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Epigenetics in Sperm, Epigenetic Diagnostics, and Transgenerational Inheritance
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Jennifer L. M. Thorson, Millissia Ben Maamar, Michael K. Skinner
The environment has been shown to be one of the most critical factors to impact the biology of an organism. An exposure to one or multiple environmental factors (e.g., nutrition, toxicants, stress) can trigger changes in the transcriptome and impact the development of pathologies or phenotypic variation. As described above, epigenetic factors are the molecular mechanisms an organism uses to respond to an environmental change with modifications in gene expression. Most environmental factors and toxicants do not possess the capacity to alter DNA sequence or promote genetic mutations (67). However, the environment is able to dramatically influence epigenetic processes which then affect gene expression and development. In human and animal models, several studies have demonstrated that exposure to certain environmental toxicants at a specific window of development, especially when the epigenome is reprogramming, can affect the mechanisms involved in the establishment of the sperm epigenome. Since the sperm epigenome has been shown to be crucial for the fertility of the individuals, any variations could be related to male infertility (68). Some epimutations have also been shown to be transmitted via the sperm to the offspring and subsequent generations which has been defined as the concept of epigenetic transgenerational inheritance (4,6,69). Therefore, epigenetics provides a molecular mechanism for the environment to directly alter the biology of an organism (70). The presence of an altered epigenetic factor at a specific chromosomal location in response to an environmental factor is called an “epimutation” (71).
Genetics of Human Obesities: Introductory Notes
Published in Claude Bouchard, The Genetics of Obesity, 2020
Two strategies have been traditionally used by geneticists to study the role of genes in continuously distributed phenotypes in humans. As shown in Figure 4, they are referred to as the unmeasured genotype and the measured genotype approaches.45,46 The unmeasured genotype approach attempts to estimate the contribution of genetic variation to the phenotypic variance and to find quantitative evidence for single genes with detectable (major) effects on the phenotype. As inference about the contribution of genes is made from the phenotype, this approach is also referred to as the top-down strategy. Here one uses various sampling designs (twins, nuclear families, families with adoptees, extended pedigrees, etc.) in combination with statistical tools such as path analysis, variance component estimation, and complex segregation analysis. On the other hand, the measured genotype approach is based on direct measurement of genetic variation at the protein or DNA levels in an effort to assess the impact of allelic variation on the phenotypic variation. Since inference about the role of genes is made from DNA to the phenotype, this approach is at times referred to as the bottom-up strategy.46 Direct measures of genetic variation may be obtained by studying gene products or, better still, DNA sequences. Advances in recombinant DNA technology over the last two decades have made possible the measure of genetic variation at the DNA level and have provided the impetus necessary for the extensive use of the measured genotype approach in human genetic studies.
A Retrospective View of the Inherited Errors of the Thyroid System
Published in Geraldo Medeiros-Neto, John Bruton Stanbury, Inherited Disorders of the Thyroid System, 2019
Geraldo Medeiros-Neto, John Bruton Stanbury
An important advance was when, in 1967, Refetoff and his colleagues4 began their studies of members of a family with peripheral resistance to the action of thyroid hormone. In addition to admirable clinical descriptions of the syndrome and its course in this family and a number of others, there have been two thrusts of these investigations. One is the exploitation of the disorder in defining the molecular biology of this abnormality, the analysis of the fine-structure changes in the genes that correspond to the hormone receptors. Perhaps nowhere else in medicine is there so much precise information about the multiple alterations in gene structure and the polymorphism of aberrant molecules involved in phenotypic variation. The other side of this coin is the wealth of information that has flowed from these studies regarding genomic control and the way receptors interact with responsive elements of chromatin.
What do we know about the variability in survival of patients with amyotrophic lateral sclerosis?
Published in Expert Review of Neurotherapeutics, 2020
Pamela A. McCombe, Fleur C Garton, Matthew Katz, Naomi R Wray, Robert D Henderson
Additionally, with improved (more comprehensive) genetic screening an architecture consistent with oligogenic inheritance (more than one pathogenic variant in a relevant ALS gene) has been described [37–39]. For example, screening 97 families for multiple ALS variants, identified five families that carried two known mutations (i.e. C9orf72 HRE + TARDBP p.N352 S) [38]. This occurred more than what would be expected by chance and was supported by findings in a sporadic population for which 7 (of the 14) TARDBP p.N352 S variant carriers, had an additional ALS variant [38]. This genetic architecture is not commonly identified (i.e. 5/97 = 5% of familial cases, 1% of clinic population) [40] and other risk variants may also play a role due to a shared haplotype/common ancestor (a polygenic architecture). Due to the few cases identified it remains difficult to determine if this influences phenotypic variation in survival and future studies will need to determine if a burden of pathogenic variants can alter survival.
Primary adrenal insufficiency due to hereditary apolipoprotein AI amyloidosis: endocrine involvement beyond hypogonadism
Published in Amyloid, 2018
Adriana Pané, Sabina Ruiz, Aida Orois, Daniel Martínez, Mattia Squarcia, Lydia Sastre, Pablo Ruiz, Joan Caballería, Mireia Mora, Felicia A. Hanzu, Irene Halperin
So far, approximately 20 APOA1 variants responsible for systemic amyloidosis have been mapped. Each specific mutation results in a syndrome that is distinct with respect to age of onset, form of presentation, pattern of organ distribution, rate of progression, and prognosis [7]. The clinical manifestations of apoAI-derived (AApoAI) amyloidosis frequently involve the liver, kidneys, larynx, skin and myocardium. Furthermore, in some cases, it can also affect the testes and adrenal glands. Indeed, hypergonadotropic hypogonadism is considered almost pathognomonic of this form of the disease [8]. However, its clinical spectrum is extremely heterogeneous, even amongst individuals with identical variants. Some patients develop extensive visceral amyloid deposits and end-stage renal or liver failure as young adults, while others simply display laryngeal and/or skin amyloid [9]. For this reason, it is believed that multiple genetic and environmental factors may contribute to phenotypic variation [10].
A novel NLRP3 variant in two unrelated patients with cryopyrin-associated periodic syndrome
Published in Modern Rheumatology Case Reports, 2018
Yukako Maeda, Kazushi Izawa, Haruna Nakaseko, Yoko Okada, Yoshitaka Honda, Takeshi Shiba, Masahiko Nishitani, Hiroshi Nihira, Eitaro Hiejima, Takayuki Tanaka, Tomoki Kawai, Takahiro Yasumi, Shintaro Ono, Naomi Iwata, Toshio Heike, Ryuta Nishikomori
To date, two previous studies [3,6] reported three patients harbouring a p.Met659Lys (1976T>A) variant; this variation occurs at the same site reported herein, but involves a different amino acid substitution. Patients with the p.Met659Lys variant were diagnosed with FCAS. However, we diagnosed the two cases harbouring the p.Met659Arg variant as MWS because both had periodic or continuous rash and fever in the absence of cold exposure and the symptoms lasted several days. There is some degree of genotype-phenotype correlation in CAPS. However, even the same variant, for example p.Arg260Trp, is responsible for both FCAS and MWS. Also there are reports of phenotypic variation even in patients with the same variants in the same family. The mechanism that same variants or different amino acid substitutions in the same position can cause different phenotype remains to be elucidated.