The mutational dynamics of short tandem repeats in large, multigenerational families

Cody J. Steely, W. Scott Watkins, Lisa Baird, Lynn B. Jorde

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Background: Short tandem repeats (STRs) compose approximately 3% of the genome, and mutations at STR loci have been linked to dozens of human diseases including amyotrophic lateral sclerosis, Friedreich ataxia, Huntington disease, and fragile X syndrome. Improving our understanding of these mutations would increase our knowledge of the mutational dynamics of the genome and may uncover additional loci that contribute to disease. To estimate the genome-wide pattern of mutations at STR loci, we analyze blood-derived whole-genome sequencing data for 544 individuals from 29 three-generation CEPH pedigrees. These pedigrees contain both sets of grandparents, the parents, and an average of 9 grandchildren per family. Results: We use HipSTR to identify de novo STR mutations in the 2nd generation of these pedigrees and require transmission to the third generation for validation. Analyzing approximately 1.6 million STR loci, we estimate the empirical de novo STR mutation rate to be 5.24 × 10−5 mutations per locus per generation. Perfect repeats mutate about 2 × more often than imperfect repeats. De novo STRs are significantly enriched in Alu elements. Conclusions: Approximately 30% of new STR mutations occur within Alu elements, which compose only 11% of the genome, but only 10% are found in LINE-1 insertions, which compose 17% of the genome. Phasing these mutations to the parent of origin shows that parental transmission biases vary among families. We estimate the average number of de novo genome-wide STR mutations per individual to be approximately 85, which is similar to the average number of observed de novo single nucleotide variants.

Original languageEnglish
Article number253
JournalGenome Biology
Issue number1
StatePublished - Dec 2022

Bibliographical note

Funding Information:
We thank the Utah Genome Project, the George S. and Dolores Doré Eccles Foundation, and the H.A. and Edna Benning Society for sequencing funds. We thank all of the Utah individuals who participated in the CEPH consortium. Additionally, we would like to thank members of the Jorde and Quinlan labs for their helpful feedback and discussion on this project. The review history is available as Additional file 7

Funding Information:
The authors thank Norimichi Kitagawa, Ph.D., from Ritsumeikan University, for his inspiration for this study. We also thank Shinya Harada, Ph.D., from Kumamoto University for his support. This work was supported by the JSPS KAKENHI (grant number: JP19H00631 and JP20H05801).

Publisher Copyright:
© 2022, The Author(s).


  • Mutations
  • Pedigrees
  • Short tandem repeats

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology


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