Skewness of X-chromosome inactivation increases with age and varies across birth cohorts in elderly Danish women

Abstract

Mosaicism in blood varies with age, and cross-sectional studies indicate that for women, skewness of X-chromosomal mosaicism increases with age. This pattern could, however, also be due to less X-inactivation in more recent birth cohorts. Skewed X-chromosome inactivation was here measured longitudinally by the HUMARA assay in 67 septuagenarian and octogenarian women assessed at 2 time points, 10 years apart, and in 10 centenarian women assessed at 2 time points, 2-7 years apart. Skewed X-chromosome inactivation was also compared in 293 age-matched septuagenarian twins born in 1917-1923 and 1931-1937, and 212 centenarians born in 1895, 1905 and 1915. The longitudinal study of septuagenarians and octogenarians revealed that 16% (95% CI 7-29%) of the women developed skewed X-inactivation over a 10-year period. In the cross-sectional across-birth cohort study, the earlier-born septuagenarian (1917-1923) and centenarian women (1895) had a higher degree of skewness than the respective recent age-matched birth cohorts, which indicates that the women in the more recent cohorts, after the age of 70, had not only changed degree of skewness with age, they had also undergone less age-related hematopoietic sub-clone expansion. This may be a result of improved living conditions and better medical treatment in the more recent birth cohorts.

Figure 1

Lexis diagram of populations of women with measured degree of skewed X-inactivation. Blue: 1895 birth cohort with repeated measures at the latest follow-up participation. Green: 1905 birth cohort (cross-sectional). Note There are no repeated measures, thus the 1905 cohort is not included in longitudinal studies. Purple: 1915 birth cohort (cross-sectional). Red: LSADT with repeated measures at follow-up. Gray: MADT (cross-sectional).

Figure 2

Longitudinal change in degree of skewed X-chromosome inactivation (DS) plotted at baseline in 1997 and follow-up in 2007 twin women (N = 67) from the LSADT cohort.

Figure 3

Cross-sectionally and longitudinally estimated changes in degree of skewed X-chromosome inactivation (DS) with age. Ten-year longitudinal changes of DS at baseline (1997) and follow-up (2007) in LSADT. Cross-sectional age changes were estimated using the LSADT (1997) and the 1905 birth cohort at 93 years of age and the 1895 centenarians.

Figure 4

Co-twin correlations in degree of skewed X-chromosome inactivation (DS) within 23 twin pairs. Twin correlation of DS at baseline in 1997 (grey dots) and at follow-up in 2007 (black dots) with connected lines for each twin pair. Twin 1 is the twin with the largest numeric change in DS.