iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: http://pubmed.ncbi.nlm.nih.gov/36979362/
Evolutionary Origin of MUTYH Germline Pathogenic Variations in Modern Humans - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Feb 24;13(3):429.
doi: 10.3390/biom13030429.

Evolutionary Origin of MUTYH Germline Pathogenic Variations in Modern Humans

Fengxia Xiao  1   2 , Jiaheng Li  1 , Philip Naderev Panuringan Lagniton  1 , Si Hoi Kou  1 , Huijun Lei  1 , Benjamin Tam  1 , San Ming Wang  1
Affiliations

Evolutionary Origin of MUTYH Germline Pathogenic Variations in Modern Humans

Fengxia Xiao et al. Biomolecules. .

Abstract

MUTYH plays an essential role in preventing oxidation-caused DNA damage. Pathogenic germline variations in MUTYH damage its function, causing intestinal polyposis and colorectal cancer. Determination of the evolutionary origin of the variation is essential to understanding the etiological relationship between MUTYH variation and cancer development. In this study, we analyzed the origins of pathogenic germline variants in human MUTYH. Using a phylogenic approach, we searched MUTYH pathogenic variants in modern humans in the MUTYH of 99 vertebrates across eight clades. We did not find pathogenic variants shared between modern humans and the non-human vertebrates following the evolutionary tree, ruling out the possibility of cross-species conservation as the origin of human pathogenic variants in MUTYH. We then searched the variants in the MUTYH of 5031 ancient humans and extinct Neanderthals and Denisovans. We identified 24 pathogenic variants in 42 ancient humans dated between 30,570 and 480 years before present (BP), and three pathogenic variants in Neanderthals dated between 65,000 and 38,310 years BP. Data from our study revealed that human MUTYH pathogenic variants mostly arose in recent human history and partially originated from Neanderthals.

Keywords: MUTYH; ancient humans; archaeological; evolutionary origin; pathogenic variant; phylogenic.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Distribution of human MUTYH variants in 100 vertebrates of 8 clades. (a) Human MUTYH PVs; (b) Human MUTYH BVs. White cell: same as human wild type; red cell: same as human variants; light blue cell: different from both human wild type and variants; gray cell: gaps or unaligned. X axis: the shared variants, Y axis: the 100 species from human in Primate to lamprey in Fish. The schematic diagram of MUTYH functional domains and binding sites is shown on top of the figures.
Figure 2
Figure 2
Geographic distribution of human MUTYH PVs in ancient humans. A total of 24 human MUTYH PVs were identified in 42 ancient individuals, mostly from Europe and Asia, dated from 30,570 to 480 years BP. One of the 42 individuals had 2 PVs, and each of the other 41 individuals had 1 PV. Three PVs were also identified in the Neanderthals (triangle dots) of Croatia and Russia, dated between 65,000 and 38,310 years BP.
Figure 3
Figure 3
Distribution of MUTYH PVs shared in ancient individuals. It shows 21 codon positions of the 24 MUTYH PVs detected in 42 ancient individuals, of which 23 were located at functional domains. Each line represents one codon position with the PV number at the top (same order as in Table 1 dating from the oldest to the newest). Each codon position had one variant, except for 3 positions that had 2 variants represented by the number “2” at the bottom of the line. The top 3 clustered functional domains were EndoIII-iron–sulfur cluster (FeS)-like (15 PVs), EndoIII-6-Helix_barrel (12 PVs) and Nudix-like (12 PVs). Other domains included replication protein A1 (RPA1) binding site (5 PVs), mitochondrial localization signal (MLS) (3 PVs), HUS1 binding site (2 PVs), linker (2 PVs) and nuclear localization signal (NLS) (1 PV).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. David S.S., O’Shea V.L., Kundu S. Base-Excision Repair of Oxidative DNA Damage. Nature. 2007;447:941–950. doi: 10.1038/nature05978. - DOI - PMC - PubMed
    1. Mazzei F., Viel A., Bignami M. Role of MUTYH in Human Cancer. Mutat. Res. Fundam. Mol. Mech. Mutagen. 2013;743–744:33–43. doi: 10.1016/j.mrfmmm.2013.03.003. - DOI - PubMed
    1. Bedics G., Kotmayer L., Zajta E., Hegyi L.L., Brückner E.Á., Rajnai H., Reiniger L., Bödör C., Garami M., Scheich B. Germline MUTYH Mutations and High-Grade Gliomas: Novel Evidence for a Potential Association. Genes Chromosomes Cancer. 2022;61:622–628. doi: 10.1002/gcc.23054. - DOI - PMC - PubMed
    1. Slupska M.M., Baikalov C., Luther W.M., Chiang J.H., Wei Y.F., Miller J.H. Cloning and Sequencing a Human Homolog (HMYH) of the Escherichia Coli MutY Gene Whose Function Is Required for the Repair of Oxidative DNA Damage. J. Bacteriol. 1996;178:3885–3892. doi: 10.1128/jb.178.13.3885-3892.1996. - DOI - PMC - PubMed
    1. Banda D.M., Nuñez N.N., Burnside M.A., Bradshaw K.M., David S.S. Repair of 8-OxoG:A Mismatches by the MUTYH Glycosylase: Mechanism, Metals and Medicine. Free Radic. Biol. Med. 2017;107:202–215. doi: 10.1016/j.freeradbiomed.2017.01.008. - DOI - PMC - PubMed

Publication types

Substances

Grants and funding

This research was funded by the Macau Science and Technology Development Fund (No. 085/2017/A2, 0077/2019/AMJ, 0032/2022/A1), the University of Macau Fund (No. SRG2017-00097-FHS, MYRG2019-00018-FHS, 2020-00094-FHS) and the Faculty of Health Sciences, University of Macau (No. FHSIG/SW/0007/2020P, MOE Frontiers Science Center for Precision Oncology pilot grant, and a startup fund) to S.M.W.