Genes that improved fitness also cost modern humans: evidence for genes with antagonistic effects on longevity and disease

Byars, Sean G.; Voskarides, Konstantinos

doi:10.1093/emph/eoz002

Cited by 9 publications

(6 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, evidence for the antagonistic pleiotropy hypothesis in humans have been contested [11][12][13][14] , and the hypothesis still lacks a genomic test. Furthermore, it is unclear whether mutations contributing to aging were selectively favored and whether the selection arose from their benefits earlier in life.…”

Section: Introductionmentioning

confidence: 99%

Evidence for the role of selection for reproductively advantageous alleles in human aging

Long

Zhang

2023

Preprint

View full text Add to dashboard Cite

The antagonistic pleiotropy hypothesis posits that natural selection for pleiotropic mutations that confer earlier or more reproduction but impair the post-reproductive life causes aging. This hypothesis of the evolutionary origin of aging is supported by case studies but lacks unambiguous genomic evidence. Here we genomically test this hypothesis using the genotypes, reproductive phenotypes, and death registry of 276,406 UK Biobank participants. We observe a strong, negative genetic correlation between reproductive traits and lifespan. Individuals with higher polygenetic scores for reproduction (PGSR) have lower survivorships to age 76 (SV76), andPGSRincreased over birth cohorts from 1940 to 1969. Similar trends are found from individual genetic variants examined.PGSRandSV76remain negatively correlated upon the control of the offspring number, revealing horizontal pleiotropy between reproduction and lifespan. Intriguingly, regardless ofPGSR, having two children maximizesSV76. These and other findings strongly support the antagonistic pleiotropy hypothesis of aging in humans.

show abstract

Section: Introductionmentioning

confidence: 99%

Evidence for the role of selection for reproductively advantageous alleles in human aging

Long

Zhang

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Voskarides appropriately emphasizes the relevance of George Williams' classic theory of "antagonistic pleiotropy", 8 in which selection for an allele's beneficial effects in early life can have deleterious consequences in late life. 9 A 2018 meta-analysis of 247 Genome-Wide Association Studies (GWAS) identified an association between 1377 cancer-associated genes in populations living in extremely cold environments and very high altitudes. [10][11][12] It is suggested that genetic variants that contributed to the survival of early humans living in these extreme environments are now associated with cancer incidence in contemporary populations, that is, the accumulation of deleterious mutations in tumorsuppressor, apoptosis, and cell cycle regulation genes.…”

mentioning

confidence: 99%

“…We appreciate the strongly supportive and positive comments by Voskarides 7 about our article published in this journal, 6 which suggested that human‐specific polymorphic pseudogenization of SIGLEC12 protects against advanced cancer progression. Voskarides appropriately emphasizes the relevance of George Williams' classic theory of “antagonistic pleiotropy”, 8 in which selection for an allele's beneficial effects in early life can have deleterious consequences in late life 9 . A 2018 meta‐analysis of 247 Genome‐Wide Association Studies (GWAS) identified an association between 1377 cancer‐associated genes in populations living in extremely cold environments and very high altitudes 10‐12 .…”

mentioning

confidence: 99%

Ongoing selection for a uniquely human null allele of SIGLEC12 in world‐wide populations may protect against the risk of advanced carcinomas

2021

View full text Add to dashboard Cite

Resonse to Voskarides Letter Ongoing Selection for a uniquely human null allele of SIGLEC12 in worldwide populations may protect against risk of advanced carcinomas The CD33-related subset of Siglecs (Sialic Acid binding Immunoglobulin superfamily Lectins) are well-known signalling receptors on immune cells, but Siglec-XII is also expressed on epithelial cell surfaces (1, 2). A point mutation eliminating the canonical sialic acid-binding function of Siglec-XII is unique to humans (2, 3) and fixed in all populations worldwide. We and others reported a further

show abstract

“…This is related to a special evolutionary process known as "antagonistic pleiotropy", first proposed by George Williams, 5 one of the most well‐known evolutionary biologists of the past century. He suggested that genetic variants selected as beneficial for survival at young ages, may have a deleterious effect later in life 6,7 . Selection of deleterious variants in DNA repair genes (considered as one of the main classes of tumor suppressor genes in mammals) is vital for unicellular organisms escaping extinction.…”

mentioning

confidence: 99%

“…He suggested that genetic variants selected as beneficial for survival at young ages, may have a deleterious effect later in life. 6,7 Selection of deleterious variants in DNA repair genes (considered as one of the main classes of tumor suppressor genes in mammals) is vital for unicellular organisms escaping extinction. Bacteria, protozoa, and monocellular fungi become very resistant under stressful conditions (antibiotics, oxidative stress, nutrient limitation, and other) when carrying mutations in DNA repair genes like MSH2, PMS1, RAD51, and others.…”

mentioning

confidence: 99%

Broadening the spectrum of cancer genes under selection in human populations

Voskarides

2021

FASEB BioAdvances

Self Cite

View full text Add to dashboard Cite

There is an increasing accumulation of evidence showing that the frequency of many human diseases has been formed by evolutionary procedures. Siddiqui et al. 1 performed an amazing study published in this journal, showing that SIGLEC12 gene expression is associated with advanced cancer progression in humans. They performed a multi-level experimental and statistical analysis. In a multi-tissue carcinoma array, the gene product was present in ~80% of tissues and only 35% in a set of normal epithelial tissues. Forced expression of the gene in a SIGLEC12 null carcinoma cell line had the consequence of enriching the transcription of genes associated with cancer progression, especially those related with KRAS and YAP/TAZ pathways. Compared with chimpanzees, it seems that the human receptor Siglec12 has lost its ligand after the human/chimpanzee lineage split, but notably the ligand gene remained in the chimpanzee genome. The authors also found evidence, using the Fst and Tajima D statistics, that a SIGLEC12 null allele in human populations, ranging from 38% in sub-Saharan Africans to 86% in native American populations, is under positive selection. They propose that the functional SIGLEC12 gene is currently under an elimination process in human populations, since its encoded protein, for unknown reasons, activates carcinogenic pathways.This study of Siddiqui et al. 1 adds to previous studies that showed significant evidence for the action of natural selection on cancer genes. All human populations have high incidences of cancer, but some have especially much higher risk for certain cancer types. Voskarides 2 has presented data showing that populations living in extreme cold environments and extreme high altitudes have the highest cancer incidence in the world. Linear regression analysis supports the fact that the cancer-cold association is a world-wide phenomenon. Analysis of 247 Genome Wide Association Studies (GWAS) showed that this association has a genetic base. Cancer genes and especially tumor suppressor genes were found to be under selection in Inuit, Eskimos and Alaska Indians. Genetic variants that contributed to the survival of humans in extreme environments are probably associated with cancer incidence today. A similar evolutionary process was revealed for human populations living at extreme high altitudes, like Ethiopians

show abstract

Genes that improved fitness also cost modern humans: evidence for genes with antagonistic effects on longevity and disease

Cited by 9 publications

References 7 publications

Evidence for the role of selection for reproductively advantageous alleles in human aging

Evidence for the role of selection for reproductively advantageous alleles in human aging

Ongoing selection for a uniquely human null allele of SIGLEC12 in world‐wide populations may protect against the risk of advanced carcinomas

Broadening the spectrum of cancer genes under selection in human populations

Contact Info

Product

Resources

About