Moderate prevalence and evolutionary causes of paralogous compensation in humans.
6 affiliations
- 1State Key Laboratory of Animal Biodiversity Conservation and Integrated Pest Management, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
- 2University of Chinese Academy of Sciences, Beijing 100049, China.
- 3State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
- 4State Key Laboratory of Complex, Severe, and Rare Diseases, Center for Bioinformatics, National Infrastructures for Translational Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
- 5Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
- 6Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Abstract
Paralogous compensation drives genetic robustness; however, its in vivo prevalence in humans and the evolutionary forces shaping it remain unresolved. We CRISPR-screened 678 human paralog pairs to identify pairs with negative genetic interactions (nGIs) or compensatory paralogs, and integrated our results with four studies to assemble two complementary resources: the 2168-pair Union and 4859-pair Ito datasets. We extrapolated to the organismal level by classifying paralogs as core (broadly compensating, 99 Union/120 Ito pairs), conditional (111/566) or non-interacting (1958/4173), and testing for enriched compensatory signals in core pairs relative to the latter two groups. Core nGI pairs consistently showed prenatal co-expression, depletion of disease genes and enrichment for upregulation after paralog loss in cancer, though the signals were often moderate. Evolutionary analyses found similar fractions (∼2%) of core compensators among both ancient and young paralogs. Ancient pairs retain overlaps likely under pleiotropic and dosage constraints. Incomplete small-scale duplication mechanisms limit compensation among young pairs, except X-derived retrogenes, which are overrepresented among core nGIs (∼14%). This is consistent with selection to counteract male germline X inactivation and subsequent out-of-testis expansion. Overall, paralogous compensation is moderately prevalent in vivo in humans, shaped by multiple evolutionary forces acting on ancient or young duplicates.
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BibTeX
@article{shen2026moderate,
title = {{Moderate prevalence and evolutionary causes of paralogous compensation in humans.}},
author = {Jieyu Shen and Daqi Yu and Wenjia Wang and Tianhan Su and Dingding Wang and Junbo Liang and Yiqiong Guo and Shangqi Zhao and Huijing Ma and Jichang Wang and Xiaoyue Wang and Yong E Zhang},
journal = {National science review},
year = {2026},
month = sep,
doi = {10.1093/nsr/nwag565},
url = {https://europepmc.org/article/MED/42953730},
note = {CC BY},
}
RIS
TY - JOUR
TI - Moderate prevalence and evolutionary causes of paralogous compensation in humans.
AU - Jieyu Shen
AU - Daqi Yu
AU - Wenjia Wang
AU - Tianhan Su
AU - Dingding Wang
AU - Junbo Liang
AU - Yiqiong Guo
AU - Shangqi Zhao
AU - Huijing Ma
AU - Jichang Wang
AU - Xiaoyue Wang
AU - Yong E Zhang
PY - 2026
DA - 2026/09/03
JO - National science review
DO - 10.1093/nsr/nwag565
UR - https://europepmc.org/article/MED/42953730
AB - Paralogous compensation drives genetic robustness; however, its in vivo prevalence in humans and the evolutionary forces shaping it remain unresolved. We CRISPR-screened 678 human paralog pairs to identify pairs with negative genetic interactions (nGIs) or compensatory paralogs, and integrated our results with four studies to assemble two complementary resources: the 2168-pair Union and 4859-pair Ito datasets. We extrapolated to the organismal level by classifying paralogs as core (broadly compensating, 99 Union/120 Ito pairs), conditional (111/566) or non-interacting (1958/4173), and testing for enriched compensatory signals in core pairs relative to the latter two groups. Core nGI pairs consistently showed prenatal co-expression, depletion of disease genes and enrichment for upregulation after paralog loss in cancer, though the signals were often moderate. Evolutionary analyses found similar fractions (∼2%) of core compensators among both ancient and young paralogs. Ancient pairs retain overlaps likely under pleiotropic and dosage constraints. Incomplete small-scale duplication mechanisms limit compensation among young pairs, except X-derived retrogenes, which are overrepresented among core nGIs (∼14%). This is consistent with selection to counteract male germline X inactivation and subsequent out-of-testis expansion. Overall, paralogous compensation is moderately prevalent in vivo in humans, shaped by multiple evolutionary forces acting on ancient or young duplicates.
SN - 2095-5138
SN - 2053-714X
ER -