How family histories can inform research about germ cell exposures: the example of autism

Abstract

Throughout the scientific literature, heritable traits are routinely presumed to be genetic in origin. However, as emerging evidence from the realms of genetic toxicology and epigenomics demonstrate, heritability may be better understood as encompassing not only DNA sequence passed down through generations, but also disruptions to the parental germ cells causing de novo mutations or epigenetic alterations, with subsequent shifts in gene expression and functions in offspring. The Beyond Genes conference highlighted advances in understanding these aspects at molecular, experimental and epidemiological levels. In this commentary I suggest that future research on this topic could be inspired by collecting parents’ germ cell exposure histories, with particular attention to cases of families with multiple children suffering idiopathic disorders. In so doing I focus on the endpoint of autism spectrum disorders (ASD). Rates of this serious neurodevelopment disability have climbed around the world, a growing crisis that cannot be explained by diagnostic shifts. ASD’s strong heritability has prompted a research program largely focused on DNA sequencing to locate rare and common variants, but decades of this gene-focused research have revealed surprisingly little about the molecular origins of the disorder. Based on my experience as the mother of two children with idiopathic autism, and as a research philanthropist and autism advocate, I suggest ways researchers might probe parental germ cell exposure histories to develop new hypotheses that may ultimately reveal sources of non-genetic heritability in a subset of idiopathic heritable pathologies.

Epigenetics Role in Spermatozoa Function: Implications in Health and Evolution—An Overview

“…Actually, it is hypothesized that a great part of idiopathic infertility cases would have an epigenetic origin, being more frequent than the exclusive genetics ones [ 22 , 29 , 45 ]. It is worth highlighting that the shorter latency period of the spermatozoa compared with the oocyte makes the probability of gaining epigenetic modifications smaller [ 23 , 46 ]. The main roles of epigenetics in sperm functions and how they can be altered are discussed below.…”

“…Perturbations in the spermatozoa genesis, even if they do not affect fertility, can still influence the embryo through epigenetics [ 9 , 28 , 50 ]. It has been demonstrated that disturbances in methylome, packaging proteins, transcriptome, or proteome conduct abnormal development and pregnancy loss [ 8 , 9 , 16 , 17 , 23 , 28 , 43 ]. Some of the most common origins are imprinting mismatches and the P1:P2 disbalance [ 16 , 17 , 28 ].…”

“…That implies that the phenotype of an organism could be influenced by the environment that its ascendents were exposed to [ 10 , 27 , 33 ]. In this way, successive generations would possess a common phenotypic character that cannot be exclusively explained by genetic inheritance [ 16 , 23 ]; that is, epigenetic inheritance [ 10 , 27 , 31 ]. Epigenetic inheritance can be intergenerational (between two consecutive generations) or transgenerational (between no consecutive generations) [ 28 , 30 ].…”

“…A possible definition of epigenetics is that it is the set of phenomena by which a group of mechanisms (epigenome) regulates expression without altering DNA sequence [ 22 ] by changing the accessibility or availability of elements involved in the transcription and translation processes [ 17 ]. These mechanisms respond to environmental conditions, either the extracellular or the external environment [ 10 , 17 , 23 , 24 , 25 ]. Expression patterns define each cell type and its intratypic variation, that is to say, the phenotypic identity of the cell [ 1 , 26 ].…”

Beyond Genes: Germline Disruption in the Etiology of Autism Spectrum Disorders

“…The autism family population represents a vast and generally untapped resource for addressing novel questions about germline exposures. In particular, parents who have strong recurrence of autism in their offspring could be questioned about their (and therefore their germ cells’) exposure histories or that of their parents (Escher, 2021 ). While such data would be anecdotal in nature, it could contribute valuable information to generate new hypotheses about the heritable origins of autism.…”