Inherent Instability of Simple DNA Repeats Shapes an Evolutionarily Stable Distribution of Repeat Lengths

Overview

Journal bioRxiv

Date 2025 Jan 20

PMID 39829886

Authors

Ryan J McGinty

Daniel J Balick

Sergei M Mirkin

Shamil R Sunyaev

Affiliations

Soon will be listed here.

Abstract

Using the Telomere-to-Telomere reference, we assembled the distribution of simple repeat lengths present in the human genome. Analyzing over two hundred mammalian genomes, we found remarkable consistency in the shape of the distribution across evolutionary epochs. All observed genomes harbor an excess of long repeats, which are prone to developing into repeat expansion disorders. We measured mutation rates for repeat length instability, quantitatively modeled the per-generation action of mutations, and observed the corresponding long-term behavior shaping the repeat length distribution. We found that short repetitive sequences appear to be a straightforward consequence of random substitution. Evolving largely independently, longer repeats (10+ nucleotides) emerge and persist in a rapidly mutating dynamic balance between expansion, contraction and interruption. These mutational processes, collectively, are sufficient to explain the abundance of long repeats, without invoking natural selection. Our analysis constrains properties of molecular mechanisms responsible for maintaining genome fidelity that underlie repeat instability.

References

Whittaker J, Harbord R, Boxall N, Mackay I, Dawson G, Sibly R . Likelihood-based estimation of microsatellite mutation rates. Genetics. 2003; 164(2):781-7. PMC: 1462577. DOI: 10.1093/genetics/164.2.781. View

Kruglyak S, Durrett R, Schug M, Aquadro C . Distribution and abundance of microsatellites in the yeast genome can Be explained by a balance between slippage events and point mutations. Mol Biol Evol. 2000; 17(8):1210-9. DOI: 10.1093/oxfordjournals.molbev.a026404. View

Goldmann J, Wong W, Pinelli M, Farrah T, Bodian D, Stittrich A . Parent-of-origin-specific signatures of de novo mutations. Nat Genet. 2016; 48(8):935-9. DOI: 10.1038/ng.3597. View

Kelkar Y, Eckert K, Chiaromonte F, Makova K . A matter of life or death: how microsatellites emerge in and vanish from the human genome. Genome Res. 2011; 21(12):2038-48. PMC: 3227094. DOI: 10.1101/gr.122937.111. View

Tsutakawa S, Thompson M, Arvai A, Neil A, Shaw S, Algasaier S . Phosphate steering by Flap Endonuclease 1 promotes 5'-flap specificity and incision to prevent genome instability. Nat Commun. 2017; 8:15855. PMC: 5490271. DOI: 10.1038/ncomms15855. View

Strand M, Prolla T, Liskay R, Petes T . Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature. 1993; 365(6443):274-6. DOI: 10.1038/365274a0. View

Han J, Hsu C, Zhu Z, Longshore J, Finley W . Over-representation of the disease associated (CAG) and (CGG) repeats in the human genome. Nucleic Acids Res. 1994; 22(9):1735-40. PMC: 308057. DOI: 10.1093/nar/22.9.1735. View

Wang G, Vasquez K . Dynamic alternative DNA structures in biology and disease. Nat Rev Genet. 2022; 24(4):211-234. PMC: 11634456. DOI: 10.1038/s41576-022-00539-9. View

An J, Lin K, Zhu L, Werling D, Dong S, Brand H . Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. Science. 2018; 362(6420). PMC: 6432922. DOI: 10.1126/science.aat6576. View

10.

Baptiste B, Ananda G, Strubczewski N, Lutzkanin A, Khoo S, Srikanth A . Mature microsatellites: mechanisms underlying dinucleotide microsatellite mutational biases in human cells. G3 (Bethesda). 2013; 3(3):451-63. PMC: 3583453. DOI: 10.1534/g3.112.005173. View

11.

Rolfsmeier M, Lahue R . Stabilizing effects of interruptions on trinucleotide repeat expansions in Saccharomyces cerevisiae. Mol Cell Biol. 1999; 20(1):173-80. PMC: 85072. DOI: 10.1128/MCB.20.1.173-180.2000. View

12.

Erwin G, Gursoy G, Al-Abri R, Suriyaprakash A, Dolzhenko E, Zhu K . Recurrent repeat expansions in human cancer genomes. Nature. 2022; 613(7942):96-102. DOI: 10.1038/s41586-022-05515-1. View

13.

Jonsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E . Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017; 549(7673):519-522. DOI: 10.1038/nature24018. View

14.

Sia E, Kokoska R, Dominska M, Greenwell P, Petes T . Microsatellite instability in yeast: dependence on repeat unit size and DNA mismatch repair genes. Mol Cell Biol. 1997; 17(5):2851-8. PMC: 232137. DOI: 10.1128/MCB.17.5.2851. View

15.

Field D, Wills C . Abundant microsatellite polymorphism in Saccharomyces cerevisiae, and the different distributions of microsatellites in eight prokaryotes and S. cerevisiae, result from strong mutation pressures and a variety of selective forces. Proc Natl Acad Sci U S A. 1998; 95(4):1647-52. PMC: 19132. DOI: 10.1073/pnas.95.4.1647. View

16.

Mirkin S . Expandable DNA repeats and human disease. Nature. 2007; 447(7147):932-40. DOI: 10.1038/nature05977. View

17.

Xu X, Peng M, Fang Z . The direction of microsatellite mutations is dependent upon allele length. Nat Genet. 2000; 24(4):396-9. DOI: 10.1038/74238. View

18.

Habraken Y, Sung P, Prakash L, Prakash S . Binding of insertion/deletion DNA mismatches by the heterodimer of yeast mismatch repair proteins MSH2 and MSH3. Curr Biol. 1996; 6(9):1185-7. DOI: 10.1016/s0960-9822(02)70686-6. View

19.

Rajan-Babu I, Dolzhenko E, Eberle M, Friedman J . Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications. Nat Rev Genet. 2024; 25(7):476-499. DOI: 10.1038/s41576-024-00696-z. View

20.

Putnam C . Strand discrimination in DNA mismatch repair. DNA Repair (Amst). 2021; 105:103161. PMC: 8785607. DOI: 10.1016/j.dnarep.2021.103161. View