Hasan Khatib

Sexual selection theory provides a unifying framework for understanding how cognitive traits, reproductive strategies, and molecular mechanisms coevolve to maximize fitness. Across species, evidence shows that cognitive performance predicts reproductive success through both male–male competition and female mate choice, with individuals displaying superior problem-solving, social dominance, or courtship skills achieving greater mating success. Sexual selection also favors alternative strategies, including sexual mimicry and socially induced sex change, which allow individuals to navigate competitive mating environments and optimize reproductive output. At a mechanistic level, the close evolutionary coupling of cognition and reproduction is reflected in shared cellular, molecular, and genetic architectures between the brain and reproductive tissues, particularly sperm. Conserved genes and pathways involved in signaling, metabolism, epigenetic regulation, and stress responses link neural function to gamete performance across species. We hypothesized that natural selection on cognitive or reproductive traits drives coordinated evolution of shared genetic and molecular pathways between the brain and reproductive tissues, resulting in conserved mechanisms that support both behavioral and fertilization success. To test this hypothesis, we investigated the extent to which the brain and reproductive tissues share conserved genes and molecular pathways, and whether these shared mechanisms provide evidence for coordinated evolution between cognitive and reproductive functions.

Background/Objectives: Parental environmental factors can shape developmental outcomes through epigenetic mechanisms that regulate gene expression. While maternal dietary effects on offspring epigenetics have been well characterized, the impact of paternal diet on embryonic DNA methylation remains poorly understood. Here, we investigated the effect of paternal methionine supplementation on DNA methylation patterns in preimplantation embryos in Polypay sheep. Methods: Four yearling rams (two control and two methionine-supplemented) were bred to twelve ewes following estrus synchronization and superovulation. Embryos were collected after natural mating and analyzed using whole-genome bisulfite sequencing (WGBS). Results: A total of 842 differentially methylated cytosines (DMCs) were identified in embryos derived from methionine-supplemented sires compared to controls, with 835 hypermethylated and 7 hypomethylated. The majority of DMCs were located in intergenic regions, with minimal representation in exonic regions. To assess overlap between parental dietary effects, DMCs identified in this study were compared with those previously reported in embryos derived from methionine-supplemented dams. Eight hypermethylated DMCs were shared between the two datasets, while no hypomethylated DMCs overlapped. To evaluate the functional relevance of differentially methylated genes, we performed siRNA-mediated knockdown of SSU72, a gene associated with multiple DMCs. Knockdown of SSU72 resulted in an average 18% decrease in blastocyst formation rate (p < 0.001). Conclusions: These results demonstrate that paternal methionine supplementation alters embryonic DNA methylation patterns and that affected genes may play critical roles in early embryonic development, contributing to fetal programming.

Evolutionary success in mammals requires coordinated regulation of cognitive functions and reproductive capacity. Such coordination must involve shared genes and molecular pathways between the brain and germ cells, yet direct evidence linking cognition to reproduction across species remains limited. Here, proteomic and transcriptomic analyses were performed experimentally in Ovis aries and Rattus norvegicus, while transcriptomic datasets from Mus musculus, Macaca mulatta, and Homo sapiens were analyzed in silico. We identified 8,464 protein-coding genes shared between the brain and sperm/testis and conserved across five species. In rats, 8,444 of these genes were also shared between the brain and the ovary. Functional annotation classified 3,890 genes as associated with both neurological and reproductive functions, and 1,752 as uncharacterized in these contexts, highlighting candidates for future studies on reproductive and neurological disorders. These findings reveal a deeply conserved genetic network linking neurological and reproductive systems, underscoring the evolutionary interplay that supports mammalian fitness.

Neural tube closure relies on tightly coordinated morphogenetic programs integrating convergent extension, apical constriction of the neuroepithelium, and precise cell-cell interactions across germ layers. Disruption of these processes results in myelomeningocele, a severe complex congenital defect with lifelong multisystem consequences whose genetic and epigenetic determinants remain poorly defined. Using a sheep population with naturally occurring myelomeningocele, we quantified substantial heritability (0.42–0.68) and generated the first integrated multi-omics, multi-tissue atlas of this condition in any mammalian species. Genetic, transcriptomic, and whole-genome DNA methylation profiling across ectoderm- and mesoderm-derived tissues revealed shared and lineage-specific perturbations converging on cell-adhesion, cytoskeletal, migratory, inflammatory, and folate-responsive pathways. Chromosome 24 emerged as a multi-omics hotspot enriched for differentially expressed genes, differentially methylated regions, and candidate regulatory loci of GWAS signals, overlapping with human neurological and embryonic development trajectories. Cross-tissue network analyses highlighted coordinated disruption of neurulation-critical gene modules, establishing sheep as a robust translational model for mechanistic dissection of neural tube defect biology.

Epigenetic mechanisms profoundly regulate gene expression, developmental trajectories, and phenotypic variation, extending biological influence beyond DNA sequence alone. A growing body of evidence suggests that environmental exposures, including pollutants, drugs, stress, and diet, can induce germline and early embryonic epimutations that alter developmental programs with lasting consequences for neurodevelopmental and cognitive outcomes. However, the fields most relevant to these processes have largely developed independently. These include germline epigenetics, early embryonic patterning, neurodevelopment and cognitive regulation, and intergenerational or transgenerational inheritance. Each field has its own conceptual frameworks and mechanistic models. This fragmentation obscures the biological reality that these systems are tightly interconnected: environmentally induced epigenetic perturbations in gametes can reshape the epigenetic landscape of the early embryo, influence lineage allocation during gastrulation, and ultimately modify the molecular architecture of the developing central nervous system. A systems–biology perspective capable of linking germline epimutations and early embryonic epigenetic instability to later neurodevelopmental and cognitive phenotypes and their potential inheritance is therefore required. This review synthesizes current evidence across these traditionally isolated domains and proposes a coherent mechanistic framework linking germ cell epimutations and early embryonic epigenetic instability to the emergence of neurodevelopmental and cognitive phenotypes. By bridging these conceptual gaps, we aim to establish a cohesive foundation for understanding how early epigenetic disruptions generate long-lasting and in some cases heritable effects on brain development and cognitive function.

The recent rise in global food insecurity has renewed scientific interest in understanding the long-term health consequences of early-life nutritional deprivation. This study critically evaluates the experimental designs and methodological approaches of key publications examining the epigenetic and phenotypic effects of the Dutch and Chinese famines. Specifically, these studies were assessed for sample size, control group selection, relevance of tissue sampling, timing of famine exposure, and the quality of statistical reporting. Research on both famines has centered on prenatal exposure and subsequent health outcomes, providing important insights into how in utero nutritional deprivation may lead to long-lasting epigenetic modifications. These changes have been linked to elevated risks for metabolic, cardiovascular, and neuropsychiatric disorders. Despite these contributions, many studies exhibited notable limitations, including small sample sizes, questionable accuracy in reporting health outcomes, and issues with the selection of control groups. Such methodological shortcomings may have led to the misinterpretation of some findings. Ongoing and recent famines in regions such as Sudan, Somalia, and Gaza—driven by conflict and environmental disasters, including droughts and floods—represent some of the most pressing humanitarian crises of our time. Lessons from studies of the 20th-century Dutch and Chinese famines can inform the design of future research on the biological and intergenerational consequences of famine and trauma. Improved study designs will enhance the ability to generate reliable evidence and guide global health strategies for populations at risk of transgenerational effects from nutritional deprivation.

Epigenetic reprogramming during gametogenesis and early embryogenesis involves genome-wide erasure and re-establishment of DNA methylation, ensuring developmental plasticity. However, specific genomic regions, such as imprinted loci and transposable elements, can escape this reprogramming, allowing environmentally induced epigenetic marks to persist and potentially transmit across generations. This review summarizes current advances in intergenerational and transgenerational epigenetic inheritance in mammals, with emphasis on nutritional influences. Seminal studies from the Dutch famine cohorts and the viable yellow agouti (Avy) mouse model established that maternal diet could remodel the epigenome and induce long-term phenotypic effects. Extending these findings to livestock, our recent studies demonstrate that both maternal and paternal methionine supplementation alter DNA methylation and influence growth and fertility traits in sheep. Notably, some epigenetic marks and phenotypic effects persist through the F4 generation, providing rare evidence of stable transgenerational epigenetic inheritance in a mammalian livestock model. These findings highlight nutrition as a powerful modulator of the germline and embryonic epigenome. Understanding how dietary factors shape heritable epigenetic variation offers new opportunities to improve animal health, fertility, and productivity, while providing fundamental insights into the mechanisms and evolutionary relevance of epigenetic inheritance in mammals.

Environmental factors can influence gene expression and developmental outcomes through epigenetic modifications. Although maternal diet influences offspring DNA methylation and phenotypes, its effects on the oocyte and the resulting embryonic epigenome remain poorly understood. Here, we investigated the effect of maternal methionine supplementation on DNA methylation patterns in oocytes and embryos in Polypay sheep. Whole-genome bisulfite sequencing (WGBS) was performed on oocytes collected from 16 twin ewe pairs (8 methionine-treated and 8 controls). These ewes were later bred to control rams, and embryos were flushed for WGBS as well. In oocytes, 2,056 differentially methylated cytosines (DMCs) were identified. Additionally, 17 mitochondrial DMCs were identified, with 12 hypermethylated and 5 hypomethylated. In embryos, 113 DMCs were identified. Mitochondrial DNA analysis revealed 22 hypermethylated DMCs. To assess the inheritance of methyl marks, we compared DMCs between oocytes and embryos. While no direct overlaps were found in nuclear DNA, 3 CpGs exhibited opposite methylation trends - hypomethylated in oocytes but hypermethylated in embryos. In contrast, 5 mitochondrial DMCs overlapped between oocytes and embryos. To functionally assess the role of differentially methylated genes, we performed siRNA-mediated knockdown of 2 embryo DMC-associated genes: SCRIB and CERS3. Knockdown of SCRIB led to a 16.4% average decrease in blastocyst formation rate (p = 0.001), while CERS3 knockdown resulted in a 9.5% decrease (p = 0.005). These results demonstrate that maternal methionine supplementation alters nuclear and mitochondrial DNA methylation in oocytes and embryos, and that affected genes may play critical roles in early embryonic development, contributing to fetal programming.

The recent rise in global food insecurity has renewed scientific interest in understanding the long-term health consequences of early-life nutritional deprivation. This study critically evaluates the experimental designs and methodological approaches of key publications examining the epigenetic and phenotypic effects of the Dutch and Chinese famines. Specifically, these studies were assessed for sample size, control group selection, relevance of tissue sampling, timing of famine exposure, and the quality of statistical reporting. Research on both famines has centered on prenatal exposure and subsequent health outcomes, providing important insights into how in utero nutritional deprivation may lead to long-lasting epigenetic modifications. These changes have been linked to elevated risks for metabolic, cardiovascular, and neuropsychiatric disorders. Despite these contributions, many studies exhibited notable limitations, including small sample sizes, questionable accuracy in reporting health outcomes, and issues with the selection of control groups. Such methodological shortcomings may have led to misinterpretation of some findings. Ongoing and recent famines in regions such as Sudan, Somalia, and Gaza—driven by conflict and environmental disasters, including droughts and floods—represent some of the most pressing humanitarian crises of our time. Lessons learned from studies of the 20th century Dutch and Chinese famines can inform the design of future research on the biological and intergenerational consequences of famine and trauma. Improved study designs will enhance the ability to generate reliable evidence and guide global health strategies for populations at risk of transgenerational effects from nutritional deprivation.