TY - JOUR
T1 - Bottleneck and selection in the germline and maternal age influence transmission of mitochondrial DNA in human pedigrees
AU - Zaidi, Arslan A.
AU - Wilton, Peter R.
AU - Su, Marcia Shu Wei
AU - Paul, Ian M.
AU - Arbeithuber, Barbara
AU - Anthony, Kate
AU - Nekrutenko, Anton
AU - Nielsen, Rasmus
AU - Makova, Kateryna D.
N1 - Funding Information:
ACKNOWLEDGMENTS. We are grateful to Jessica Beiler and clinical nurses from PSU College of Medicine Pediatric Clinical Research Office for sample collection, Bonnie Higgins for help with experiments, and Boris Rebolledo-Jaramillo for reading the paper. This work was funded by NIH grant R01GM116044. Additional funding was provided by the Office of Science Engagement, Eberly College of Sciences, The Huck Institute of Life Sciences and the Institute for CyberScience at Penn State, as well as, in part, under grants from the Pennsylvania Department of Health using Tobacco Settlement and CURE Funds. The department specifically disclaims responsibility for any analyses, interpretations, or conclusions.
Funding Information:
We are grateful to Jessica Beiler and clinical nurses from PSU College of Medicine Pediatric Clinical Research Office for sample collection, Bonnie Higgins for help with experiments, and Boris Rebolledo-Jaramillo for reading the paper. This work was funded by NIH grant R01GM116044. Additional funding was provided by the Office of Science Engagement, Eberly College of Sciences, The Huck Institute of Life Sciences and the Institute for CyberScience at Penn State, as well as, in part, under grants from the Pennsylvania Department of Health using Tobacco Settlement and CURE Funds. The department specifically disclaims responsibility for any analyses, interpretations, or conclusions.
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/12/10
Y1 - 2019/12/10
N2 - Heteroplasmy—the presence of multiple mitochondrial DNA (mtDNA) haplotypes in an individual—can lead to numerous mitochondrial diseases. The presentation of such diseases depends on the frequency of the heteroplasmic variant in tissues, which, in turn, depends on the dynamics of mtDNA transmissions during germline and somatic development. Thus, understanding and predicting these dynamics between generations and within individuals is medically relevant. Here, we study patterns of heteroplasmy in 2 tissues from each of 345 humans in 96 multigenerational families, each with, at least, 2 siblings (a total of 249 mother–child transmissions). This experimental design has allowed us to estimate the timing of mtDNA mutations, drift, and selection with unprecedented precision. Our results are remarkably concordant between 2 complementary population-genetic approaches. We find evidence for a severe germline bottleneck (7–10 mtDNA segregating units) that occurs independently in different oocyte lineages from the same mother, while somatic bottlenecks are less severe. We demonstrate that divergence between mother and offspring increases with the mother’s age at childbirth, likely due to continued drift of heteroplasmy frequencies in oocytes under meiotic arrest. We show that this period is also accompanied by mutation accumulation leading to more de novo mutations in children born to older mothers. We show that heteroplasmic variants at intermediate frequencies can segregate for many generations in the human population, despite the strong germline bottleneck. We show that selection acts during germline development to keep the frequency of putatively deleterious variants from rising. Our findings have important applications for clinical genetics and genetic counseling.
AB - Heteroplasmy—the presence of multiple mitochondrial DNA (mtDNA) haplotypes in an individual—can lead to numerous mitochondrial diseases. The presentation of such diseases depends on the frequency of the heteroplasmic variant in tissues, which, in turn, depends on the dynamics of mtDNA transmissions during germline and somatic development. Thus, understanding and predicting these dynamics between generations and within individuals is medically relevant. Here, we study patterns of heteroplasmy in 2 tissues from each of 345 humans in 96 multigenerational families, each with, at least, 2 siblings (a total of 249 mother–child transmissions). This experimental design has allowed us to estimate the timing of mtDNA mutations, drift, and selection with unprecedented precision. Our results are remarkably concordant between 2 complementary population-genetic approaches. We find evidence for a severe germline bottleneck (7–10 mtDNA segregating units) that occurs independently in different oocyte lineages from the same mother, while somatic bottlenecks are less severe. We demonstrate that divergence between mother and offspring increases with the mother’s age at childbirth, likely due to continued drift of heteroplasmy frequencies in oocytes under meiotic arrest. We show that this period is also accompanied by mutation accumulation leading to more de novo mutations in children born to older mothers. We show that heteroplasmic variants at intermediate frequencies can segregate for many generations in the human population, despite the strong germline bottleneck. We show that selection acts during germline development to keep the frequency of putatively deleterious variants from rising. Our findings have important applications for clinical genetics and genetic counseling.
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U2 - 10.1073/pnas.1906331116
DO - 10.1073/pnas.1906331116
M3 - Article
C2 - 31757848
AN - SCOPUS:85076249649
SN - 0027-8424
VL - 116
SP - 25172
EP - 25178
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 50
ER -