{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:49:49Z","timestamp":1785131389798,"version":"3.55.0"},"reference-count":115,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This critical and selective review synthesizes the accumulating body of biological evidence supporting a process we term epigenetic\u2013genetic coupling as a mechanistic basis for Lamarckian inheritance of somatically acquired adaptations. We propose that evolutionary processes in mammals and higher vertebrates can involve deaminase-driven, reverse transcriptase-mediated, RNA-templated targeted homologous recombination. We contrast well-established examples of \u201cSoft\u201d, reversible epigenetic inheritance with historical and contemporary evidence suggestive of stable, DNA-integrated \u201cHard\u201d Lamarckian transgenerational inheritance. Our analysis indicates that the establishment of \u201cHard\u201d Lamarckian inheritance may require specific population dynamics, including inbreeding or interbreeding among phenotypically affected offspring, together with sustained and defined environmental stimuli over one or more generations to consolidate the acquired traits at the genomic level. We also present molecular and cellular evidence supporting RNA-to-DNA genetic feedback mechanisms involving targeted genomic integration, primarily mediated by the DNA repair\u2013associated reverse transcriptase activity of DNA polymerase \u03b7. Finally, we review diversification mechanisms in molecular and cellular immunology that now routinely employ single-molecule, real-time, long-read genomic sequencing (6\u20138 kb). We recommend the broader application of these technologies in future breeding and experimental programs across other somatic systems. Their deployment offers a robust strategy for securing definitive \u201cHard\u201d molecular evidence of Lamarckian acquired inheritance in diverse biological contexts; including somatically acquired immunity, as well as adaptive behavioral and central nervous system phenotypes. This is compatible with our over-arching goal\u2014to provide an experimental road map of conceptual options to drive future experimentation in acquired inheritance breeding programs.<\/jats:p>","DOI":"10.3390\/ijms27042003","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T08:50:03Z","timestamp":1771577403000},"page":"2003","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Epigenetic\u2013Genetic Coupling and Understanding the Molecular and Cellular Basis of Lamarckian Inheritance"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8952-1536","authenticated-orcid":false,"given":"Robyn A.","family":"Lindley","sequence":"first","affiliation":[{"name":"Department Clinical Pathology, Victorian Comprehensive Cancer Centre (VCCC), University of Melbourne, Melbourne 3052, Australia"},{"name":"GMDx Group Ltd., 117 Hawthorn East, Melbourne 3123, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5622-2855","authenticated-orcid":false,"given":"Reginald M.","family":"Gorczynski","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1X5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4700-3156","authenticated-orcid":false,"given":"Edward J.","family":"Steele","sequence":"additional","affiliation":[{"name":"Melville Analytics Pty Ltd. and Immunomics, Brisbane 4169, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"ref_1","unstructured":"Steele, E.J. 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