Genetic and Epigenomic Footprints of Folate

Salbaum, J. Michael; Kappen, Claudia

doi:10.1016/b978-0-12-398397-8.00006-x

Cited by 52 publications

(21 citation statements)

References 149 publications

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“…Their dependency on sunlight and diet make them ideal candidates to study the genetic patterns of adaptation to the new environments that humans encountered on their way out of Africa. Furthermore, there is an overlap of four genes associated with metabolism, regulation and action of these vitamins which suggests that these interact as regulators of an integrated cellular machinery controlling gene expression [ 35 ]. We found evidence of positive selection in genes responsible for, or responsive to, action of vitamin D 3 in bones in East Asians (Han Chinese and Japanese).…”

Section: Discussionmentioning

confidence: 99%

Genes Regulated by Vitamin D in Bone Cells Are Positively Selected in East Asians

et al. 2015

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Vitamin D and folate are activated and degraded by sunlight, respectively, and the physiological processes they control are likely to have been targets of selection as humans expanded from Africa into Eurasia. We investigated signals of positive selection in gene sets involved in the metabolism, regulation and action of these two vitamins in worldwide populations sequenced by Phase I of the 1000 Genomes Project. Comparing allele frequency-spectrum-based summary statistics between these gene sets and matched control genes, we observed a selection signal specific to East Asians for a gene set associated with vitamin D action in bones. The selection signal was mainly driven by three genes CXXC finger protein 1 (CXXC1), low density lipoprotein receptor-related protein 5 (LRP5) and runt-related transcription factor 2 (RUNX2). Examination of population differentiation and haplotypes allowed us to identify several candidate causal regulatory variants in each gene. Four of these candidate variants (one each in CXXC1 and RUNX2 and two in LRP5) had a >70% derived allele frequency in East Asians, but were present at lower (20–60%) frequency in Europeans as well, suggesting that the adaptation might have been part of a common response to climatic and dietary changes as humans expanded out of Africa, with implications for their role in vitamin D-dependent bone mineralization and osteoporosis insurgence. We also observed haplotype sharing between East Asians, Finns and an extinct archaic human (Denisovan) sample at the CXXC1 locus, which is best explained by incomplete lineage sorting.

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Section: Discussionmentioning

confidence: 99%

Genes Regulated by Vitamin D in Bone Cells Are Positively Selected in East Asians

et al. 2015

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“…The blood of alcoholic individuals (Cravo et al, 1996) or experimental animal models of chronic alcoholism (Halsted et al, 2002) exhibit this alcohol-induced folate reduction. As folate is the main methyl group donor in the cell, this ethanol-induced reduction could affect many methylation reactions (Salbaum & Kappen, 2012). To date, there is no mechanism, biochemical, molecular or enzymatic that could explain this reduction in folate, although ethanol has been shown to also induce changes in the transport of folate (Legault, Bertrand-Lehouillier, & McGraw, 2018;Lussier et al, 2018;Portales-Casamar et al, 2016).…”

Section: Epigenetic Changesmentioning

confidence: 99%

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

Petrelli

Bendelac

Hicks

et al. 2019

Genesis

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Summary Fetal Alcohol Spectrum Disorder (FASD) is a set of neurodevelopmental malformations caused by maternal consumption of alcohol during pregnancy. FASD sentinel facial features are unique to the disorder, and microcephaly is common in severe forms of FASD. Retinoic acid deficiency has been shown to cause craniofacial malformations and microcephaly in animal models reminiscent of those caused by prenatal alcohol exposure. Alcohol exposure affects the migration and survival of cranial neural crest cells, which are required for proper frontonasal prominence and pharyngeal arch development. Defects in craniofacial development are further amplified by the many downstream pathways that are transcriptionally controlled retinoic acid target genes, including Shh signaling. Recent evidence shows that alcohol exposure itself is sufficient to induce retinoic acid deficiency in the embryo. These data suggest that retinoic acid deficiency is an important underlying etiology of FASD. In disorders like Vitamin A Deficiency, FASD, DiGeorge (22q11.2 Deletion Syndrome), CHARGE, Smith‐Magenis, Matthew‐Wood, and Congenital Zika Syndromes, evidence is accumulating to link reduced retinoic acid signaling with developmental defects like craniofacial malformations and microcephaly. Research focus on characterizing the effects of retinoic acid deficiency during early development and on understanding the downstream signaling pathways involved in aberrant head, and craniofacial development will reveal underlying etiologies of these disorders.

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“…SAM is best known as the methyl donor for all methylation reactions for nucleic acids (DNA, RNAs, including tRNAs), proteins (including histones), lipids and other molecules. 101,[113][114][115] Moreover, by utilizing acetyl CoA, polyamine catabolism magnifies the effects of folate deficiency ( Fig 5). Acetyl CoA is the substrate for synthesizing betaine, which is the alternative methyl donor to synthesize SAM from homocysteine.…”

Section: What Are the Mechanisms?mentioning

confidence: 99%

Do gametes woo? Evidence for non-random unions at fertilization

Nadeau

2017

Preprint

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A fundamental tenet of inheritance in sexually reproducing organisms such as humans and laboratory mice is that genetic variants combine randomly at fertilization, thereby ensuring a balanced and statistically predictable representation of inherited variants in each generation. This principle is encapsulated in Mendel's First Law. But exceptions are known. With transmission ratio distortion (TRD), particular alleles are preferentially transmitted to offspring without reducing reproductive productivity. Preferential transmission usually occurs in one sex but not both and is not known to require interactions between gametes at fertilization. We recently discovered, in our work in mice and in other reports in the literature, instances where any of 12 mutant genes bias fertilization, with either too many or too few heterozygotes and too few homozygotes, depending on the mutant gene and on dietary conditions. Although such deviations are usually attributed to embryonic lethality of the under-represented genotypes, the evidence is more consistent with genetically-determined preferences for specific combinations of egg and sperm at fertilization that results in genotype bias without embryo loss. These genes and diets could bias fertilization in at least three not mutually exclusive ways. They could trigger a reversal in the order of meiotic divisions during oogenesis so that the genetics of fertilizing sperm elicits preferential chromatid segregation, thereby dictating which allele remains in the egg versus the 2 nd polar body. Bias could also result from genetic-and diet-induced anomalies in polyamine metabolism on which function of haploid gametes normally depends. Finally, secreted and cell-surface factors in female reproductive organs could control access of sperm to eggs based on their genetic content. This unexpected discovery of genetically-biased fertilization in mice could yield insights about the molecular and cellular interactions between sperm and egg at fertilization, with implications for our understanding of inheritance, reproduction, population genetics, and medical genetics. [298 words]All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/127134 doi: bioRxiv preprint first posted online Apr. 13, 2017; 3 Our understanding of inheritance in sexually reproducing organisms assumes, with good evidence, that the combination of egg and sperm at fertilization is largely independent of their genetic content. This equal transmission of alternative alleles through meiosis in heterozygotes ensures a balanced parental genetic contribution to offspring at each generation. Mendel's First Law captures this principle, which is one of the few that applies generally in biology. Independent segregation and random union of gametes at fertilization are foundations of classical, quantitative, population, evolutionary and me...

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Genetic and Epigenomic Footprints of Folate

Cited by 52 publications

References 149 publications

Genes Regulated by Vitamin D in Bone Cells Are Positively Selected in East Asians

Genes Regulated by Vitamin D in Bone Cells Are Positively Selected in East Asians

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

Do gametes woo? Evidence for non-random unions at fertilization

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