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Analysis of genetic selection at insulin receptor substrate-2 gene loci

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Abstract

Purpose

Type 2 diabetes mellitus (T2DM) is highly heritable and exhibits significant variability in prevalence between different populations. Prevalence of T2DM is higher in Asian and African relative to European populations. During evolution, traditional feast-famine cycles likely led to significant natural selection impacting metabolic genes. Human adaptation to environmental changes (food supply, lifestyle, climate, and geography) likely influenced differential selection of T2DM-associated genes. Together, insulin receptor substrate-1 and -2 (IRS1 and IRS2) genes encode the major ligands of insulin and IGF1 receptors. Irs2-deficient mice exhibit a T2DM phenotype with severe insulin resistance, and a common IRS2 polymorphism is associated with T2DM. Therefore, the present study sought evidence of natural selection at IRS2 loci.

Methods

Data were sourced from the HapMap and 1000 Genomes projects, comprising four different populations with distinct ancestries: European, Yoruba, Han Chinese, and Japanese. A three-step method was applied to detect IRS2 locus selection. The long-range haplotype (LRH) test detected unusual extended haplotypes, the integrated haplotype score (iHS) detected selection, and Wright’s F-statistics (particularly Wright’s fixation index: FST) were calculated as a measure of population differentiation.

Results

The African population exhibited highly significant LRH findings (percentile >99.9, p = 0.005–0.0009), while both the European and African populations exhibited extreme positive iHS test scores ([iHS] >2.5).

Conclusion

These findings indicate that genetic selection has occurred at the IRS2 locus, warranting further research into the adaptive evolution of metabolic disorder-associated genes.

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Acknowledgements

We thank Kyoko Yoshiuchi for secretarial contribution. We would like to thank Editage (www.editage.com) for English language editing. Dr. Issei Yoshiuchi planned this study, examined data, wrote this manuscript, thought about discussion, and edited this manuscript.

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Authors and Affiliations

  1. Departments of Diabetes, Medicine, and Genetics, Yoshiuchi Medical Diabetes Institute, 2-12-24 Asukano-minami, Ikoma City, Nara, 630-0133, Japan

    Issei Yoshiuchi

  2. Departments of Diabetes and Medicine, Yoshiuchi Medical Diabetes Family Clinic, 3-7-21 Asukano-minami, Ikoma City, Nara, 630-0133, Japan

    Issei Yoshiuchi

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  1. Issei Yoshiuchi
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Correspondence to Issei Yoshiuchi.

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The author declares no conflict of interest.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.

This article does not contain any studies with human participants performed by any of the authors.

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Informed consent was obtained from all individual participants included in the study.

Prior Presentation

We presented parts of this project at the 57th Annual Meeting of Japan Diabetes Association, Osaka, Japan, in May 2014.

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Yoshiuchi, I. Analysis of genetic selection at insulin receptor substrate-2 gene loci. J Diabetes Metab Disord 20, 307–311 (2021). https://doi.org/10.1007/s40200-021-00745-y

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