Inclusion of human centromeres in genomic browsers – will it finally come?
0 INTRODUCTION
A recent work by Jaggi et al. in Nature Reviews Genetics[1] highlights that finally the inclusion of human centromeric regions in genomic browsers has become possible. This is an urgent need, despite the genome having been claimed to be fully sequenced as far back as 23 years ago[2]. Since 2022, new possibilities of next-generation sequencing have allowed a telomere-to-telomere (T2T) assessment of all 24 human chromosomes, including repetitive units within multiple regions of the human genome that were previously difficult to analyze[1,2]. These include specifically the regions called “heterochromatic”: (i) the short arms of the five acrocentric chromosomes 13, 14, 15, 21 and 22, (ii) all (peri)centromeric regions including specifically subbands 1q12, 9q12 and 16q11.2, and (iii) the large terminal heterochromatic band in the long arm of the Y-chromosome (Yq12). Finally, those sum up to ~8% of overall human DNA[3]. Interestingly, ribosomal DNA (rDNA) is still missing from most T2T- and only modeled in T2T-CHM13 genomes[2].
GOOD TO KNOW
The review by Jaggi et al.[1] correctly highlights that the T2T approach is based on long-read sequencing and the assembly of complete genomes. It also discusses what is known about human centromeres, which are essential chromosomal regions that ensure accurate chromosome segregation and genome stability; here, Jaggi et al.[1] referred to Logsdon et al.[4]. Other papers (e.g., ref.[5]) may also be of interest to readers to show the extent to which these data are changing the study of centromeres and other loci, from evolution to inheritance to pinpointing the exact kinetochore site; these advances have by far surpassed anything cytogenetics has achieved. They also emphasize that hundreds of cases of neocentromere formation in human subjects along all chromosomes have been reported in the literature. The function of these neocentromeres remains largely enigmatic, despite new sequencing and epigenetic data reviewed in[1]. CENtromere proteins and RNA-DNA hybrids are mentioned in the context of epigenetics. The review also covers evolutionary aspects of and genetic engineering concerning centromeric DNAs. Finally, the authors seem to imply that due to T2T data, high dynamics within centromeric DNA were discovered and described for the first time.
ADDITIONAL POINTS WHICH SHOULD HAVE BEEN CONSIDERED
Although the paper is clearly written from a molecular genetics perspective, it deals with chromosome biology. From a molecular perspective, the paper may seem comprehensive, but not from a cytogenetic perspective, which is increasingly being overlooked over time. To have the full picture of the progress achieved by T2T sequencing concerning centromeres, the following points should be added.
Higher-order repeat units
The sequence of the higher-order repeat units (HORs), which form the different human centromeres, was characterized long before the Human Genome Project. Chromosome-specific alpha-, beta- and satellite III DNAs were characterized, sequenced and mapped already in the 1980s[3,6]. However, this data was never incorporated into genome browsers[7]. This is even less understandable, as the sequenced satellite DNAs are easy to find, e.g., in the National Center for Biotechnology Information (NCBI) browser (https://www.ncbi.nlm.nih.gov/; nucleotides section) when searching for names such as D7Z1 (centromere 7 alpha-satellite DNA probe) or DYZ1 (human Y-chromosome specific repeated DNA family 1). Accordingly, the sequences of all commercially available DNA probes for labeling individual human centromeres have been known for decades, yet they still cannot be found in any current genomic browser; their inclusion based on the T2T data is still awaited. Their range of sizes in different individuals was even characterized, as was their molecular cytogenetic localization[6].
Cytogenetic detectable dynamics of centromeric DNA
Having said this, it is clear that the high dynamics within centromeric DNA was apparent from the outset of its molecular genetic detection. This dynamic is also familiar to any cytogeneticist performing routine chromosome banding: all of the aforementioned chromosomal heterochromatic regions exhibit significant variation within the normal human population. The International System for Human Cytogenomic Nomenclature (ISCN)[8] has its own chapter suggesting around 20 specific abbreviations for describing heterochromatic variants which can be found on the majority of each of the 24 human chromosomes. Accordingly, the insight that heterochromatic DNA is highly dynamic is not new and is not based on T2T data (alone), given that it is non-coding DNA and is subject to less evolutionary pressure than other gene-rich regions. Accordingly, it is not surprising that over 250 heterochromatic variants are known, which are expressed as molecular cytogenetic visible variants in terms of size, composition, and location, based on satellite DNA amplification, deletion, translocation or inversion[2,9] (subpage https://cs-tl.de/DB/CA/HCM/0-Start.html). However, insights into how the heterochromatin may vary at the DNA level are new as stated by Jaggi et al.[1].
Evolutionary aspects of heterochromatin
The fact that the centromeric, heterochromatic parts of the genome develop faster and independently of the rest of the genome is also evident from molecular cytogenetic data. It was already shown in the 1990s that human centromeric alpha-satellite DNAs do not hybridize to chromosomes of other species, not even those of our closest relatives (great apes)[10].
Expression of satellite DNA as RNA
It is surprising that the expression of RNA derived from satellite DNAs is not mentioned by Jaggi et al.[1]. The fact that this satellite DNA is expressed as long non-coding RNA during embryogenesis and tumor development[3,11] would be of interest in the context of this review. This point is important because it highlights the biological significance of centromeric DNA addressing one of the major challenges facing humanity: understanding the biology of cancer[12].
About human neocentric chromosomes
Overall, Jaggi et al.'s paper[1] summarizes the current view of the field of constitutional human genetics, which is unfortunately becoming increasingly molecular. Nevertheless, the chromosomal perspective is important, as demonstrated by the ChromoSomics databases [9 - Subpage https://cs-tl.de/DB/CA/sSMC/0-Start.html]. Contrary to what is shown in Table 1 in[1] as a summary of "nearly 150 known neocentric cases", the database on small supernumerary marker chromosomes alone includes 174 neocentrics. Therefore, it is likely that over 200 neocentrics have now been described.
CONCLUSION
In conclusion, bearing in mind the historical knowledge and chromosomal view presented here, Jaggi et al.’s paper[1] could have reached more meaningful conclusions than simply summarizing the content of the paper and celebrating the technological achievement of T2T sequencing, while looking ahead to further technological advances in the future.
DECLARATIONS
Authors’ contributions
The author contributed solely to the article.
Availability of data and materials
Not applicable.
AI and AI-assisted tools Statement
During the preparation of this manuscript, the DeepL was used solely for language editing. The tool did not influence the analysis, interpretation, or scientific content of the work. All authors take full responsibility for the accuracy, integrity, and final content of the manuscript.
Financial support and sponsorship
None.
Conflicts of interest
The author declared that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2026.
REFERENCES
1. Jaggi KE, Hoyt SJ, O'Neill RJ, Sullivan BA. A genomic and epigenomic view of human centromeres. Nat Rev Genet. 2026:Online ahead of print.
2. Nurk S, Koren S, Rhie A, et al. The complete sequence of a human genome. Science. 2022;376:44-53.
4. Logsdon GA, Ebert P, Audano PA, et al. Complex genetic variation in nearly complete human genomes. Nature. 2025;644:430-41.
5. Corda L, Volpe E, Dallali H, et al. Cell line-matched reference enables high-precision functional genomics. Nat Commun. 2025;16:11194.
6. Liehr T. Benign & pathological chromosomal imbalances. In: Microscopic and submicroscopic copy number variations (CNVs) in genetics and counseling, 1st ed. Oxford: Academic Press; 2014.
7. Liehr T. About classical molecular genetics, cytogenetic and molecular cytogenetic data not considered by Genome Reference Consortium and thus not included in genome browsers like UCSC, Ensembl or NCBI. Mol Cytogenet. 2021;14:20.
8. ISCN 2024 - an international system for human cytogenomic nomenclature (2024). Cytogenet Genome Res. 2024;164:1-224.
9. Liehr T. ChromoSomics databases. Available from: https://cs-tl.de/Start.html [Last accessed on 22 Apr 2026].
10. Baldini A, Miller DA, Shridhar V, Rocchi M, Miller OJ, Ward DC. Comparative mapping of a gorilla-derived alpha satellite DNA clone on great ape and human chromosomes. Chromosoma. 1991;101:109-14.
11. Weise A, Ornellas AA, Alves G, et al. Satellite DNA amplification in advanced prostate cancer is largely independent from euchromatic and oncogene amplicons. J Histochem Cytochem. 2025;73:109-13.
Cite This Article
Open Access
How to Cite
Download Citation
Export Citation File:
Type of Import
Tips on Downloading Citation
Citation Manager File Format
Type of Import
Direct Import: When the Direct Import option is selected (the default state), a dialogue box will give you the option to Save or Open the downloaded citation data. Choosing Open will either launch your citation manager or give you a choice of applications with which to use the metadata. The Save option saves the file locally for later use.
Indirect Import: When the Indirect Import option is selected, the metadata is displayed and may be copied and pasted as needed.
About This Article
Copyright
Data & Comments
Data
0
Comments
Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at support@oaepublish.com.