Identifying adaptive alleles in the human genome: from selection mapping to functional validation

Werren, Elizabeth; Garcia, Obed A; Bigham, Abigail W.

doi:10.1007/s00439-020-02206-7

Cited by 15 publications

(14 citation statements)

References 282 publications

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“…Whether this increase in stem cell numbers persists over time is currently under investigation. However, increased fitness conferred to heterozygous mice at this timepoint provides intriguing insights into other selective pressures that may have promoted accumulation of this polymorphism in humans (Werren et al, 2021). Sepsis, where emergency hematopoiesis is an essential determinant in survival, is an interesting and highly evolutionarily significant avenue of exploration for the study of MLKL S132P polymorphism frequency (Boomer et al, 2011; Brinkworth and Valizadegan, 2021).…”

Section: Discussionmentioning

confidence: 99%

A common humanMLKLpolymorphism confers resistance to negative regulation by phosphorylation

Garnish

Martin

Kauppi

et al. 2022

Preprint

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Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. We show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKL S132P in biological membranes and MLKL S132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo, Mlkl S131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.

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Section: Discussionmentioning

confidence: 99%

A common humanMLKLpolymorphism confers resistance to negative regulation by phosphorylation

Garnish

Martin

Kauppi

et al. 2022

Preprint

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“…Finally, as noted above, there are strong differential allele frequencies of the sentinel PPP1R15A variant across global ancestral populations, a pattern that has been reported for other COVID-19 host susceptibility variants [49, 50]. Infection-related variants have been found for multiple viruses in regions under selective pressure or with allele frequency differences across populations [51]. As sample sizes increase for COVID-19 related genetic analysis, it will also be interesting to examine the associations of red blood cell related variants with COVID-19 severity, given potential links with oxygenation/clotting during disease progression.…”

Section: Discussionmentioning

confidence: 85%

Genetic Examination of Hematological Parameters in SARS-CoV-2 Infection and COVID-19

Rowland

Sun

Wang

et al. 2022

Preprint

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Background: People hospitalized with COVID-19 often exhibit hematological alterations, such as lower lymphocyte and platelet counts, which have been reported to associate with disease prognosis. It is unclear whether inter-individual variability in baseline hematological parameters prior to acute infection influences risk of SARS-CoV-2 infection and progression to severe COVID-19. Methods: We assessed the association of blood cell counts and indices with incident SARS-CoV-2 infection and severe COVID-19 in UK Biobank and the Vanderbilt University Medical Center Synthetic Derivative (VUMC SD). Since genetically determined blood cell measures better represent cell abundance across the lifecourse, we used summary statistics from genome-wide association studies to assess the shared genetic architecture of baseline blood cell counts and indices on COVID-19 outcomes. Results: We observed inconsistent associations between measured blood cell indices and both SARS-CoV-2 infection and COVID-19 hospitalization in UK Biobank and VUMC SD. In Mendelian randomization analyses using genetic summary statistics, no putative causal relationships were identified between COVID-19 related outcomes and hematological indices after adjusting for multiple testing. We observed overlapping genetic association signals between hematological parameters and COVID-19 traits. For example, we observed overlap between infection susceptibility-associated variants at PPP1R15A and red blood cell parameters, and between disease severity-associated variants at TYK2 and lymphocyte and platelet phenotypes. Conclusions: We did not find convincing evidence of a relationship between baseline hematological parameters and susceptibility to SARS-CoV-2 infection or COVID-19 severity, though this relationship should be re-examined as larger and better-powered genetic analyses of SARS-CoV-2 infection and severe COVID-19 become available.

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“…If these populations are not small (as is the case here), then there is reason to suspect natural selection. If the allele in the homozygote state (and possibly in the heterozygote state) is accompanied by deleterious effects, as discussed in the introduction, then there is even more reason to suspect natural selection (Jobling et al, 2014;Werren et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

The distribution in native populations from Mexico and Central America of the C677T variant in the MTHFR gene

Reyes

Godfrey

Ming

et al. 2021

American J Hum Biol

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Objectives: To explore evolutionary hypotheses for the high frequencies of a substitution in the methylenetetrahydrofolate reductase (MTHFR) gene, in Mexican and Central American Indigenous populations. Materials and methods: We obtained allele frequencies for the C677T variant in the MTHFR gene and ecological information for 37 indigenous samples from Mexico and Central America. We calculated Hardy-Weinberg equilibrium and computed Fst statistics. We computed correlations between the samples' allele frequencies and ecological and geochemical variables. Results: Many of the samples have extremely high frequencies of the T allele ( q = 0.62, median = 0.66). In this region, the frequency of the T allele decreases from Southeast to Northwest and is significantly correlated with longitude, latitude, altitude, and insolation. Conclusions:The native people of Central America and Mexico evolved high frequencies of an allele which has been shown to produce deleterious clinical effects including neural tube effects, cardiovascular events, and cancer. This allele has a clinal distribution in the region, perhaps associated with solar irradiation. As (Contreras-Cubas et al., 2016) noted, the traditional diet of these populations, which is high in folate, has likely mitigated the negative effect of the allele. It is of primary importance that their rights to their homeland and traditional diets be respected. It is a matter of Public Health to investigate whether this allele is a factor in the current wave of cardiovascular diseases affecting the majority population of this region, since it descends from the Native peoples and the Mediterranean population, which also has high frequencies of the allele.

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Identifying adaptive alleles in the human genome: from selection mapping to functional validation

Cited by 15 publications

References 282 publications

A common humanMLKLpolymorphism confers resistance to negative regulation by phosphorylation

A common humanMLKLpolymorphism confers resistance to negative regulation by phosphorylation

Genetic Examination of Hematological Parameters in SARS-CoV-2 Infection and COVID-19

The distribution in native populations from Mexico and Central America of the C677T variant in the MTHFR gene

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