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Advanced age increases frequencies of de novo mitochondrial mutations in macaque oocytes and somatic tissues

Arbeithuber, Barbara, Cremona, Marzia A., Hester, James, Barrett, Alison, Higgins, Bonnie, Anthony, Kate, Chiaromonte, Francesca, Diaz, Francisco J., Makova, Kateryna D.·2022·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2118740119PMC PMC9169796
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Abstract

Significance: Multiple human genetic diseases are caused by mutations in the maternally transmitted DNA of mitochondria, the powerhouses of the cell. It is important to study how these mutations arise and accumulate with age, especially because humans in many societies now choose to have children at an older age. However, this is difficult to accomplish in humans, particularly for female germline cells, oocytes. To overcome this limitation, we studied mitochondrial mutation origins and accumulation with age in a primate model species, rhesus macaque. We found that new mutations accumulate the fastest in metabolically active liver and the slowest in oocytes. Thus, primate oocytes might have developed a mechanism to protect their mitochondrial DNA from excessive mutations, allowing reproduction later in life.

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Fig. 1. Age-related increase in mutation frequency. (A) Liver, muscle, and oocyte samples were sequenced from 1- to 23-y-old macaques, classified into four age groups: young, intermediate 1, intermediate 2, and old. (B) Mixed-effects linear model analyzing the effect of age on mutation frequencies (a piecewise model was used for oocytes). Curves show the predicted mutation frequency based on the fixed-effect part of the model. Dots are the observed mutation frequencies per tissue per macaque; predicted frequencies and bootstrap confidence intervals are in SI Appendix, Fig. S5B. (C) Mutation frequencies measured in liver, muscle, and single oocytes shown for each macaque and for each age group. The average mutation frequency among oocytes analyzed for an animal was calculated; the results did not change qualitatively when each oocyte was considered individually (SI Appendix, Table S3 and Fig. S6). P values are for a permutation test comparing young and old age groups (one-sided test based on medians; 10,000 permutations; corrected for multiple testing, see Materials and Methods). (D) Tissue-specific mutation frequencies (i.e., total number of tissue-specific mutations divided by the product of mtDNA region length and mean DCS depth) for each age group in protein-coding (11,370 bp), rRNA (2,505 bp), tRNA (1,504 bp), D-loop (1085 bp), and OriL (33 bp; including a 3-bp overlap with tRNA) sequences. Mutation frequencies for noncoding sequences outside of the D-loop and OriL (98 bp) are shown in SI Appendix, Table S6. Mutation frequency bars are shown with 95% Poisson confidence intervals.
Fig. 1. Age-related increase in mutation frequency. (A) Liver, muscle, and oocyte samples were sequenced from 1- to 23-y-old macaques, classified into four age groups: young, intermediate 1, intermediate 2, and old. (B) Mixed-effects linear model analyzing the effect of age on mutation frequencies (a piecewise model was used for oocytes). Curves show the predicted mutation frequency based on the fixed-effect part of the model. Dots are the observed mutation frequencies per tissue per macaque; predicted frequencies and bootstrap confidence intervals are in SI Appendix, Fig. S5B. (C) Mutation frequencies measured in liver, muscle, and single oocytes shown for each macaque and for each age group. The average mutation frequency among oocytes analyzed for an animal was calculated; the results did not change qualitatively when each oocyte was considered individually (SI Appendix, Table S3 and Fig. S6). P values are for a permutation test comparing young and old age groups (one-sided test based on medians; 10,000 permutations; corrected for multiple testing, see Materials and Methods). (D) Tissue-specific mutation frequencies (i.e., total number of tissue-specific mutations divided by the product of mtDNA region length and mean DCS depth) for each age group in protein-coding (11,370 bp), rRNA (2,505 bp), tRNA (1,504 bp), D-loop (1085 bp), and OriL (33 bp; including a 3-bp overlap with tRNA) sequences. Mutation frequencies for noncoding sequences outside of the D-loop and OriL (98 bp) are shown in SI Appendix, Table S6. Mutation frequency bars are shown with 95% Poisson confidence intervals.CC BY-NC-ND · PubMed Central
Fig. 2. Analysis of variant hotspots. (A) The observed and expected distributions of the number of macaques with individual variants in liver, muscle, and oocytes (with all oocytes from an animal considered together). (B) Distribution of mutations (normalized by the length of the respective region) among D-loop, OriL, noncoding DNA outside of OriL and D-loop, protein-coding regions, rRNA, and tRNA, shown separately for each tissue, and for mutations observed in 1–2, 3–4, or >4 macaques. Numbers indicate the total number of mutations analyzed (due to overlapping annotation of regions, some mutations were counted twice). The proportion of mtDNA occupied by each region is shown on the right. (C) Hairpin structure of OriL; variant hotspots are in blue. (D) hN/hS ratios for mutations observed in 1–2, 3–4, or >4 macaques. Numbers indicate the total number of mutations analyzed. In muscle of intermediate 2 animals, we did not find any synonymous mutations and, thus, could not compute the hN/hS ratio.
Fig. 2. Analysis of variant hotspots. (A) The observed and expected distributions of the number of macaques with individual variants in liver, muscle, and oocytes (with all oocytes from an animal considered together). (B) Distribution of mutations (normalized by the length of the respective region) among D-loop, OriL, noncoding DNA outside of OriL and D-loop, protein-coding regions, rRNA, and tRNA, shown separately for each tissue, and for mutations observed in 1–2, 3–4, or >4 macaques. Numbers indicate the total number of mutations analyzed (due to overlapping annotation of regions, some mutations were counted twice). The proportion of mtDNA occupied by each region is shown on the right. (C) Hairpin structure of OriL; variant hotspots are in blue. (D) hN/hS ratios for mutations observed in 1–2, 3–4, or >4 macaques. Numbers indicate the total number of mutations analyzed. In muscle of intermediate 2 animals, we did not find any synonymous mutations and, thus, could not compute the hN/hS ratio.CC BY-NC-ND · PubMed Central
Fig. 3. Correlation of MAFs for inheritable heteroplasmies between different tissues and correlation of the normalized variance with age. (A) MAF of heteroplasmies in heart vs. muscle. (B) MAF of heteroplasmies in liver vs. muscle. (C) MAF of heteroplasmies in heart vs. liver. (D) MAF of heteroplasmies in somatic tissues (averaged among liver, muscle, and heart) vs. oocytes (averaged among all oocytes studied per animal). (E and F) Correlations of MAFs in muscle and heart, separated into young (E) and intermediate 2 plus old (F) age groups. Additional correlations between somatic tissues are in SI Appendix, Fig. S15. (G and H) Correlations of mean MAFs in somatic tissues and mean MAFs of all oocytes analyzed per animal, separately for young (G) and intermediate 2 plus old (H) age groups. (I and J) Correlation of the normalized variance of heteroplasmy MAF for somatic tissues (I) or single oocytes (J) with age. The gray bands are confidence intervals around the regression line, and the dashed lines are the 1:1 relationship. Dot size for oocyte plots reflects the number of sampled oocytes for each animal and heteroplasmic site.
Fig. 3. Correlation of MAFs for inheritable heteroplasmies between different tissues and correlation of the normalized variance with age. (A) MAF of heteroplasmies in heart vs. muscle. (B) MAF of heteroplasmies in liver vs. muscle. (C) MAF of heteroplasmies in heart vs. liver. (D) MAF of heteroplasmies in somatic tissues (averaged among liver, muscle, and heart) vs. oocytes (averaged among all oocytes studied per animal). (E and F) Correlations of MAFs in muscle and heart, separated into young (E) and intermediate 2 plus old (F) age groups. Additional correlations between somatic tissues are in SI Appendix, Fig. S15. (G and H) Correlations of mean MAFs in somatic tissues and mean MAFs of all oocytes analyzed per animal, separately for young (G) and intermediate 2 plus old (H) age groups. (I and J) Correlation of the normalized variance of heteroplasmy MAF for somatic tissues (I) or single oocytes (J) with age. The gray bands are confidence intervals around the regression line, and the dashed lines are the 1:1 relationship. Dot size for oocyte plots reflects the number of sampled oocytes for each animal and heteroplasmic site.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Arbeithuber, B., Cremona, M. A., Hester, J., Barrett, A., Higgins, B., Anthony, K., Chiaromonte, F., Diaz, F. J., & Makova, K. D.
Affiliations
  • Department of Biology, The Pennsylvania State University, University Park, PA 16802
  • Department of Operations and Decision Systems, Université Laval, Québec, QC G1V0A6, Canada
  • Department of Animal Science, The Pennsylvania State University, University Park, PA 16802
  • Center for Medical Genomics, The Pennsylvania State University, University Park, PA 16802
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2022-04-08
Volume
119
Issue
15
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.2118740119
PMC
PMC9169796
Cited by
40
References
4
Language
en
Licence
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Funders
HHS | National Institutes of Health (R01GM116044)

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