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Results: A methodical cross-population analysis of 232 polymorphic pseudogenes, including 35 new examples, reveals that human olfactory signalling, drug metabolism and immunity are among the systems most impacted by the variable presence of LoF variants at high frequencies. Within this dataset, a total of 179 genes presented polymorphic LoF variants in all analysed populations. Transcriptome and proteome analysis confirmed that although these genes may harbour LoF alleles, when the coding allele is present, the gene remains active and can play a functional role in various metabolic pathways, including drug\/xenobiotic metabolism and immunity. The observation that many polymorphic pseudogenes are members of multigene families argues that genetic redundancy may play a key role in compensating for the inactivation of one paralogue. Conclusions: The distribution, expression and integration of cellular\/biological networks in relation to human polymorphic pseudogenes, provide novel insights into the architecture of the human genome and the dynamics of gene gain and loss with likely functional impact.<\/jats:p>","DOI":"10.1007\/s00439-024-02715-9","type":"journal-article","created":{"date-parts":[[2024,11,2]],"date-time":"2024-11-02T21:18:39Z","timestamp":1730582319000},"page":"1465-1479","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Polymorphic pseudogenes in the human genome - a comprehensive assessment"],"prefix":"10.1007","volume":"143","author":[{"given":"M\u00f3nica","family":"Lopes-Marques","sequence":"first","affiliation":[]},{"given":"M. Jo\u00e3o","family":"Peixoto","sequence":"additional","affiliation":[]},{"given":"David N.","family":"Cooper","sequence":"additional","affiliation":[]},{"given":"M. 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