The contribution of parent-to-offspring transmission of telomeres to the heritability of telomere length in humans

Abstract

Leukocyte telomere length (LTL) is a heritable trait with two potential sources of heritability (h 2 ): inherited variation in non-telomeric regions (e.g., SNPs that influence telomere maintenance) and variability in the lengths of telomeres in gametes that produce offspring zygotes (i.e., "direct" inheritance). Prior studies of LTL h 2 have not attempted to disentangle these two sources. Here, we use a novel approach for detecting the direct inheritance of telomeres by studying the association between identity-by-descent (IBD) sharing at chromosome ends and phenotypic similarity in LTL. We measured genome-wide SNPs and LTL for a sample of 5,069 Bangladeshi adults with substantial relatedness. For each of the 7,254 relative pairs identified, we used SNPs near the telomeres to estimate the number of chromosome ends shared IBD, a proxy for the number of telomeres shared IBD (T shared ). We then estimated the association between T shared and the squared pairwise difference in LTL ((ΔLTL) 2 ) within various classes of relatives (siblings, avuncular, cousins, and distant), adjusting for overall genetic relatedness (ϕ).The association between T shared and (ΔLTL) 2 was inverse among all relative pair types. In a metaanalysis including all relative pairs (ϕ >0.05), the association between T shared and (ΔLTL) 2 (P=0.002) was stronger than the association between ϕ and (ΔLTL) 2 (P=0.45). Our results provide strong evidence that telomere length (TL) in parental germ cells impacts TL in offspring cells and contributes to LTL h 2 despite telomere "reprogramming" during embryonic development. Applying our method to larger studies will enable robust estimation of LTL h 2 attributable to direction transmission.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Determinants of telomere length across human tissues

“…In other words, our results suggest that offspring (zygotes) inherit telomeres from germ cells that vary in TL due to ancestry, and these ancestry-based differences in TL are mitotically transmitted to daughter cells, and eventually to cells in many adult tissue types. This "direct transmission" of TL from parent to offspring (28) would result in the observed ancestry-based differences across many tissue types (summarized in Figure 2D). One likely cause of this ancestry-based difference is natural section on SNPs know to impact TL (29), although selection on TL itself could also contribute.…”

Genetic and Epigenetic Regulation of Telomere Length: Current Findings, Methodological Limitations and Possibilities for Future Studies

“…As discussed above TL is a heritable trait with two potential sources of heritability: inherited genetic variation (e.g. SNPs affecting telomere maintenance (see Table 1)) and variability in the lengths of telomeres in gametes that produce offspring zygotes [49]. The latter, is described as "direct" transmission of telomeres [50].…”

“…However, telomeres undergo a "reprogramming" event during early embryogenesis and it remains unclear to what extent reprogramming alters the impact of germ cell TL on offspring TL [50]. Recent observations provide evidence that TL in parental germ cells impacts TL in offspring cells and contributes to LTL heritability despite telomere "reprogramming" during embryogenesis [49]. However, larger studies are required to provide a robust estimation of LTL heritability by 'direct' transmission.…”

Telomere length and chromosomal instability for predicting individual radiosensitivity and risk via machine learning

“…air pollution 28 , UV 29 ) as well. Telomere length is a highly heritable trait, as is telomere length regulation [30][31][32][33] , supportive of individual variation in telomeric response to specific stressors. Interestingly, short telomeres have been proposed as hallmarks of radiosensitivity 34 , and ionizing radiation (IR) exposure has been shown to evoke both shortening and lengthening of telomeres [35][36][37][38][39][40] .…”

“…Given that telomere length is influenced by a variety of genetic factors [30][31][32][33] and exposures including IR exposure [35][36][37][38][39][40] , we reasoned that a patient's telomeric outcome post-radiation therapy, rather than their pre-treatment (baseline) measures, would be most informative for assessing individual risks for radiation late effects and long-term health consequences. Furthermore, since patient-derived pre-radiation therapy samples irradiated in vitro provide an informative proxy for individual patient radiosensitivity and response in vivo [49][50][51] , an effective means to accurately predict an individual patient's telomeric outcome post-radiation therapy could be developed, thereby improving personalized treatment strategies and individual outcomes.…”