Evidence for germline non-genetic inheritance of human phenotypes and diseases
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(2020) 12:136
REVIEW
Open Access
Evidence for germline non-genetic inheritance of human phenotypes and diseases Liana Senaldi1 and Matthew Smith-Raska1,2*
Abstract It is becoming increasingly apparent that certain phenotypes are inherited across generations independent of the information contained in the DNA sequence, by factors in germ cells that remain largely uncharacterized. As evidence for germline non-genetic inheritance of phenotypes and diseases continues to grow in model organisms, there are fewer reports of this phenomenon in humans, due to a variety of complications in evaluating this mechanism of inheritance in humans. This review summarizes the evidence for germline-based non-genetic inheritance in humans, as well as the significant challenges and important caveats that must be considered when evaluating this process in human populations. Most reports of this process evaluate the association of a lifetime exposure in ancestors with changes in DNA methylation or small RNA expression in germ cells, as well as the association between ancestral experiences and the inheritance of a phenotype in descendants, down to great-grandchildren in some cases. Collectively, these studies provide evidence that phenotypes can be inherited in a DNA-independent manner; the extent to which this process contributes to disease development, as well as the cellular and molecular regulation of this process, remain largely undefined. Keywords: Human epigenetic inheritance, Human disease inheritance, Transgenerational epigenetic inheritance, Sperm DNA methylation, Sperm small RNAs, Thyroid hormone epigenetics, Reduced sensitivity to thyroid hormone, Överkalix study, Parent-of-origin
Introduction The traditional Mendelian model of inheritance states that phenotypes are inherited based on the transmission of DNA sequences across generations, and diseases are inherited when these DNA sequences are abnormal. In model organisms, it is becoming increasingly apparent that phenotypes and disease risk can be inherited from sperm and oocytes in the absence of DNA mutations or variations. This non-genetic inheritance is based on the concept that non-DNA molecules in sperm and oocytes * Correspondence: [email protected] 1 Division of Newborn Medicine, Department of Pediatrics, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, USA 2 Drukier Institute for Children’s Health, Weill Cornell Medicine, New York, NY, USA
are inherited at fertilization and modify the phenotype of the offspring, sometimes across multiple generations. The central concept in this field is that an organism’s exposures (diet, stress, chemicals, etc.) affect the composition of germline non-DNA molecules, and in this manner, these exposures can affect phenotypes in descendants. Localization of this phenomenon to the germ cells is proven by the use of in vitro fertilization with surrogate “mothers” carrying the fetus who never experienced the exposure [1]. While there are multiple examples of this phenomenon across a variety of model organisms
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