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Evolutionarily conserved pachytene piRNA loci are highly divergent among modern humans

Nature Ecology & Evolution volume 4, pages 156–168 (2020)Cite this article

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Abstract

In the fetal mouse testis, PIWI-interacting RNAs (piRNAs) guide PIWI proteins to silence transposons but, after birth, most post-pubertal pachytene piRNAs map to the genome uniquely and are thought to regulate genes required for male fertility. In the human male, the developmental classes, precise genomic origins and transcriptional regulation of postnatal piRNAs remain undefined. Here, we demarcate the genes and transcripts that produce postnatal piRNAs in human juvenile and adult testes. As in the mouse, human A-MYB drives transcription of both pachytene piRNA precursor transcripts and messenger RNAs encoding piRNA biogenesis factors. Although human piRNA genes are syntenic to those in other placental mammals, their sequences are poorly conserved. In fact, pachytene piRNA loci are rapidly diverging even among modern humans. Our findings suggest that, during mammalian evolution, pachytene piRNA genes are under few selective constraints. We speculate that pachytene piRNA diversity may provide a hitherto unrecognized driver of reproductive isolation.

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Fig. 1: Three classes of human postnatal piRNA genes.
Fig. 2: Three groups of adult samples.
Fig. 3: Dysregulated expression of A-MYB and HIWI in group 3 adult testis.
Fig. 4: Feedforward regulation of piRNA production by A-MYB is conserved in macaque.
Fig. 5: Comparative genomic analysis of human piRNA genes.
Fig. 6: Sequence variation for different genomic features within the human population.

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Data availability

Sequencing data are available from the National Center for Biotechnology Information Sequence Read Archive using accession number PRJNA506245 and from the Gene Expression Omnibus using accession number GSE135791.

References

  1. Aravin, A. et al. A novel class of small RNAs bind to MILI protein in mouse testes. Nature 442, 203–207 (2006).

    CAS  PubMed  Google Scholar 

  2. Girard, A., Sachidanandam, R., Hannon, G. J. & Carmell, M. A. A germline-specific class of small RNAs binds mammalian PIWI proteins. Nature 442, 199–202 (2006).

    PubMed  Google Scholar 

  3. Grivna, S. T., Beyret, E., Wang, Z. & Lin, H. A novel class of small RNAs in mouse spermatogenic cells. Genes Dev. 20, 1709–1714 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Lau, N. C. et al. Characterization of the piRNA complex from rat testes. Science 313, 363–367 (2006).

    CAS  PubMed  Google Scholar 

  5. Vagin, V. V. et al. A distinct small RNA pathway silences selfish genetic elements in the germline. Science 313, 320–324 (2006).

    CAS  PubMed  Google Scholar 

  6. Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128, 1089–1103 (2007).

    CAS  PubMed  Google Scholar 

  7. Fu, Y. et al. The genome of the Hi5 germ cell line from Trichoplusia ni, an agricultural pest and novel model for small RNA biology. eLife 7, e31628 (2018).

    PubMed  PubMed Central  Google Scholar 

  8. Lewis, S. H. et al. Pan-arthropod analysis reveals somatic piRNAs as an ancestral defence against transposable elements. Nat. Ecol. Evol. 2, 174–181 (2018).

    PubMed  Google Scholar 

  9. Ozata, D. M., Gainetdinov, I., Zoch, A., O’Carroll, D. & Zamore, P. D. PIWI-interacting RNAs: small RNAs with big functions. Nat. Rev. Genet. 20, 89–108 (2018).

    Google Scholar 

  10. Aravin, A. A. et al. A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol. Cell 31, 785–799 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kuramochi-Miyagawa, S. et al. DNA methylation of retrotransposon genes is regulated by PIWI family members MILI and MIWI2 in murine fetal testes. Genes Dev. 22, 908–917 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Aravin, A. A., Sachidanandam, R., Girard, A., Fejes-Toth, K. & Hannon, G. J. Developmentally regulated piRNA clusters implicate MILI in transposon control. Science 316, 744–747 (2007).

    CAS  PubMed  Google Scholar 

  13. Goh, W. S. et al. piRNA-directed cleavage of meiotic transcripts regulates spermatogenesis. Genes Dev. 29, 1032–1044 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Li, X. Z. et al. An ancient transcription factor initiates the burst of piRNA production during early meiosis in mouse testes. Mol. Cell 50, 67–81 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Wu, P. H. et al. An evolutionarily conserved piRNA-producing locus required for male mouse rertility. Preprint at bioRxiv https://doi.org/10.1101/386201 (2018).

  16. Vourekas, A. et al. MILI and MIWI target RNA repertoire reveals piRNA biogenesis and function of MIWI in spermiogenesis. Nat. Struct. Mol. Biol. 19, 773–781 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang, P. et al. MIWI and piRNA-mediated cleavage of messenger RNAs in mouse testes. Cell Res. 25, 193–207 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Homolka, D. et al. PIWI slicing and RNA elements in precursors instruct directional primary piRNA biogenesis. Cell Rep. 12, 418–428 (2015).

    CAS  PubMed  Google Scholar 

  19. Xu, M. et al. Mice deficient for a small cluster of PIWI-interacting RNAs implicate PIWI-interacting RNAs in transposon control. Biol. Reprod. 79, 51–57 (2008).

    CAS  PubMed  Google Scholar 

  20. Gainetdinov, I., Colpan, C., Arif, A., Cecchini, K. & Zamore, P. D. A single mechanism of biogenesis, initiated and directed by PIWI proteins, explains piRNA production in most animals. Mol. Cell 71, 775–790.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bolcun-Filas, E. et al. A-MYB (MYBL1) transcription factor is a master regulator of male meiosis. Development 138, 3319–3330 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ha, H. et al. A comprehensive analysis of piRNAs from adult human testis and their relationship with genes and mobile elements. BMC Genomics 15, 545 (2014).

    PubMed  PubMed Central  Google Scholar 

  23. Williams, Z. et al. Discovery and characterization of piRNAs in the human fetal ovary. Cell Rep. 13, 854–863 (2015).

    CAS  PubMed  Google Scholar 

  24. Jan, S. Z. et al. Unraveling transcriptome dynamics in human spermatogenesis. Development 144, 3659–3673 (2017).

    PubMed  PubMed Central  Google Scholar 

  25. Turner, J. M. Meiotic sex chromosome inactivation. Development 134, 1823–1831 (2007).

    CAS  PubMed  Google Scholar 

  26. Carmell, M. A. et al. MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Dev. Cell 12, 503–514 (2007).

    CAS  PubMed  Google Scholar 

  27. Saito, K. et al. Specific association of PIWI with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome. Genes Dev. 20, 2214–2222 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Aravin, A. A. et al. The small RNA profile during Drosophila melanogaster development. Dev. Cell 5, 337–350 (2003).

    CAS  PubMed  Google Scholar 

  29. Meistrich, M. L. Effects of chemotherapy and radiotherapy on spermatogenesis in humans. Fertil. Steril. 100, 1180–1186 (2013).

    CAS  PubMed  Google Scholar 

  30. Deng, W. & Lin, H. Miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Dev. Cell 2, 819–830 (2002).

    CAS  PubMed  Google Scholar 

  31. Katzen, A. L., Kornberg, T. B. & Bishop, J. M. Isolation of the proto-oncogene c-myb from D. melanogaster. Cell 41, 449–456 (1985).

    CAS  PubMed  Google Scholar 

  32. Lipsick, J. S. et al. Functional evolution of the Myb oncogene family. Blood Cells Mol. Dis. 27, 456–458 (2001).

    CAS  PubMed  Google Scholar 

  33. Kumar, S., Stecher, G., Suleski, M. & Hedges, S. B. TimeTree: a resource for timelines, timetrees, and divergence times. Mol. Biol. Evol. 34, 1812–1819 (2017).

    CAS  PubMed  Google Scholar 

  34. Auton, A. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).

    PubMed  Google Scholar 

  35. Reuter, M. et al. MIWI catalysis is required for piRNA amplification-independent LINE1 transposon silencing. Nature 480, 264–267 (2011).

    CAS  PubMed  Google Scholar 

  36. Wang, W. et al. Slicing and binding by Ago3 or Aub trigger PIWI-bound piRNA production by distinct mechanisms. Mol. Cell 59, 819–830 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Andersen, P. R., Tirian, L., Vunjak, M. & Brennecke, J. A heterochromatin-dependent transcription machinery drives piRNA expression. Nature 549, 54–59 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Klattenhoff, C. et al. The Drosophila HP1 homolog Rhino is required for transposon silencing and piRNA production by dual-strand clusters. Cell 138, 1137–1149 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Mohn, F., Sienski, G., Handler, D. & Brennecke, J. The Rhino–Deadlock–Cutoff complex licenses noncanonical transcription of dual-strand piRNA clusters in Drosophila. Cell 157, 1364–1379 (2014).

    CAS  PubMed  Google Scholar 

  40. Zhang, Z. et al. The HP1 homolog Rhino anchors a nuclear complex that suppresses piRNA precursor splicing. Cell 157, 1353–1363 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Gainetdinov, I., Skvortsova, Y., Kondratieva, S., Funikov, S. & Azhikina, T. Two modes of targeting transposable elements by piRNA pathway in human testis. RNA 23, 1614–1625 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Hirano, T. et al. Small RNA profiling and characterization of piRNA clusters in the adult testes of the common marmoset, a model primate. RNA 20, 1223–1237 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Soumillon, M. et al. Cellular source and mechanisms of high transcriptome complexity in the mammalian testis. Cell Rep. 3, 2179–2190 (2013).

    CAS  PubMed  Google Scholar 

  44. Bastos, H. et al. Flow cytometric characterization of viable meiotic and postmeiotic cells by Hoechst 33342 in mouse spermatogenesis. Cytometry A 65, 40–49 (2005).

    PubMed  Google Scholar 

  45. Han, B. W. et al. piRNA-guided transposon cleavage initiates Zucchini-dependent, phased piRNA production. Science 348, 817–821 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Han, B. W., Wang, W., Zamore, P. D. & Weng, Z. piPipes: a set of pipelines for piRNA and transposon analysis via small RNA-seq, RNA-seq, degradome- and CAGE-seq, ChIP-seq and genomic DNA sequencing. Bioinformatics 31, 593–595 (2015).

    CAS  PubMed  Google Scholar 

  47. Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with bowtie 2. Nat. Methods 9, 357–359 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang, Z., Theurkauf, W. E., Weng, Z. & Zamore, P. D. Strand-specific libraries for high-throughput RNA sequencing (RNA-seq) prepared without poly(A) selection. Silence 3, 9 (2012).

    PubMed  PubMed Central  Google Scholar 

  49. Adiconis, X. et al. Comparative analysis of RNA sequencing methods for degraded or low-input samples. Nat. Methods 10, 623–629 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Morlan, J. D., Qu, K. & Sinicropi, D. V. Selective depletion of rRNA enables whole transcriptome profiling of archival fixed tissue. PLoS ONE 7, e42882 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    Google Scholar 

  52. Li, H. et al. The sequence alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    PubMed  PubMed Central  Google Scholar 

  53. Anders, S., Pyl, P. T. & Huber, W. HTSeq—a python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).

    CAS  PubMed  Google Scholar 

  54. Priness, I., Maimon, O. & Ben-Gal, I. Evaluation of gene-expression clustering via mutual information distance measure. BMC Bioinformatics 8, 111 (2007).

    PubMed  PubMed Central  Google Scholar 

  55. Ashar-Patel, A. et al. FLT1 and transcriptome-wide polyadenylation site (PAS) analysis in preeclampsia. Sci. Rep. 7, 12139 (2017).

    PubMed  PubMed Central  Google Scholar 

  56. Sheppard, S., Lawson, N. D. & Zhu, L. J. Accurate identification of polyadenylation sites from 3′ end deep sequencing using a naive bayes classifier. Bioinformatics 29, 2564–2571 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Yang, Z., Bruno, D. P., Martens, C. A., Porcella, S. F. & Moss, B. Genome-wide analysis of the 5′ and 3′ ends of vaccinia virus early mRNAs delineates regulatory sequences of annotated and anomalous transcripts. J. Virol. 85, 5897–5909 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).

    PubMed  PubMed Central  Google Scholar 

  59. Pertea, M. et al. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat. Biotechnol. 33, 290–295 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Keinan, A., Mullikin, J. C., Patterson, N. & Reich, D. Measurement of the human allele frequency spectrum demonstrates greater genetic drift in East Asians than in Europeans. Nat. Genet. 39, 1251–1255 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank D. Conte and members of the Zamore Laboratory for discussions and comments on the manuscript, and K. Orwig for providing testis specimens. The silhouettes have not been altered in any way. This work was supported in part by National Institutes of Health grants (nos. R37GM062862 to P.D.Z. and P01HD078253 to Z.W. and P.D.Z.).

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  1. These authors contributed equally: Deniz M. Özata, Tianxiong Yu.

Authors and Affiliations

  1. RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA

    Deniz M. Özata, Haiwei Mou, Ildar Gainetdinov, Cansu Colpan, Katharine Cecchini, Pei-Hsuan Wu & Phillip D. Zamore

  2. Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA

    Tianxiong Yu, Yasin Kaymaz, Kaili Fan, Alper Kucukural & Zhiping Weng

  3. Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, People’s Republic of China

    Tianxiong Yu & Kaili Fan

  4. Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA, USA

    Katharine Cecchini & Phillip D. Zamore

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Contributions

D.M.Ö., Z.W. and P.D.Z. conceived and designed the experiments. D.M.Ö., H.M., I.G., C.C., K.C. and P.-H.W. performed the experiments. Y.T., D.M.Ö., Y.K., K.F. and A.K. analysed the sequencing data. D.M.Ö., Z.W. and P.D.Z. wrote the manuscript.

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Correspondence to Zhiping Weng or Phillip D. Zamore.

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Extended data

Extended Data Fig. 1 Strategy for defining human post-natal piRNA genes.

a, Strategy for transcriptome assembly, identification of piRNA precursor transcripts, and annotation of genomic loci. Pink rectangles: input for analyses; gray rectangles: bioinformatic tools. Green hexagons: output from analyses. b,c, Histograms showing the change in the abundance of piRNAs produced from piRNA genes between juvenile and adult samples. The analysis was conducted twice: once with the set of samples used to define the piRNA genes (b) and then with an independent set of samples to validate the annotations (c). d, Genomic positions of 182 human piRNA-producing loci on the 22 autosomal chromosomes. Two pre-pachytene piRNA genes were identified on the X chromosome.

Extended Data Fig. 2 Examples of human post-natal piRNA genes.

a, An exemplary pre-pachytene piRNA gene. b, Uni- and bi-directional pachytene piRNA genes. Human piRNA cluster boundaries annotated in Ref. 10 (dark green) and Ref. 11 (purple).

Extended Data Fig. 3 Analyses of transcription start sites (TSS) and transcript 3′ ends for human piRNA genes.

a, Heatmaps displaying the H3K4me3 ChIP-seq signal around the transcription start sites of piRNA-producing genes from adult testis and the results of Cap-seq and PAS-seq around TSS and transcript 3′ ends for piRNA-producing genes from adult testes. Kidney serves as a negative control. Data are reported as uniquely mapping reads per million reads (RPM). b, Metagene plot of Cap-seq and PAS-seq signals 5 kb upstream of the TSS and 5 kb downstream of the transcript 3′ ends of pre-pachytene and pachytene piRNA genes for juvenile and adult testis samples. Graphs report trimmed mean (that is, lowest and highest 5% removed). c, piRNA density per 1 kb within exons and introns of the pre-pachytene and pachytene piRNA genes defined by our analysis.

Extended Data Fig. 4 Three classes of human post-natal piRNA genes.

a, Cumulative distributions of the percentage of 25–31 nt long piRNAs explained by the length of annotated genomic sequence for the piRNA-producing loci defined here or previously10,11,12. b, Percentage of transposon sequences present in piRNA-producing, protein-coding, and lncRNA genes. Gray line indicates the transposons content of the entire human genome. c, Percentage of different classes of transposons within the piRNA-producing genes.

Extended Data Fig. 5 Characterization of the mouse repro9 mutation within exon 6 of A-Myb.

a, The repro9 mutation creates a stronger 5′ splice site within exon 6 of A-Myb, leading to a truncated mRNA. Splice site strength was determined using MaxEntScan13. b, Heatmaps of the relative abundance of mouse piRNAs mapping to previously defined piRNA genes14. piRNA abundance was normalized to the total number of mapped reads. Spg: spermatogonia; SpI: primary spermatocytes.

Extended Data Fig. 6 Three groups of adult testes defined by length distribution of total piRNAs and A-MYB and HIWI expression.

a, The abundance of piRNAs was normalized to the total number of genome-mapping reads. b,c, Relative protein abundance of A-MYB (b) and HIWI (c) in adult testis samples. ACTIN serves as a loading control, while mouse A-Mybrepro9 and Miwi−/− mutant testis lysates provide negative controls. Each lane contained 75 µg protein of testis lysate.

Extended Data Fig. 7 Molecular characterization of group 3 testes.

a, piRNA length distribution, hematoxylin and eosin (H&E) stained testis sections, and immunohistochemical detection of A-MYB and HIWI for representative samples from groups 1, 2, and 3. b, Scatter plot of steady-state transcript abundance of transcripts in group 1 versus group 3 testes. Each dot represents mean abundance of an mRNA. c, Gene ontology analysis of mRNAs detected in group 3 samples and whose abundance changed >3-fold (FDR <0.05) compared to group 1.

Extended Data Fig. 8 Three classes of human post-natal piRNA genes expressed by group 1, group 2, and juvenile testis samples.

a, Histogram shows the change in the abundance of piRNAs produced from piRNA genes between juvenile and healthy adult testis samples (groups 1 and 2). b, MA plot showing change in mean piRNA abundance comparing healthy adult (groups 1 and 2) to juvenile testis samples for 182 annotated piRNA-producing loci.

Extended Data Fig. 9 Comparative analysis of human piRNA-producing genes.

a, Long RNA and piRNA abundance for different genomic features including piRNA-producing genes; protein-coding genes; lincRNA genes; and 22,604 randomly selected, 10 kb, non-transcribed genomic regions. b, DNA sequence conservation of different genomic features for 46 eutherian mammals calculated using PhyloP15. The 22,604 randomly selected, 10 kb, non-transcribed genomic regions, which do not produce piRNAs, provide a background control.

Extended Data Fig. 10 mRNA abundance of transcripts from orthologous genes that produce pre-pachytene piRNAs in humans and evolutionary classes of human pachytene piRNA genes.

a, Transcript abundance in representative primate, rodent, marsupial, and bird species for mRNAs that produce piRNAs in placental mammals and for mRNAs expressed in other species but that make piRNAs only in humans. Expression data for species other than human testis was obtained from EMBL-EMI Expression Atlas. b, An exemplary pre-pachytene piRNA gene that is syntenic across other species, but piRNA source in placental mammals only, in primates only, in humans only. c, Abundance of piRNAs from the syntenic locations for human pachytene piRNA loci in other animals. Credit: silhouettes from http://phylopic.org. Rat by Rebecca Groom; https://creativecommons.org/licenses/by/3.0/. Opossum by Sarah Werning; https://creativecommons.org/licenses/by/3.0/.

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Özata, D.M., Yu, T., Mou, H. et al. Evolutionarily conserved pachytene piRNA loci are highly divergent among modern humans. Nat Ecol Evol 4, 156–168 (2020). https://doi.org/10.1038/s41559-019-1065-1

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