---
title: "Mathematical genomics of SRY and HMG‑box compositional signatures across mammals"
id: "biorxiv-19-mathematical-genomics-of-sry-proteins-and-their-associated-hmg-box-domains"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-19-mathematical-genomics-of-sry-proteins-and-their-associated-hmg-box-domains"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.10.18.759944v1?rss=1"
published_at: "2026-10-25T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Mathematical genomics of SRY and HMG‑box compositional signatures across mammals
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-19-mathematical-genomics-of-sry-proteins-and-their-associated-hmg-box-domains
- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.10.18.759944v1?rss=1)
- **Published At:** 2026-10-25T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study analyzed 65 full-length **SRY** proteins and 38 **HMG box** subsequences drawn from 75 mammalian species, using alignment-independent quantitative genomics. - Investigators integrated amino-acid composition, dipeptide counts, Shannon entropy, dominant-residue profiling, hydropathy n-grams, longest hydropathy runs, and cumulative proximity measures to define compositional signatures. - Data indicated the HMG box is more compositionally constrained than full-length SRY: basic residues dominate, cysteine is rare, entropy clusters near 4.0, and polar content averaged about 58.44%. - Twenty-five of 38 HMG boxes shared approximately 57.97% polar residues, whereas full-length SRY proteins showed broader variation across taxa. - Rodent SRY proteins displayed high polar and glutamine-rich profiles; cetacean SRY sequences showed lower polar content. - Proximity-based clustering produced stronger taxonomic consistency when applied to **HMG box** domains than to terminal regions, which blurred domain-level signals. - Predicted structural state across the data set was dominated by **intrinsic disorder**; the authors observed how polyQ-rich rodent sequences can confound ordered-state predictions. - Cumulative proximity identified Bos taurus and Bos grunniens as the only pair clustering at both full-length and HMG-box levels, suggesting multivariate proximity is a stringent test of compositional similarity. - The authors proposed these alignment-independent quantitative signatures as a framework for interpreting SRY variation and clinical mutations, and noted the need for denser taxon sampling, structural modeling, and experimental validation to link compositional drift to DNA binding, bending, or reproductive outcomes.
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Sarif Hassan, Nabanita Mukherjee, Moumita Sil, ARUNAVA GOSWAMI, Guy W. Dayhoff II, Andrey P. Anisimov, [ View ORCID Profile](http://orcid.org/0000-0002-4037-5857)Vladimir N Uversky doi: https://doi.org/10.64898/2026.10.18.759944 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. Dr. Sk. Sarif Hassan 1 Department of Mathematics, Pingla Thana Mahavidyalaya, India; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Dr.%2BSk.%2BSarif%2BHassan%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Hassan%20DS&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ADr.%2BSk.%2BSarif%2BHassan%2B) * [ORCID record for Dr. Sk. Sarif Hassan](http://orcid.org/0000-0003-4331-722X "Open in new tab") * For correspondence: sarimif@gmail.com Nabanita Mukherjee 2 Jangipur College, India; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Nabanita%2BMukherjee%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Mukherjee%20N&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ANabanita%2BMukherjee%2B) Moumita Sil 3 Indian Statistical Institute, Kolkata; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Moumita%2BSil%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Sil%20M&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMoumita%2BSil%2B) ARUNAVA GOSWAMI 4 INDIAN STATISTICAL INSTITUTE; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=ARUNAVA%2BGOSWAMI%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=GOSWAMI%20A&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AARUNAVA%2BGOSWAMI%2B) Guy W. Dayhoff II 5 University of Maryland School of Pharmacy, USA; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Guy%2BW.%2BDayhoff%2B%3Cspan%2Bclass%3D%22nlm-suffix%22%3EII%3C/span%3E "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Dayhoff%20GW&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AGuy%2BW.%2BDayhoff%2BII) Andrey P. Anisimov 6 State Research Center for Applied Microbiology and Biotechnology, Russia; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Andrey%2BP.%2BAnisimov%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Anisimov%20AP&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AAndrey%2BP.%2BAnisimov%2B) Vladimir N Uversky 7 University of South Florida * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Vladimir%2BN%2BUversky%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Uversky%20VN&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AVladimir%2BN%2BUversky%2B) * [ORCID record for Vladimir N Uversky](http://orcid.org/0000-0002-4037-5857 "Open in new tab") * [Abstract](https://www.biorxiv.org/content/10.64898/2026.10.18.759944v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5901258/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.10.18.759944v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5901258/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.10.18.759944v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5901258/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.10.18.759944v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5901258/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## Abstract Male sex determination in mammals depends on sex‑determining region Y (SRY), a transcription factor whose high-mobility group box (HMG box) binds and bends DNA to activate SOX9. The divergent N- and C-terminal domains lack sequence homology and have been dismissed as passive linkers, yet alignment-based homology cannot reveal whether they retain a hidden compositional grammar. We applied quantitative genomics to 65 full-length mammalian SRY proteins and 38 HMG-box subsequences across 75 mammals, integrating amino acid and dipeptide compositions, Shannon entropy, dominant-residue profiles, hydropathy-based n-gram spectra, longest hydropathy stretches, and cumulative proximity. The HMG box is tightly constrained: basic residues dominated, cysteine was nearly absent, entropy clustered near 4.0, polar content averaged 58.44\%, and 25 of 38 HMG boxes shared 57.97\% polar residues, whereas full-length SRY varied more, with rodents showing high polar and glutamine-rich profiles and cetaceans low polar content. Proximity-based clustering was more taxonomically consistent at the HMG level, while terminal regions blurred domain-level signals. Across 65 SRY proteins and 38 HMG domains, intrinsic disorder was the dominant predicted state, and a polyQ-rich rodent SRY illustrated how low-complexity repeats can produce misleading ordered predictions, underscoring the need for consensus disorder analysis in rapidly evolving intrinsically disordered regions. Cumulative proximity analysis identified \textit{Bos taurus} and \textit{Bos grunniens} as the only pair proximally clustered at both the full-length SRY and SRY-HMG levels, establishing multivariate proximity as a stringent criterion of compositional similarity satisfied by a single mammalian pair. These results suggest that SRY and its HMG box each carry a distinct compositional grammar, quantifiable only through alignment-independent signatures, with compositional individuality being the rule rather than the exception. These quantitative signatures provide a framework for interpreting SRY variation, assessing clinical mutations, and understanding evolutionary pressures shaping sex determination. Denser taxon sampling, structural modeling, and experimental tests are needed to clarify whether HMG-box drift and terminal-region variation affect DNA binding, bending, or reproductive function. ### Competing Interest Statement The authors have declared no competing interest. ## Funder Information Declared Ministry of Science and Higher Education of the Russian Federation, $075-15-2025-525$ Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY-ND 4.0 International license](http://creativecommons.org/licenses/by-nd/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. 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[ Download PDF](https://www.biorxiv.org/content/10.64898/2026.10.18.759944v1.full.pdf) Print/Save Options [Download PDF](https://www.biorxiv.org/content/biorxiv/early/2026/10/25/2026.10.18.759944.full.pdf)Full Text & In-line FiguresXML [More Info](https://www.biorxiv.org/about/FAQ#PrintOptions "More Information on Print/Save Options") [ Email](https://www.biorxiv.org/ "Email this Article") [ Share](https://www.biorxiv.org/) Mathematical genomics of SRY proteins and their associated HMG‑Box domains across mammals Dr. Sk. Sarif Hassan, Nabanita Mukherjee, Moumita Sil, ARUNAVA GOSWAMI, Guy W. Dayhoff II, Andrey P. Anisimov, Vladimir N Uversky bioRxiv 2026.10.18.759944; doi: https://doi.org/10.64898/2026.10.18.759944 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. 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