by real time quantitative PCR is not a good predictor of an individual’s age. The presence of large inter-individual variation in telomere length prevents developing a formula to predict age from DNA with accuracy. Telomere length differences at birth (Ohki et al. 2001), telomere attrition differences between males and females (Baird et al. 2005), non-linear telomere length loss during different stages of life (Rufer et al. 1999), genetic factors and environmental factors give rise to the large amount of variation of telomere lengths present in the population.

Chapter 5

Influence of inheritance on telomere length

5.1 Introduction

As discussed in the preceding Chapter 4, Telomere lengths of 167 individuals aged 1- 96 years old were measured using quantitative real time PCR. The aim was to develop a formula to predict the age of a person by analysing telomere length in the general population. Although, relative telomere length was found to decreases with age (r = - 0.185, P <0.05), the age prediction value was only 4% in the general population (1% in females, 9% in males), and it is too low for use in forensic purposes. The presence of large inter individual variation in telomere length prevents developing a formula to predict age from DNA with accuracy. This may be due to the fact that telomere length is inherited with varying degrees of paternal and maternal influences.

As stated in Section 2.7, telomere length and chromosome specific telomere length patterns have been reported to be inherited (Graakjaer et al. 2004; Njajou et al. 2007; Rufer et al. 1999; Slagboom et al. 1994), with the percentage of inheritance varying according to the sample population analysed: for instance 78% inheritance observed in twins (Slagboom et al. 1994) and 44% observed in Amish population (Njajou et al. 2007). The differences in inheritance values could be due to the different study population, age ranges, and pedigree structures (Njajou et al. 2007). The mode of inheritance of telomere length is not yet clear, and two hypotheses have been put forward on this (Nawrot et al. 2004; Njajou et al. 2007; Nordfjäll et al. 2005). According to Nowrot et al., telomere length inheritance is linked to the X chromosome (Nawrot et al. 2004), whereas Nordfjall et al. and Njajou et al. have

suggested that telomere length is paternally inherited (Njajou et al. 2007; Nordfjäll et al. 2005).

Studies that have been carried out to determine the mode of inheritance examined the correlation between parental telomere length and children’s telomere length (Table 5.1) (Nawrot et al. 2004; Njajou et al. 2007; Nordfjäll et al. 2005). In the Nowrot et al.(Nawrot et al. 2004) Study, the presence of statistically significant high correlation of telomere lengths between mother and children, and father and daughter, but notably not with father and son, helped to construct the hypothesis that the X chromosome plays a major role in telomere length determination. It was suggested that the DKC1 gene present on the X chromosome is the factor behind X linked inheritance. The protein dyskerin coded by the DKC1, aids in stable accumulation of the hTR component of telomerase. Missense mutations in the DKC1 gene cause a premature ageing syndrome called dyskeratosis congenita (Reviewed in (Collins et al. 2002)). Polymorphisms present in the DKC1 gene possibly regulate the telomere length of individuals by regulating the expression of telomerase.

Contrary to observations made by Nowrot et al (Nawrot et al. 2004), both Nordfjall et al. and Njajou et al. observed high correlation of telomere lengths between father and children but not between mother and children (Table 5.1), concluding that telomere length is paternally inherited (Njajou et al. 2007; Nordfjäll et al. 2005). They failed to observe X-linked inheritance, since the correlation of telomere lengths between mothers and children was low.

Table 5.1 – The correlation values of parent –children telomere lengths in 3 different

studies.

Mode of inheritance Parent children combinations Correlation (r) Significance (p) X – linked inheritance Nowrot et al (Nawrot et al. 2004) Father – daughter Father- son Mother-daughter Mother-son 0.62 0.09 0.59 0.34 <0.0001 0.63 <0.0001 0.013 Paternal inheritance Nordfjal et al (Nordfjäll et al. 2005) Father – daughter Father- son Mother-daughter Mother-son 0.578 0.558 0.161 0.141 0.005 0.011 0.463 0.577 Paternal inheritance Njajou et al (Njajou et al. 2007) Father – daughter Father- son Mother-daughter Mother-son 0.43 0.56 0.18 0.21 <0.001 <0.001 0.05 0.05

The influence of parental age at conception/birth on the telomere length of an individual has been studied (Meyer et al. 2007; Njajou et al. 2007; Unryn et al. 2005). Unryn et al. (Unryn et al. 2005) and Meyer et al. (Meyer et al. 2007) discovered that father’s age at conception/birth had a statistically significant correlation with children’s telomere length. This could be explained by the fact that telomere length increases with age in sperm cells due to the activity of the enzyme telomerase (Allsopp et al. 1992). The positive correlation between father’s age at conception with individual’s telomere length meant that the older the father’s age at conception the longer the telomere lengths of the children (Unryn et al. 2005). In a study done on an Amish population, Njajou et al. found a positive borderline significance of both the parents age at conception with children’s telomere length (Njajou et al. 2007).

The present study was also aimed at assessing the influence of inheritance of telomere length and the effect of parents’ age at conception on the telomere length of an individual. From the total sample of 167 individuals, telomere lengths of 18 families (n = 79), which had more than 3 members per family, were used for this study. From the sample population, telomere lengths of father-daughter (n = 10), father-son (n = 11), mother – daughter (n = 23) and mother- son (n = 16) pairs were compared to assess the mode of inheritance of telomere length. Telomere lengths of the sample were measured by real-time quantitative PCR (Cawthon 2002), as described in section 2.4.1. If there is strong maternal and/or paternal influence on the length of telomeres of an individual, the effect of these factors could be incorporated into the age prediction formula. The more variables included into the age prediction formula the more its accuracy will be increased.