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Germline

The germline refers to the population of cells in sexually reproducing multicellular organisms that give rise to gametes—sperm in males and eggs in females—thereby serving as the conduit for passing genetic information from parents to offspring across generations.^[1] These cells, known as germ cells, originate early in embryonic development and undergo specialized processes to maintain genetic continuity.^[2] Unlike other cell types, germline cells ensure the heritability of traits, forming the foundational link in reproduction and evolution.^[3] A key distinction exists between the germline and somatic cells, the latter comprising all non-reproductive body cells that build tissues and organs but do not contribute to genetic inheritance.^[1] This separation, conceptualized as the Weismann barrier by biologist August Weismann in the late 19th century, posits that genetic changes in somatic cells cannot influence the germline, thereby preventing the inheritance of acquired characteristics and directing evolutionary change through germline variations alone.^[4] In animals, germline specification typically occurs during early embryogenesis via inductive signaling, such as bone morphogenetic proteins (BMPs) in mammals, leading to the formation of primordial germ cells (PGCs) that migrate to the developing gonads.^[2] This process involves epigenetic remodeling, including DNA demethylation, to erase parental imprints and prepare cells for totipotency in the next generation.^[2] Germline mutations, alterations in DNA occurring in germ cells, are heritable and present in every cell of an individual's offspring, contrasting with somatic mutations that affect only the carrier and are not passed on.^[5] These mutations serve as the primary source of genetic variation driving natural selection and evolutionary adaptation, as they alone can propagate through populations.^[6] In humans, germline mutations underlie inherited disorders such as cystic fibrosis or Huntington's disease when pathogenic, but they also contribute to species resilience by introducing beneficial diversity.^[7] Contemporary research into germline editing, using tools like CRISPR-Cas9, raises profound ethical questions about altering heritable genomes to prevent diseases, though such interventions remain controversial and regulated due to risks of unintended evolutionary impacts.^[8]

Fundamentals

Definition and Characteristics

The germline refers to the continuous lineage of cells in sexually reproducing organisms that gives rise to gametes, such as sperm and ova, thereby ensuring the vertical transmission of genetic material across generations.^[9] This lineage originates from primordial germ cells (PGCs) and is distinct in its role as the sole conduit for heritable genetic information, contrasting with somatic cells that support organismal function but do not contribute to offspring.^[1] The concept of the germline was first articulated by August Weismann in his 1892 work Das Keimplasma, where he described the "germ plasm" as an immortal substance confined to reproductive cells, separate from the mortal soma.^[10] Key characteristics of germline cells include their initial diploid state, which undergoes meiosis to produce haploid gametes capable of fertilization.^[11] Early germline cells maintain genomic fidelity through mechanisms that shield them from somatic influences, such as environmental stressors or epigenetic modifications in body tissues, thereby preserving the integrity of hereditary information.^[12] This protection is essential for evolutionary stability, as alterations in the germline can propagate to future generations, unlike somatic changes that are confined to the individual.^[13] In humans, PGCs emerge around week 2 of embryonic development and actively migrate to the developing gonads between weeks 3 and 5, where they proliferate and differentiate into gamete precursors.^[14] In the model organism Caenorhabditis elegans, the germline is specified through inductive signals from surrounding somatic cells, mediated by pathways like GLP-1/Notch, which promote stem cell maintenance in the distal gonad.^[11] These examples illustrate the conserved yet diverse strategies for establishing and safeguarding the germline across species.

Distinction from Somatic Cells

Somatic cells constitute all non-reproductive cells in the body that do not contribute to the formation of offspring, serving instead to support the organism's structure, function, and maintenance.^[4] Unlike germline cells, which form the heritable lineage through gametes, somatic cells undergo repeated mitotic divisions to proliferate and differentiate into specialized tissues but do not participate in meiosis, the reductive division essential for gamete production.^[15] This fundamental separation ensures that somatic cells are dedicated to the individual's phenotype rather than intergenerational transmission. The distinction between germline and somatic cells is epitomized by the Weismann barrier, a conceptual and mechanistic isolation that prevents genetic changes in somatic cells from influencing the germline.^[4] Proposed by August Weismann, this barrier maintains a unidirectional flow of genetic information from germline to soma during development, while blocking reverse transmission, thereby protecting hereditary material from somatic alterations.^[16] As a result, somatic mutations, which accumulate due to environmental exposures or errors in mitosis, remain confined to the affected individual and are not passed to descendants.^[17] Functionally, germline cells prioritize genetic stability and totipotency—the capacity to give rise to an entire organism—through mechanisms that minimize mutation rates, which are nearly two orders of magnitude lower than in somatic cells.^[17] In contrast, somatic cells emphasize organismal viability and adaptability, rendering them expendable as they support immediate physiological needs without concern for long-term heritability.^[4] This dichotomy underscores the germline's role in evolutionary continuity. For instance, somatic mutations driving cancer development, such as those in tumor suppressor genes, are not inherited by offspring, whereas germline variants like pathogenic mutations in BRCA1 confer hereditary risks, increasing lifetime breast cancer incidence to 55-72% in carriers.^[18]

Development and Specification

Embryonic Origins in Animals

In animal embryos, the germline originates through one of two primary specification mechanisms: preformation or induction. Preformation involves the inheritance of maternally deposited cytoplasmic determinants, known as germ plasm, which autonomously direct cells toward the primordial germ cell (PGC) fate. In Drosophila melanogaster, this process occurs at the posterior pole of the oocyte, where electron-dense structures called polar granules within the germ plasm specify pole cells as PGCs during early embryogenesis.^[19] These granules, first described ultrastructurally, contain RNA and proteins that repress somatic gene expression and promote germline identity.^[20] In contrast, induction specifies PGCs through extrinsic signaling from neighboring tissues, predominant in vertebrates. In mice, bone morphogenetic protein (BMP) signaling from the extraembryonic ectoderm induces PGC fate in proximal epiblast cells around embryonic day 6.25 (E6.25), coinciding with gastrulation. This pathway activates key transcription factors, including BLIMP1 (encoded by Prdm1) and PRDM14, which repress somatic programs and initiate epigenetic reprogramming for pluripotency erasure. In humans, PGC specification similarly arises from the epiblast during gastrulation, approximately 2-3 weeks post-fertilization, with BLIMP1 and PRDM14 expression marking the onset of germline commitment.^[21] Following specification, PGCs migrate to the developing gonads. In mammals, PGCs emerge near the base of the allantois, traverse the hindgut endoderm, and travel through the dorsal mesentery to reach the genital ridges by around E10.5 in mice or 5-6 weeks in humans.^[22] This directed migration is guided by the chemokine stromal cell-derived factor 1 (SDF-1, also known as CXCL12) and its receptor CXCR4, establishing a gradient from the genital ridges that attracts PGCs while preventing ectopic colonization.^[23] Upon arriving at the genital ridges, PGCs undergo sexual differentiation influenced by the gonadal soma. In XY embryos, they become prospermatogonia, entering a quiescent G0/G1 mitotic arrest to preserve the germline genome until birth.^[24] In XX embryos, they differentiate into oogonia, which proliferate mitotically before initiating meiosis around E13.5 in mice, forming nests that support oogenesis. This bifurcation ensures sex-specific gametogenesis while maintaining germline isolation from somatic lineages.

Germline Formation in Plants

In plants, unlike animals where the germline is segregated early in embryogenesis, there is no dedicated germline lineage; instead, the germline emerges late during post-embryonic development from somatic cells that retain totipotency throughout the plant's life cycle.^[25] This totipotency allows any somatic cell, particularly those in the floral meristems, to reprogram into reproductive lineages, enabling remarkable developmental plasticity.^[25] The formation process involves epigenetic reprogramming, including hypomethylation of transposable elements during reproductive development, primarily in gamete companion cells and mediated by the DNA demethylase DEMETER (DME), which targets approximately 10,000 loci to regulate gene expression and imprinting during germline development.^[26] Female germline specification occurs in the megaspore mother cell (MMC), a hypodermal cell in the ovule primordium, while male specification takes place in the microspore mother cell (also called pollen mother cell or PMC) within the anther's sporogenous tissue.^[25] Key stages commence with the floral transition, orchestrated by ABC model genes such as APETALA1 (AP1), which integrate environmental and endogenous signals to establish floral meristem identity and initiate reproductive organ formation. This is followed by meiosis in the sporogenous tissue: the MMC undergoes meiosis to produce a linear tetrad of megaspores, with only the chalazal-most one typically developing into the functional megaspore, whereas the PMC produces a tetrahedral tetrad of microspores.^[25] In Arabidopsis thaliana, a model angiosperm, germline precursors in the anthers and ovules originate from subepidermal somatic cells in the floral meristem and undergo asymmetric periclinal divisions to establish the reproductive lineage, without any cell migration.^[25] For example, in the male pathway, archesporial cells in the anther's L2 layer divide asymmetrically to yield a larger inner cell that becomes the primary sporogenous cell and eventually the PMC, while the smaller outer cell contributes to the somatic anther wall.^[27] Similarly, in the female pathway, a single somatic cell differentiates into the MMC, which then executes asymmetric meiotic divisions to form the embryo sac precursor.^[25]

Evolutionary Role

Weismann's Germ Plasm Theory

August Weismann, a German biologist, proposed the germ plasm theory in the late 1880s as a foundational explanation for heredity and evolution, positing that the germ plasm—a hypothetical, continuous, and immortal substance within germ cells—serves as the sole carrier of hereditary information across generations.^[10] This theory emphasized a strict separation between the germ plasm, which remains unaltered and is passed intact from parent to offspring, and the somatoplasm of somatic cells, which undergoes changes during an organism's lifetime but does not influence heredity.^[4] Weismann's ideas, detailed in his 1893 book The Germ-Plasm: A Theory of Heredity, directly refuted Lamarckian inheritance by arguing that acquired characteristics in the soma cannot be transmitted to the germline, thereby ensuring the stability of species traits while allowing for evolutionary change through variations in the germ plasm itself.^[10] To support his theory, Weismann conducted a notable experiment in the 1880s involving white mice, in which he surgically removed the tails of 68 individuals across five generations (later extended to 22 generations by his students), observing that the offspring consistently produced full-length tails without any progressive shortening.^[28] This outcome provided empirical evidence against the inheritance of acquired traits, as the somatic modification (tail amputation) failed to alter the germ plasm, reinforcing the unidirectional flow of hereditary information from germ to soma.^[29] Weismann interpreted these results as confirmation that the germ plasm is isolated from environmental influences on the body, acting as an unchanging repository of genetic determinants.^[10] Theoretically, Weismann's framework laid early groundwork for the central dogma of molecular biology by establishing that hereditary information flows unidirectionally from the germline to somatic development, without reverse transmission from soma to germ.^[4] This isolation mechanism explained how evolutionary adaptations could accumulate without diluting the hereditary material, influencing later neo-Darwinian synthesis by prioritizing random variations in the germ plasm over directed somatic changes.^[28] While Weismann's theory faced initial criticisms for its speculative nature and lack of direct observation of the germ plasm, modern refinements acknowledge its core principle of germline-soma separation but incorporate epigenetic mechanisms that allow limited soma-to-germline influences under specific conditions, without undermining the overall barrier to acquired trait inheritance.^[30] Contemporary genetics retains the theory's emphasis on the germline's primacy in heredity, viewing the germ plasm concept as an prescient analog to DNA continuity.^[4]

Impact on Heritable Variation

The exclusivity of the germline as the conduit for heritable genetic changes underpins Darwinian evolution by ensuring that only variations arising in germ cells—such as point mutations, insertions, deletions, and structural rearrangements—can be transmitted to subsequent generations and subjected to natural selection.^[31] In contrast, somatic mutations, which occur in non-reproductive tissues, influence only the individual organism and do not contribute to evolutionary adaptation across populations.^[31] This separation, formalized in Weismann's germ plasm theory, channels evolutionary progress through germline-derived alleles that enhance fitness, such as those conferring resistance to environmental pressures.^[31] Processes within the germline, particularly during meiosis, introduce and shuffle genetic variation while imposing bottlenecks that constrain its scope. Meiotic recombination breaks linkage disequilibrium and generates novel allele combinations, promoting adaptive diversity, whereas random fertilization merges haploid gametes to restore diploidy, though this reduces effective population size and can amplify genetic drift.^[32] In sexual organisms, these mechanisms counteract Muller's ratchet—the irreversible accumulation of deleterious mutations in asexual lineages—by enabling the purging of harmful variants through recombination, thus maintaining long-term evolutionary viability compared to asexual reproduction.^[33] For instance, in bdelloid rotifers, evidence of historical recombination suggests partial evasion of ratchet effects despite apparent asexuality.^[33] Over evolutionary timescales, the high fidelity of germline replication preserves beneficial adaptations by minimizing erroneous transmission, with DNA maintenance mechanisms evolved to keep mutation rates low and sustain genetic stability across generations.^[34] According to the neutral theory of molecular evolution, most germline mutations are selectively neutral and fixate at a rate equal to the mutation rate itself, as proposed by Kimura; in humans, this germline mutation rate is approximately 1.2 × 10^{-8} per nucleotide site per generation, providing a steady supply of variation without overwhelming adaptive signals.^[35] However, rare instances of horizontal gene transfer in eukaryotes, such as gene acquisition from bacteria or fungi into plant or animal germlines, introduce exogenous material that can accelerate adaptation and occasionally disrupt strict vertical inheritance patterns.^[36]

Genetic Integrity

DNA Damage and Repair Processes

DNA damage in the germline arises from both endogenous and exogenous sources, posing a unique risk due to the potential for heritable transmission to offspring. Endogenous damage includes replication errors, such as base mismatches and insertions/deletions, which occur at rates of approximately 10^{-8} per base pair per generation after proofreading and mismatch repair, as well as spontaneous deamination of bases like cytosine to uracil and oxidative lesions from reactive oxygen species (ROS), generating approximately 10,000 base lesions per cell per day (or ~400 per hour) and 2,300 single-strand breaks per cell per hour. Exogenous damage encompasses ionizing radiation inducing double-strand breaks and base lesions like 8-oxoguanine, ultraviolet (UV) radiation forming cyclobutane pyrimidine dimers, and chemical adducts from environmental agents such as tobacco smoke. Unlike somatic cells, unrepaired germline damage can propagate mutations across generations, amplifying evolutionary pressures for robust protective mechanisms. Several DNA repair pathways safeguard germline integrity by addressing specific damage types. Base excision repair (BER) targets oxidative lesions, such as 8-oxoguanine, through enzymes like OGG1 for base removal and PARP-1 for processing abasic sites, replacing 1–10 nucleotides to restore sequence fidelity. Nucleotide excision repair (NER) excises bulky UV-induced adducts, including cyclobutane pyrimidine dimers, via proteins like XPC for damage recognition and TFIIH for unwinding, operating through global genome or transcription-coupled subpathways. For double-strand breaks prevalent during meiosis, homologous recombination (HR) predominates as an error-free mechanism, utilizing sister chromatids as templates with key players like RAD51 and BRCA2 to facilitate strand invasion and repair. Germline cells exhibit specialized adaptations to enhance repair efficiency and prevent transmission of damaged DNA. Checkpoint kinases ATM and ATR activate upon double-strand breaks or replication stress, phosphorylating targets like H2AX to halt cell cycle progression—such as in meiotic prophase—until repair completes, with ATM particularly crucial in oocytes via the MRN complex. Oocytes maintain robust antioxidant systems, including superoxide dismutases (SOD), glutathione peroxidase (GSH-Px), and reduced glutathione (GSH), to mitigate ROS-induced damage and preserve ovarian reserve. These mechanisms contribute to a germline mutation rate of approximately 1.2 × 10^{-8} per nucleotide per generation in humans, over an order of magnitude lower than somatic rates (around 2.8 × 10^{-7} per base pair), underscoring their role in genomic stability.

Mutations and Their Transmission

Germline mutations encompass a range of genetic alterations that occur in the DNA sequence of germ cells and can be transmitted to offspring, serving as a primary source of heritable variation. These mutations are classified into several types, including point mutations, which involve the substitution of a single nucleotide base; insertions and deletions (indels), which add or remove small segments of DNA; and copy number variations (CNVs), which result in duplications or deletions of larger genomic regions affecting multiple genes.^[37]^[38]^[39] Point mutations and indels typically arise at rates of approximately 1-2 × 10^{-8} per base pair per generation in humans, while CNVs occur less frequently but impact more bases on average.^[37] Germline mutations are further distinguished as de novo, which originate anew in the parental germline or early embryonic stages and are not present in the parents' somatic cells, or inherited, which are passed down from one or both parents through successive generations.^[40]^[39] De novo mutations account for a significant portion of severe early-onset disorders, contributing to conditions like autism spectrum disorder and intellectual disability.^[40] The transmission of germline mutations follows principles of Mendelian inheritance, where during meiosis, homologous chromosomes segregate independently, ensuring that each allele has an equal probability of being passed to gametes.^[41] This segregation results in a 50% chance of transmitting a heterozygous mutation to offspring, assuming no distortion in meiotic processes.^[42] However, linkage disequilibrium—the non-random association of alleles at nearby loci—can influence the inheritance of haplotypes, causing certain mutations to be transmitted together more frequently than expected by chance, particularly in regions of low recombination.^[37] Failures in DNA repair mechanisms during gametogenesis can increase the incidence of these mutations, though the focus here is on their downstream transmission patterns.^[40] Detection of germline mutations, especially de novo variants, relies on whole-genome sequencing of family trios consisting of parents and offspring, where variants absent in both parents but present in the child are identified as de novo through high-coverage reads and probabilistic modeling.^[43]^[44] Tools like PhaseByTransmission enhance accuracy by phasing variants and filtering false positives, achieving detection rates for single nucleotide variants and short indels with over 95% precision in pedigrees.^[43] Paternity confirmation, essential to distinguish true de novo mutations from inherited ones, often employs single nucleotide polymorphisms (SNPs) analyzed via targeted genotyping or sequencing, providing robust statistical exclusion probabilities exceeding 99.99% in trio analyses.^[45]^[46] Clinically, germline mutations underlie numerous hereditary diseases, with notable examples including cystic fibrosis caused by variants in the CFTR gene, which disrupts chloride transport and affects approximately 1 in 2,500 to 3,500 newborns in populations of European descent.^[47] Another key instance is Lynch syndrome, resulting from pathogenic variants in DNA mismatch repair genes such as MLH1, MSH2, MSH6, and PMS2, predisposing individuals to colorectal and other cancers with a population prevalence of about 1 in 279 for carriers of these mutations.^[48]^[49] Overall, de novo and inherited germline mutations contribute to severe monogenic disorders with an estimated birth prevalence of 1 in 213 to 448, highlighting their role in pediatric and adult morbidity.^[50]

Epigenetic Dynamics

Inheritance of Epigenetic Marks

Epigenetic marks in the germline, including DNA methylation, histone modifications such as H3K4me3, and non-coding RNAs, play crucial roles in transmitting regulatory information to offspring without altering the underlying DNA sequence.^[14] During primordial germ cell (PGC) development, a profound epigenetic reprogramming occurs, characterized by waves of erasure that reset most somatic epigenetic marks to establish totipotency.^[51] Specifically, global DNA demethylation in mouse PGCs begins around embryonic day 8.5 and peaks by embryonic day 13.5, reducing methylation levels to below 10% across the genome, while histone modifications like H3K9me2 are also broadly erased.^[52] Non-coding RNAs, particularly piRNAs, contribute to this process by guiding silencing machinery to target repetitive elements, preventing their mobilization during reprogramming.^[53] Genomic imprinting represents a key exception to this widespread erasure, involving parent-of-origin-specific DNA methylation patterns that are established in the germline and maintained through generations.^[54] For instance, at the IGF2/H19 locus on mouse chromosome 7 (human chromosome 11), the paternal allele is methylated at the imprinting control region (ICR), allowing IGF2 expression and repressing H19, while the maternal allele shows the opposite pattern, leading to monoallelic expression in offspring.^[55] Mammals possess over 100 such imprinted genes, clustered in regions like 11p15 in humans, where these marks ensure differential expression critical for embryonic growth and development.^[54] These imprints are protected from PGC erasure and re-established during gametogenesis, with paternal imprints set in prospermatogonia and maternal ones in growing oocytes.^[56] The maintenance of these epigenetic marks during DNA replication relies on specialized enzymes, particularly DNA methyltransferases (DNMTs). DNMT1, in complex with UHRF1, recognizes hemi-methylated DNA at replication forks and methylates the newly synthesized strand, preserving patterns like those in imprinted loci across cell divisions in the germline.^[57] This mechanism ensures faithful transmission, resulting in consistent monoallelic expression of genes such as IGF2 in progeny somatic cells.^[55] Histone modifications and non-coding RNAs are similarly propagated, with H3K4me3 marks recruited by reader proteins during replication to maintain active chromatin states at specific promoters.^[14] Despite extensive reprogramming, certain marks persist or are selectively retained, particularly those silencing retrotransposons to safeguard genomic integrity. In the male germline, DNA methylation at young retrotransposons like LINE1 elements is re-established post-PGC erasure, preventing their transcription and integration during spermatogenesis.^[58] PiRNAs further reinforce this silencing by directing DNA methylation and histone repression (e.g., H3K9me3) to transposon clusters, with these marks partially escaping early embryonic demethylation waves.^[59] In the preimplantation embryo, while global DNA demethylation occurs, imprinted and retrotransposon-silencing marks are partially protected, allowing their transmission to the next generation.^[56]

Transgenerational Epigenetic Effects

Transgenerational epigenetic effects refer to environmentally induced changes in the germline epigenome that persist and influence phenotypes across multiple generations, bypassing traditional DNA sequence alterations. These effects primarily involve modifications to epigenetic marks, such as DNA methylation and histone modifications, which can be transmitted through gametes despite partial reprogramming in the germline. In animals, such inheritance challenges the classical view of epigenetic marks being erased between generations, allowing acquired traits to potentially affect descendants.^[60] Key mechanisms include paramutation-like processes mediated by small RNAs, such as piwi-interacting RNAs (piRNAs) and small interfering RNAs (siRNAs), which can enter the germline and induce heritable gene silencing. In C. elegans, these small RNAs travel from somatic tissues to the germline, directing DNA methylation or histone modifications that maintain silencing for several generations, exemplifying RNA-directed epigenetic inheritance. A prominent example is the exposure of pregnant rats to the fungicide vinclozolin during gonadal development, which induces differential DNA methylation regions (DMRs) in sperm; these epimutations persist in the F3 generation and beyond, leading to increased rates of reproductive diseases and altered sperm motility in male descendants. However, the reproducibility of these vinclozolin effects has been debated, with some studies failing to replicate findings in different strains and criticisms regarding statistical analyses.^[61]^[62]^[63]^[64]^[65] This demonstrates how environmental toxins can reprogram the germline epigenome, resulting in transgenerational disease susceptibility. Evidence in humans and mammalian models supports these mechanisms, with the Dutch Hunger Winter famine of 1944–1945 providing a historical case where prenatal exposure to malnutrition altered DNA methylation at growth-related genes, such as IGF2, in offspring, correlating with increased risks of metabolic disorders like obesity and schizophrenia decades later. Similarly, in the agouti viable yellow (A<sup>vy</sup>) mouse model, maternal dietary supplementation with methyl donors like folic acid during pregnancy hypermethylates the intracisternal A particle (IAP) retrotransposon promoter upstream of the agouti gene, reducing ectopic expression and preventing transgenerational obesity and yellow coat color in progeny; without such intervention, hypomethylation leads to heritable metabolic dysfunction. These cases highlight how nutritional environments can impose lasting epigenetic changes on the germline, influencing offspring health.^[66]^[67]^[68]^[69] Distinguishing true transgenerational effects from intergenerational parental influences remains a significant challenge, as germline reprogramming in mammals—occurring in primordial germ cells and early embryos—typically erases most epigenetic marks, potentially confounding direct transmission with indirect phenotypic carryover. For instance, while vinclozolin effects span three or more generations in rats, critics argue that incomplete reprogramming or behavioral factors may amplify rather than transmit marks directly, necessitating rigorous controls like in vitro fertilization to isolate germline-specific changes. Recent advances post-2020, including studies on RNA-mediated epigenetic inheritance in C. elegans, have provided mechanistic insights into multi-generational stability of silencing, with heritable marks contributing to gene repression across generations.^[60]^[70]^[71]^[72]^[73] These findings fuel debates on a potential Lamarckian revival, where acquired environmental adaptations could influence evolution, though many researchers caution against overinterpreting such effects as adaptive or truly Lamarckian, emphasizing their rarity in vertebrates due to reprogramming barriers.^[74]

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SNPs are useful as supplementary markers in paternity cases, especially when STR results are ambiguous, providing decisive genetic information.
[45]
Improving the rigor of mutation reports: Biologic parentage and de ...
There are a number of ways this can be accomplished. In most cases, paternity can be readily confirmed using 5–10 STRP markers. If extensive SNP data already ...
[46]
Pathogenic germline variants in cancer predisposition genes in ...
Our study suggests that CFTR and SPINK1 are potential cancer predisposition genes. Extended panel genetic testing improved PGV detection rates.
[47]
Lynch syndrome, molecular mechanisms and variant classification
Nov 24, 2022 · Lynch syndrome (LS) is a hereditary cancer predisposition disease, caused by germline variants that impair the DNA mismatch repair (MMR) system ...
[48]
Prevalence and Penetrance of Major Genes and Polygenes for ... - NIH
We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1= 1 in 1946, MSH2= 1 in 2841, MSH6= 1 in 758, PMS2= 1 in 714), 1 in ...
[49]
Prevalence and architecture of de novo mutations in developmental ...
We estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448, depending on parental age.
[50]
Cellular dynamics associated with the genome-wide epigenetic ...
Jul 15, 2007 · We previously reported that primordial germ cells (PGCs) in mice erase genome-wide DNA methylation and histone H3 lysine9 dimethylation ...
[51]
Mechanisms of epigenetic inheritance of variable traits through the ...
Here, we focus on the molecular mechanisms most commonly studied in the field of epigenetics which are DNA methylation, chromatin and small non-coding RNAs.Transgene Induced Heritable... · Plant Epialleles And The... · Memory Of Germline Gene...<|control11|><|separator|>
[52]
Mammalian Genomic Imprinting - PMC - PubMed Central - NIH
Approximately 100 imprinted genes have been reported in mammals thus far. Imprinted genes are controlled by cis-acting regulatory elements, termed imprinting ...
[53]
Epigenetic regulation of the Igf2/H19 gene cluster - PMC - NIH
Igf2 (insulin‐like growth factor 2) and H19 genes are imprinted in mammals; they are expressed unevenly from the two parental alleles.
[54]
DNA methylation dynamics during epigenetic reprogramming in the ...
DNA methylation poses a fundamental epigenetic barrier that guides and restricts differentiation and prevents regression into an undifferentiated state.
[55]
Linking DNA Methyltransferases (DNMTs) to Epigenetic Marks and ...
DNMT1 is traditionally referred to as the maintenance enzyme, copying methylation after replication, while DNMT3A/DNMT3B are de novo enzymes that establish ...Missing: germline | Show results with:germline
[56]
DNA methylation at retrotransposons protects the germline by ...
Aug 4, 2025 · Silencing evolutionary young retrotransposons by cytosine DNA methylation is essential for spermatogenesis, as failure to methylate their ...
[57]
mechanisms of retrotransposon suppression in the mouse germline
Germ cells have evolved genome defense mechanisms to suppress retrotransposon activity, which are mutagenic elements, and maintain genome stability.
[58]
Transgenerational Epigenetic Inheritance: myths and mechanisms
Silencing can be maintained into the F1 for multiple generations (F1–F5) or can become epi-allelic with multigenerational, nonstochastic inheritance. Silencing ...
[59]
Principles of Transgenerational Small RNA Inheritance in ...
Jul 24, 2017 · In this review, we discuss the path that small RNAs take from the soma to the germline, and elaborate on the mechanisms that maintain or erase parental small ...
[60]
Small RNAs mediate transgenerational inheritance of genome-wide ...
Feb 9, 2022 · Here, we report that hybridization between the inbred parents B73 and Mo17 induces trans-acting hypermethylation and hypomethylation at thousands of loci.
[61]
Vinclozolin induced epigenetic transgenerational inheritance of ...
Aug 29, 2018 · In rats, ancestral vinclozolin exposure has resulted in transgenerational increases in testis disease and associated decreases in sperm ...
[62]
Epigenetic Transgenerational Actions of Vinclozolin on Promoter ...
This study confirms that an environmental agent has the ability to induce epigenetic transgenerational changes in the sperm epigenome.
[63]
The association between prenatal famine, DNA methylation and ...
Sep 16, 2023 · Prenatal famine exposure is associated with an increased risk of mental disorders and DNA methylation changes.
[64]
Early gestation as the critical time-window for changes in the ...
Abstract. Background: The manipulation of pregnancy diets in animals can lead to changes in DNA methylation with phenotypic consequences in the offspring.
[65]
The agouti mouse model: an epigenetic biosensor for nutritional and ...
The work summarized here utilizes the A vy mouse model as an epigenetic biosensor to characterize nutritional and environmental factors affecting epigenetic ...
[66]
Diet‐induced hypermethylation at agouti viable yellow is not ...
Jun 5, 2007 · The Avy mouse remains a promising mammalian system in which to study transgenerational inheritance of environmentally induced epigenetic ...
[67]
what is mammalian transgenerational epigenetic inheritance?
A major challenge to the existence of TEI in mammals are the two distinct epigenetic reprogramming events: in primordial germ cells and in the early developing ...
[68]
Caenorhabditis Elegans as a Model for Environmental Epigenetics
Jan 20, 2025 · This article describes how Caenorhabditis elegans can fill this gap, serving as a useful model for the discovery of molecular epigenetic mechanisms that are ...
[69]
Epigenetic Echoes: Bridging Nature, Nurture, and Healing Across ...
In mammals, germline reprogramming resets histone modifications, making stable transgenerational inheritance less likely compared to model organisms like C.
[70]
From Environmental Epigenetics to the Inheritance of Acquired Traits
Jul 5, 2023 · The description of epigenetic inheritance as a Lamarckian process is incorrect from a historical point of view and useless at a scientific level.