Single-nucleotide variations of the human nuclear hormone receptor genes in 60,000 individuals

Rafah Mackeh, Alexandra K. Marr, Soha R. Dargham, Najeeb Syed, Khalid A. Fakhro, Tomoshige Kino

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Nuclear hormone receptors (NRs) mediate biologic actions of lipophilic molecules to gene transcription and are phylogenetically and functionally categorized into seven subfamilies and three groups, respectively. Single-nucleotide variations (SNVs) or polymorphisms are genetic changes influencing individual response to environmental factors and susceptibility to various disorders, and are part of the genetic diversification and basis for evolution. We sorted out SNVs of the human NR genes from 60,706 individuals, calculated three parameters (percentage of all variants, percentage of loss-of-function variants, and ratio of nonsynonymous/synonymous variants in their full protein-coding or major domain-coding sequences), and compared them with several valuables. Comparison of these parameters between NRs and control groups identified that NRs form a highly conserved gene family. The three parameters for the full coding sequence are positively correlated with each other, whereas fourNR genes are distinct from the others with much higher tolerance to protein sequence-changing variants. DNA-binding domain and N-terminal domain are respectively those bearing the least and the most variation. NR subfamilies based on their phylogenetic proximity or functionality as well as diversity of tissue distribution and numbers of partner molecules are all not correlated with the variation parameters, whereas their gene age demonstrates an association. Our results suggest that the natural selection driving the NR family evolution still operates in humans. Gene age and probably the potential to adapt to various new ligands, but not current functional diversity, are major determinants for SNVs of the human NR genes.

Original languageEnglish
Pages (from-to)77-90
Number of pages14
JournalJournal of the Endocrine Society
Volume2
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018

Fingerprint

Cytoplasmic and Nuclear Receptors
Nucleotides
Genes
Inborn Genetic Diseases
Genetic Selection
Tissue Distribution
Proteins
Ligands
Control Groups
DNA

Keywords

  • Evolution
  • Functional diversity
  • Gene age
  • Ligand-binding pocket (LBP)
  • Major domains

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

Cite this

Single-nucleotide variations of the human nuclear hormone receptor genes in 60,000 individuals. / Mackeh, Rafah; Marr, Alexandra K.; Dargham, Soha R.; Syed, Najeeb; Fakhro, Khalid A.; Kino, Tomoshige.

In: Journal of the Endocrine Society, Vol. 2, No. 1, 01.01.2018, p. 77-90.

Research output: Contribution to journalArticle

Mackeh, Rafah ; Marr, Alexandra K. ; Dargham, Soha R. ; Syed, Najeeb ; Fakhro, Khalid A. ; Kino, Tomoshige. / Single-nucleotide variations of the human nuclear hormone receptor genes in 60,000 individuals. In: Journal of the Endocrine Society. 2018 ; Vol. 2, No. 1. pp. 77-90.
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