Sex-related differences in length and erosion dynamics of human telomeres favor females

Abstract

Telomeres are repetitive DNA sequences at chromosomal ends contributing to genomic integrity. In somatic cells, telomeres are shortened during DNA reduplication. Thus, telomere erosion has been regarded as a biological clock. Applying the telomere/centromere (T/C)-FISH technique to human peripheral blood lymphocytes, we showed that pangenomically, telomere shortening is linear in centenarians and that this attrition is delayed in females. Statistics reveal a greater skewness in telomere length distribution in females. As the morphological correlate, we find abnormally long telomeres distributed at random. This "erratic extensive elongation" (EEE) of telomeres is a hitherto unrecognized phenomenon in non-neoplastic cells, and females are more successful in this respect. As evidenced by endoreduplication, EEE is transmitted to the cells' progeny. The mechanism involved is likely to be the alternative pathway of telomere elongation (ALT), counteracting erosion and already known to operate in neoplastic cells.

Keywords: T/C-FISH; alternative pathway; telomere length.

Figure 1.. Metaphases of phytohemagglutinin-stimulated peripheral blood lymphocytes.

Chromosomes were co-hybridized with peptide nucleic acid (PNA) probes (red) for telomeric sequences and the chromosome 2 centromere serving as internal reference probe, and stained with DAPI (blue). Centromere signals are marked by arrows. (a) Metaphase derived from cord blood of a male newborn, (b) Metaphase from blood of a centenarian male.

Figure 2.. Erratic extensive elongation (EEE) of single telomeres in peripheral lymphocytes.

(a) Histogram of telomere lengths of all p and q arms of chromosomes of females (green) and males (red). The dotted line represents the theoretical Gaussian distribution, the histogram in the smaller insert represents the curve of female and male values together. The actual curves are skewed to the right. (b) Skewness and kurtosis of telomere lengths of p and q arms of chromosomes of lymphocytes in all age groups. Values are limited to 150 T/C values. (c) Skewness and kurtosis of telomere lengths of p and q arms of chromosomes of female (filled circles and green line) and male probands (open circles and red line) ranging from newborns up to 90 years. Centenarians are excluded because the male group consists of only 2 persons. Values limited to 150 T/C values as mentioned above. (see “Statistical analysis” for further details).

Figure 3.. Examples of EEE.

(a) Depicts chromosomes of a newborn male with enhanced signal intensity at one p arm of chromosome 15 and at both chromatids of chromosome 16, (b). This is also the case at a single chromatid of 15q and on both chromatids of chromosome 7q in a 50-year-old male and, (c) at a single chromatid of chromosome 9p and at both arms of chromosome 10q in a male centenarian. (d) Schematic view of endoreduplication (ER), the result being a group of four homologous chromatids which emerged from one single chromatid. Note that the juxtapositions of the sister and descendant chromatids may be variable, since their three-dimensional packing is broken up by chromosome spreading. (e) Single chromosomes of a sporadic ER observed in a 40-year-old female with features of EEE. Since telomeric EEEs at 2p, 5q, 6q, and 10p are doublets and not quadruplets, EEE at these positions must have occurred one cell cycle prior to the ER event. In addition, there is a single telomeric EEE at 19q, which must have occurred during the S-phase directly preceding this ER.