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Evolutionary Origin of MUTYH Germline Pathogenic Variations in Modern Humans

Fengxia Xiao1,2, Jiaheng Li1, Philip Naderev Panuringan Lagniton1

  • 1Ministry of Education Frontiers Science Center for Precision Oncology, Cancer Centre and Institute of Translational Medicine, Department of Public Health and Medical Administration, Faculty of Health Sciences, University of Macau, Macao, China.

Biomolecules
|March 29, 2023
PubMed

Insights

Pathogenic variants in the MUTYH gene, crucial for DNA repair, mostly emerged recently in human history. Some MUTYH variants originated from Neanderthals, impacting colorectal cancer risk.

Area of Science:

  • Genetics
  • Evolutionary Biology
  • Human Genomics

Background:

  • The MUTYH gene is vital for repairing oxidative DNA damage.
  • Pathogenic germline variations in MUTYH lead to intestinal polyposis and colorectal cancer.
  • Understanding the evolutionary origin of MUTYH variants is key to cancer etiology.

Purpose of the Study:

  • To investigate the evolutionary origins of pathogenic germline variants in the human MUTYH gene.
  • To determine if human MUTYH variants are conserved across species or arose more recently.

Main Methods:

  • Phylogenetic analysis of MUTYH variants in modern humans and 99 vertebrates across eight clades.
  • Screening of MUTYH variants in 5031 ancient humans, Neanderthals, and Denisovans.

Main Results:

  • No shared pathogenic MUTYH variants were found between modern humans and non-human vertebrates.
  • Identified 24 pathogenic MUTYH variants in 42 ancient humans (30,570–480 years BP).
  • Discovered three pathogenic MUTYH variants in Neanderthals (65,000–38,310 years BP).

Conclusions:

  • Human pathogenic MUTYH variants largely originated in recent human history.
  • A portion of human MUTYH pathogenic variants have Neanderthal origins.
  • Cross-species conservation does not explain the origin of human pathogenic MUTYH variants.
Keywords:
MUTYHancient humansarchaeologicalevolutionary originpathogenic variantphylogenic

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