| Abstract |
Telomeres are composed of specialized DNA, RNA, and proteins that interact to preserve the integrity of chromosome termini.1,2 Despite this vital function, telomere length varies dramatically within and between species. Genome-wide association studies have identified multiple genes that explain a portion of this variation,3 suggesting that telomere length is inherited as a classic quantitative trait. However, telomere length is also directly inherited as a DNA sequence. Here, we show that neither the polygenic nor the direct inheritance paradigm fully accounts for telomere length inheritance, which also depends on a parent-of-origin effect on telomere elongation in the early embryo. By reciprocally crossing mouse strains with different telomere lengths, we find that telomeres elongate in hybrid embryos only when maternal telomeres are short and paternal telomeres are long. In the reciprocal cross, telomeres shorten. These differences in embryonic telomere elongation, which emerge before zygotic genome activation, predict observed differences in adult telomere length. Moreover, when telomeres do elongate, we find molecular signatures of a recombination-based mechanism of telomere elongation, called the alternative lengthening of telomeres (ALT) pathway, previously suggested to elongate telomeres in the pre-implantation embryo. We propose that ALT is triggered by a combination of genetic asymmetry in telomere length and epigenetic asymmetry between maternal and paternal chromosomes in the zygote. Our findings offer new insight into the complex interaction of genetic and epigenetic determinants of telomere length inheritance.
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