WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Lilit Nersisyan,Maria Nikogհosyan ,Arsen Arakelyan

doi:10.1038/s41598-019-55109-7

Lilit Nersisyan, Maria Nikogհosyan + Show 1 more

Open Access

https://doi.org/10.1038/s41598-019-55109-7

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Abstract

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.

Highlights

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development
While age plays a role in telomere length variation during a lifetime, our analysis show that its effect is weaker compared to inheritance factors, namely parental telomere lengths, with mother’s telomeres being the strongest predictors of offspring mean telomere length (MTL)
The well-structured and richly annotated dataset provided by the Genome of the Netherlands project has allowed us to reveal several aspects of telomere length inheritance and variability

Summary

Introduction

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. The terminal regions of linear human chromosomes are composed of telomeres - sequences of tandem TTAGGG repeats normally stretching around 10–15 kb in length They protect the chromosomes from degradation and end-to-end fusions[1] and perform a number of regulatory functions, including regulation of gene expression[2], DNA damage response[3], modulation of cellular senescence[4], proper chromosome anchoring to the nuclear membrane and segregation during meiosis[5]. While telomere length regulation and environmental factors affect TL variability in a lifetime of a single individual, TL variability between individuals is largely explained by inheritance of parental telomeres and variable TLs at birth, with a stronger link between offspring and either father’s27, or mother’s28 TL. A recent study has simulated this effect across many generations and has suggested this as a mechanism for adaptation to cancer[32]

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