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INTRODUCTION: Prodromal Parkinson's disease (PD) carriers of dual leucine-rich repeat kinase 2 (LRRK2) and glucosylceramidase ß (GBA) variants are rare, and their biomarkers are less well developed. OBJECTIVE: This study aimed to investigate the biomarkers for diagnosing the prodromal phase of LRRK2-GBA-PD (LRRK2-GBA-prodromal). METHODS: We assessed the clinical and whole-brain white matter microstructural characteristics of 54 prodromal PD carriers of dual LRRK2 (100% M239T) and GBA (95% N409S) variants, along with 76 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort. RESULTS: By analyzing the four values of 100 nodes on 20 fiber bundles, totaling 8000 data points, we identified the smallest p value in the fractional anisotropy (FA) value of the 38th segment of left corticospinal tract (L-CST) with differences between LRRK2-GBA-prodromal and HCs (p = 8.94 × 10-9). The FA value of the 38th node of the L-CST was significantly lower in LRRK2-GBA-prodromal (FA value, 0.65) compared with HCs (FA value, 0.71). The receiver-operating characteristic curve showed a cut-off value of 0.218 for the FA value of L-CST, providing sufficient sensitivity (79.2%) and specificity (72.2%) to distinguish double mutation prodromal PD from the healthy population. CONCLUSION: L-CST, especially the 38th node, may potentially serve as a biomarker for distinguishing individuals with double mutation prodromal PD from the healthy population.
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Biomarcadores , Glucosilceramidasa , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Mutación , Enfermedad de Parkinson , Síntomas Prodrómicos , Tractos Piramidales , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/diagnóstico por imagen , Masculino , Femenino , Persona de Mediana Edad , Anciano , Tractos Piramidales/diagnóstico por imagen , Tractos Piramidales/patología , Glucosilceramidasa/genética , Imagen de Difusión Tensora/métodos , Estudios de Cohortes , Lateralidad Funcional/genéticaRESUMEN
Twin studies suggest that additive genetic effects account for about a quarter of the variance in handedness. Recently, Schijven et al. used exome-wide sequencing to provide evidence for a role of rare protein-coding variants in handedness. These included the gene encoding beta-tubulin, TUBB4B, suggesting that microtubules are relevant for handedness ontogenesis.
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Lateralidad Funcional , Tubulina (Proteína) , Tubulina (Proteína)/genética , Humanos , Lateralidad Funcional/genética , Variación Genética , Microtúbulos/genéticaRESUMEN
BACKGROUND: The mechanisms determining the laterality and the rotation direction of hair whorls are unknown. Here we report observations on twins investigating the genetic bases of whorl pattern formation. Knowing that vortex phenomena may depend on geographic effects, we also provide comparative data on whorls from children born in the Northern hemisphere (France) versus children born in the Southern hemisphere (Chile). MATERIAL AND METHODS: We retrospectively included children from three populations: (1) Northern hemisphere general population, (2) Southern hemisphere general population, and (3) same-sex Northern hemisphere twins. We recorded whorl rotation direction (clockwise, counterclockwise), whorl position (left, right, central) and twinning type. Univariate logistic models were used to screen for associations between rotation direction and whorl position. For twins, the variable of interest was binary, i.e. same rotation direction (reference class) or opposite directions for each twin pair. For controls, all single combinations were included as virtual twins, and compared to real twins. Odds ratios (OR) were compared for both hemispheres, for real twins and virtual (control) twins. RESULTS: Seventy-four (37 pairs) twins and 50 children from the general population of each hemisphere were included. The OR for opposite rotation directions between two twins was ≠1 (p = 0.017), meaning that whorls rotated preferentially in the same direction in twins. ORs were <1 for Northern and Southern hemispheres, meaning that whorls rotated preferentially in the same direction in simulated twins. OR for the Northern hemisphere (0.04 [0.03; 0.05]) was less than the OR for the Southern hemisphere (0.28 [0.24; 0.32]) with no confidence interval superimposition, indicating than counterclockwise whorls were more frequent in the Southern hemisphere (p < 0.001). CONCLUSIONS: We suggest that hair whorl formation is a genetically determined developmental process that can be influenced by extrinsic environmental factors. Our results furthermore underline the general importance of studies focused on limit phenomena that can provide insights on general developmental mechanisms. We plead for large-scale epidemiological assessments of hair whorls in several Northern and Southern hemisphere populations to confirm these surprising findings suggesting significant modulations of craniofacial development by geographic effects.
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Determinismo Genético , Cabello , Niño , Humanos , Francia , Lateralidad Funcional/genética , Estudios RetrospectivosRESUMEN
Handedness is a core phenotype in clinical laterality research and several different disorders such as schizophrenia and autism spectrum disorders have been linked to a higher prevalence of non-right-handedness. Moreover, subclinical personality traits like schizotypy have been linked to a higher prevalence of non-right-handedness. The association with handedness is poorly understood for generalized anxiety disorder and specific phobias, as well as for state and trait anxiety and fear of specific stimuli in nonclinical samples. Therefore, we performed a narrative review of studies investigating handedness in anxiety disorders patients and studies that compared anxiety scores between different handedness groups. Unlike schizophrenia and autism spectrum disorders, there seems to be no strong association between anxiety disorders and handedness in adult patients, except for specific phobias. Studies often had small sample sizes and therefore a high risk to report spurious findings. Similar findings were reported in most non-clinical studies. Importantly, familial handedness affects phobia risk and antenatal maternal anxiety increased the probability of mixed-handedness. This suggests that a transgenerational, developmental perspective is essential to better understand the complex interrelations between handedness and anxiety. Familial and especially maternal handedness and anxiety disorders should be integrated into future studies on handedness and anxiety whenever possible.
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Lateralidad Funcional , Trastorno de la Personalidad Esquizotípica , Adulto , Humanos , Femenino , Embarazo , Lateralidad Funcional/genética , Trastorno de la Personalidad Esquizotípica/epidemiología , Encuestas y Cuestionarios , Trastornos de Ansiedad/epidemiología , AnsiedadRESUMEN
In studies of singletons, a range of early-life characteristics have been reported to be associated with handedness, but some of these associations have failed to replicate. We examined associations between 23 early life characteristics with handedness in a large sample of 37,495 5-year-old twins. We considered three definitions of handedness: left-handedness (LH), mixed-handedness (MH), and non-right-handedness (NRH). Our main aim was to test whether the associations with sex, birth weight, gestational age, and season of birth - as reported in singletons - replicate in twins, and to examine twin-specific variables, including zygosity, chorionicity, birth order, and intertwin delivery time. Compared to previously published data from adults born as singletons (7.23%), the prevalence of NRH was higher in both twins (16.19%) and their parents (15.09%). In the twins, LH and NRH were associated with parents' LH. Male sex and lower gestational age were associated with NRH, and LH was associated with not being breastfed. MH was related to neurodevelopmental delays and higher externalizing problems later in childhood. Other previously reported associations were not replicated, and no twin-specific characteristics were related to handedness. These results emphasize the importance of considering multiple definitions of handedness and indicate a small number of replicated associations across studies.
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Lateralidad Funcional , Gemelos , Adulto , Femenino , Humanos , Masculino , Lateralidad Funcional/genética , Gemelos/genética , Peso al Nacer , Edad Gestacional , PadresRESUMEN
The temporo-basal region of the human brain is composed of the collateral, the occipito-temporal, and the rhinal sulci. We manually rated (using a novel protocol) the connections between rhinal/collateral (RS-CS), collateral/occipito-temporal (CS-OTS) and rhinal/occipito-temporal (RS-OTS) sulci, using the MRI of nearly 3400 individuals including around 1000 twins. We reported both the associations between sulcal polymorphisms as well with a wide range of demographics (e.g. age, sex, handedness). Finally, we also estimated the heritability, and the genetic correlation between sulcal connections. We reported the frequency of the sulcal connections in the general population, which were hemisphere dependent. We found a sexual dimorphism of the connections, especially marked in the right hemisphere, with a CS-OTS connection more frequent in females (approximately 35-40% versus 20-25% in males) and an RS-CS connection more common in males (approximately 40-45% versus 25-30% in females). We confirmed associations between sulcal connections and characteristics of incomplete hippocampal inversion (IHI). We estimated the broad sense heritability to be 0.28-0.45 for RS-CS and CS-OTS connections, with hints of dominant contribution for the RS-CS connection. The connections appeared to share some of their genetic causing factors as indicated by strong genetic correlations. Heritability appeared much smaller for the (rarer) RS-OTS connection.
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Caracteres Sexuales , Lóbulo Temporal , Masculino , Femenino , Humanos , Lóbulo Temporal/diagnóstico por imagen , Imagen por Resonancia Magnética , Hipocampo , Lateralidad Funcional/genéticaRESUMEN
INTRODUCTION: Handedness is a conspicuous characteristic in human behavior, with a worldwide proportion of approximately 90% of people preferring to use the right hand for many tasks. In the Korean population, the proportion of left-handedness is relatively low at approximately 7%-10%, similar to that in other East-Asian cultures in which the use of the left hand for writing and other public activities has historically been oppressed. METHODS: In this study, we conducted two genome-wide association studies (GWASs) between right-handedness and left-handedness, and between right-handedness and ambidexterity using logistic regression analyses using a Korean community-based cohort. We also performed association analyses with previously reported variants and our findings. RESULTS: A total of 8806 participants were included for analysis, and the results identified 28 left-handedness-associated and 15 ambidexterity-associated loci; of these, two left-handedness loci (NEIL3 [rs11726465] and SVOPL [rs117495448]) and one ambidexterity locus (PDE8B/WDR41 [rs118077080]) showed near genome-wide significance. Association analyses with previously reported variants replicated ANKS1B (rs7132513) in left-handedness and ANKIB1 (rs2040498) in ambidexterity. CONCLUSION: The variants and positional candidate genes identified and replicated in this study were largely associated with brain development, cerebral asymmetry, neurological processes, and neuropsychiatric diseases in line with previous findings. As the first East-Asian GWAS related to handedness, these results may provide an intriguing reference for further human neurologic research in the future.
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Lateralidad Funcional , Estudio de Asociación del Genoma Completo , Humanos , Lateralidad Funcional/genética , Pueblo Asiatico/genética , Pueblos del Este de Asia , República de CoreaRESUMEN
Reared-apart twin studies are a powerful means for identifying the relative contributions of heredity and environment to variation in human physical and behavioural traits. One such characteristic is handedness, for which it has long been noted that approximately 20% of twin pairs are comprised of one right-handed cotwin and one left-handed cotwin. Reared-together twin studies suggest a slightly greater concordance in monozygotic (MZT) than dizygotic (DZT) twins, implying that genetics influences hand preference. We report here two studies of handedness in reared-apart twins. Study 1 synthesizes the available data and estimates that at least N = 560 same-sex reared-apart twin pairs (for which zygosity is known with reasonable confidence) have been identified. Of these, handedness data are available for both members of n = 415 pairs. We observed similar levels of concordance/discordance for reared-apart monozygotic (MZA) and dizygotic (DZA) twins. However, although direction of handedness (right or left) has frequently been examined, strength of handedness (strong or weak) has not. Study 2 examined strength of hand preference and relative hand skill, as well as right- and left-hand speed, information available for participants in the Minnesota Study of Twins Reared Apart (MISTRA). We provide evidence of heritability for right-hand and left-hand speed. We also found hand preference strength was more alike than chance in DZA, but not MZA, twins. Findings are discussed in relation to genetic and environmental influences on human handedness.
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Lateralidad Funcional , Gemelos Monocigóticos , Humanos , Gemelos Monocigóticos/genética , Lateralidad Funcional/genética , Gemelos Dicigóticos/genética , Procesos MentalesRESUMEN
The evolution of human right-handedness has been intensively debated for decades. Manual lateralization patterns in non-human primates have the potential to elucidate evolutionary determinants of human handedness, but restricted species samples and inconsistent methodologies have so far limited comparative phylogenetic studies. By combining original data with published literature reports, we assembled data on hand preferences for standardized object manipulation in 1786 individuals from 38 species of anthropoid primates, including monkeys, apes, and humans. Based on that, we employ quantitative phylogenetic methods to test prevalent hypotheses on the roles of ecology, brain size, and tool use in primate handedness evolution. We confirm that human right-handedness represents an unparalleled extreme among anthropoids and found taxa displaying population-level handedness to be rare. Species-level direction of manual lateralization was largely uniform among non-human primates and did not strongly correlate with any of the selected biological predictors, nor with phylogeny. In contrast, we recovered highly variable patterns of hand preference strength, which show signatures of both ecology and phylogeny. In particular, terrestrial primates tend to display weaker hand preferences than arboreal species. These results challenge popular ideas on primate handedness evolution, including the postural origins hypothesis. Furthermore, they point to a potential adaptive benefit of disparate lateralization strength in primates, a measure of hand preference that has often been overlooked in the past. Finally, our data show that human lateralization patterns do not align with trends found among other anthropoids, suggesting that unique selective pressures gave rise to the unusual hand preferences of our species.
About 90% of humans are right-handed. While it is known that handedness is caused by certain brain regions that are specialized in one of the two hemispheres, it is not clear how this evolved or why right-handedness dominates. Several hypotheses have been proposed to explain this extreme preference, including the use of tools, the larger size of the human brain, and the fact that humans live primarily on the ground. Many researchers have regarded the extreme population-wide preference for using the right hand as being uniquely human. However, handedness had not been studied in a standardized manner across a wide range of primates. To fill this gap in our knowledge and understand how handedness may have evolved in monkeys and apes, Caspar et al. used existing data and new experimental observations to create a large dataset of hand preference. This dataset illustrates how approximately 1800 primates across 38 species retrieve mashed food from a tube (or pieces of paper in the case of humans). Similar to humans, some species of monkey only had small proportions of ambidextrous individuals. However, no species had an extreme preference for using one specific hand the way humans do. Interestingly, Caspar et al. found that the presence of tool use as well as brain size were not associated with the degree of handedness in species. However, ground-living primates tended to show weaker individual preferences for a specific hand than tree-living species, with humans being a notable exception to the trend. These findings confirm that humans do exhibit exceptional right-handedness, being unique among primates. While the results cannot explain the cause of this behaviour, they do help to rule out some of the theories that aim to explain how this preference evolved. This will be of interest to researchers studying the origins of human behaviour as well as the emergence of asymmetries in the brain.
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Ecología , Primates , Animales , Humanos , Filogenia , Lateralidad Funcional/genética , HaplorrinosRESUMEN
Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1737), we observed moderately stable associations across age (correlation range [0.355-0.578]), but inconsistent across tissues (correlation range [- 0.384 to 0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.
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Metilación de ADN , Mucosa Bucal , Adulto , Niño , Islas de CpG , Lateralidad Funcional/genética , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
Handedness is the most commonly investigated lateralised phenotype and is usually measured as a binary left/right category. Its links with psychiatric and neurodevelopmental disorders prompted studies aimed at understanding the underlying genetics, while other measures and side preferences have been less studied. We investigated the heritability of hand, as well as foot, and eye preference by assessing parental effects (n ≤ 5028 family trios) and SNP-based heritability (SNP-h2, n ≤ 5931 children) in the Avon Longitudinal Study of Parents and Children (ALSPAC). An independent twin cohort from Hong Kong (n = 358) was used to replicate results from structural equation modelling (SEM). Parental left-side preference increased the chance of an individual to be left-sided for the same trait, with stronger maternal than paternal effects for footedness. By regressing out the effects of sex, age, and ancestry, we transformed laterality categories into quantitative measures. The SNP-h2 for quantitative handedness and footedness was 0.21 and 0.23, respectively, which is higher than the SNP-h2 reported in larger genetic studies using binary handedness measures. The heritability of the quantitative measure of handedness increased (0.45) compared to a binary measure for writing hand (0.27) in the Hong Kong twins. Genomic and behavioural SEM identified a shared genetic factor contributing to handedness, footedness, and eyedness, but no independent effects on individual phenotypes. Our analysis demonstrates how quantitative multidimensional laterality phenotypes are better suited to capture the underlying genetics than binary traits.
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Pie , Lateralidad Funcional , Niño , Lateralidad Funcional/genética , Humanos , Estudios Longitudinales , Fenotipo , Gemelos/genéticaRESUMEN
BACKGROUND: In the general population, 10.6% of people favor their left hand over the right for motor tasks. Previous research suggests higher prevalence of atypical (left-, mixed-, or non-right-) handedness in (i) twins compared to singletons, and in (ii) monozygotic compared to dizygotic twins. Moreover, (iii) studies have shown a higher rate of handedness concordance in monozygotic compared to dizygotic twins, in line with genetic factors playing a role for handedness. METHODS: By means of a systematic review, we identified 59 studies from previous literature and performed three sets of random effects meta-analyses on (i) twin-to-singleton Odds Ratios (21 studies, n = 189,422 individuals) and (ii) monozygotic-to-dizygotic twin Odds Ratios (48 studies, n = 63,295 individuals), both times for prevalence of left-, mixed-, and non-right-handedness. For monozygotic and dizygotic twin pairs we compared (iii) handedness concordance Odds Ratios (44 studies, n = 36,217 twin pairs). We also tested for potential effects of moderating variables, such as sex, age, the method used to assess handedness, and the twins' zygosity. RESULTS: We found (i) evidence for higher prevalence of left- (Odds Ratio = 1.40, 95% Confidence Interval = [1.26, 1.57]) and non-right- (Odds Ratio = 1.36, 95% Confidence Interval = [1.22, 1.52]), but not mixed-handedness (Odds Ratio = 1.08, 95% Confidence Interval = [0.52, 2.27]) among twins compared to singletons. We further showed a decrease in Odds Ratios in more recent studies (post-1975: Odds Ratio = 1.30, 95% Confidence Interval = [1.17, 1.45]) compared to earlier studies (pre-1975: Odds Ratio = 1.90, 95% Confidence Interval = [1.59-2.27]). While there was (ii) no difference between monozygotic and dizygotic twins regarding prevalence of left- (Odds Ratio = 0.98, 95% Confidence Interval = [0.89, 1.07]), mixed- (Odds Ratio = 0.96, 95% Confidence Interval = [0.46, 1.99]), or non-right-handedness (Odds Ratio = 1.01, 95% Confidence Interval = [0.91, 1.12]), we found that (iii) handedness concordance was elevated among monozygotic compared to dizygotic twin pairs (Odds Ratio = 1.11, 95% Confidence Interval = [1.06, 1.18]). By means of moderator analyses, we did not find evidence for effects of potentially confounding variables. CONCLUSION: We provide the largest and most comprehensive meta-analysis on handedness in twins. Although a raw, unadjusted analysis found a higher prevalence of left- and non-right-, but not mixed-handedness among twins compared to singletons, left-handedness was substantially more prevalent in earlier than in more recent studies. The single large, recent study which included birth weight, Apgar score and gestational age as covariates found no twin-singleton difference in handedness rate, but these covariates could not be included in the present meta-analysis. Together, the secular shift and the influence of covariates probably make it unsafe to conclude that twinning has a genuine relationship to handedness.
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Lateralidad Funcional , Gemelos Dicigóticos , Peso al Nacer , Lateralidad Funcional/genética , Humanos , Prevalencia , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genéticaRESUMEN
BACKGROUND: The functional significance and mechanisms determining the development and individual variability of structural brain asymmetry remain unclear. Here, we systematically analyzed all relevant components of the most prominent structural asymmetry, brain torque (BT), and their relationships with potential genetic and nongenetic modifiers in a sample comprising 24,112 individuals from six cohorts. METHODS: BT features, including petalia, bending, dorsoventral shift, brain tissue distribution asymmetries, and cortical surface positional asymmetries, were directly modeled using a set of automatic three-dimensional brain shape analysis approaches. Age-, sex-, and handedness-related effects on BT were assessed. The genetic architecture and phenomic associations of BT were investigated using genome- and phenome-wide association scans. RESULTS: Our results confirmed the population-level predominance of the typical counterclockwise torque and suggested a first attenuating, then enlarging dynamic across the life span (3-81 years) primarily for frontal, occipital, and perisylvian BT features. Sex/handedness, BT, and cognitive function of verbal-numerical reasoning were found to be interrelated statistically. We observed differential heritability of up to 56% for BT, especially in temporal language areas. Individual variations of BT were also associated with various phenotypic variables of neuroanatomy, cognition, lifestyle, sociodemographics, anthropometry, physical health, and adult and child mental health. Our genomic analyses identified a number of genetic associations at lenient significance levels, which need to be further validated using larger samples in the future. CONCLUSIONS: This study provides a comprehensive description of BT and insights into biological and other factors that may contribute to the development and individual variations of BT.
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Imagen por Resonancia Magnética , Fenómica , Adulto , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Niño , Lateralidad Funcional/genética , Humanos , TorqueRESUMEN
Handedness is the most widely investigated motor preference in humans. The genetics of handedness and especially the link between genetic variation, brain structure, and right-left preference have not been investigated in detail. Recently, several well-powered genome-wide association studies (GWAS) on handedness have been published, significantly advancing the understanding of the genetic determinants of left and right-handedness. In the present study, we estimated polygenic scores (PGS) of handedness-based on the GWAS by de Kovel and Francks (Sci Rep 9: 5986, 2019) in an independent validation cohort (n = 296). PGS reflect the sum effect of trait-associated alleles across many genetic loci. For the first time, we could show that these GWAS-based PGS are significantly associated with individual handedness lateralization quotients in an independent validation cohort. Additionally, we investigated whether handedness-derived polygenic scores are associated with asymmetries in gray matter macrostructure across the whole brain determined using magnetic resonance imaging. None of these associations reached significance after correction for multiple comparisons. Our results implicate that PGS obtained from large-scale handedness GWAS are significantly associated with individual handedness in smaller validation samples with more detailed phenotypic assessment.
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Lateralidad Funcional , Estudio de Asociación del Genoma Completo , Encéfalo/diagnóstico por imagen , Lateralidad Funcional/genética , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We resampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers compared to right-handers showed average differences of surface area asymmetry within the fusiform cortex, the anterior insula, the anterior middle cingulate cortex, and the precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2, and NME7-mutations in the latter can cause left to right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and the inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas nonheritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.
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Corteza Cerebral/fisiología , Lateralidad Funcional/genética , Lateralidad Funcional/fisiología , Anciano , Anciano de 80 o más Años , Conducta/fisiología , Bancos de Muestras Biológicas , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Mapeo Encefálico , Corteza Cerebral/diagnóstico por imagen , Femenino , Mano , Humanos , Lenguaje , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Lóbulo Occipital , Corteza SensoriomotoraRESUMEN
Proper left-right symmetry breaking is essential for animal development, and in many cases, this process is actomyosin-dependent. In Caenorhabditis elegans embryos active torque generation in the actomyosin layer promotes left-right symmetry breaking by driving chiral counterrotating cortical flows. While both Formins and Myosins have been implicated in left-right symmetry breaking and both can rotate actin filaments in vitro, it remains unclear whether active torques in the actomyosin cortex are generated by Formins, Myosins, or both. We combined the strength of C. elegans genetics with quantitative imaging and thin film, chiral active fluid theory to show that, while Non-Muscle Myosin II activity drives cortical actomyosin flows, it is permissive for chiral counterrotation and dispensable for chiral symmetry breaking of cortical flows. Instead, we find that CYK-1/Formin activation in RhoA foci is instructive for chiral counterrotation and promotes in-plane, active torque generation in the actomyosin cortex. Notably, we observe that artificially generated large active RhoA patches undergo rotations with consistent handedness in a CYK-1/Formin-dependent manner. Altogether, we conclude that CYK-1/Formin-dependent active torque generation facilitates chiral symmetry breaking of actomyosin flows and drives organismal left-right symmetry breaking in the nematode worm.
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Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Corteza Cerebral/metabolismo , Forminas/metabolismo , Transducción de Señal/fisiología , Proteína de Unión al GTP rhoA/metabolismo , Actomiosina/genética , Actomiosina/metabolismo , Animales , Animales Modificados Genéticamente , Blastómeros/citología , Blastómeros/metabolismo , Tipificación del Cuerpo/genética , Caenorhabditis elegans/embriología , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Corteza Cerebral/embriología , Embrión no Mamífero/citología , Embrión no Mamífero/embriología , Embrión no Mamífero/metabolismo , Forminas/genética , Lateralidad Funcional/genética , Lateralidad Funcional/fisiología , Transducción de Señal/genética , Torque , Proteína de Unión al GTP rhoA/genéticaRESUMEN
The human cerebral hemispheres show a left-right asymmetrical torque pattern, which has been claimed to be absent in chimpanzees. The functional significance and developmental mechanisms are unknown. Here, we carried out the largest-ever analysis of global brain shape asymmetry in magnetic resonance imaging data. Three population datasets were used, UK Biobank (N = 39 678), Human Connectome Project (N = 1113), and BIL&GIN (N = 453). At the population level, there was an anterior and dorsal skew of the right hemisphere, relative to the left. Both skews were associated independently with handedness, and various regional gray and white matter metrics oppositely in the two hemispheres, as well as other variables related to cognitive functions, sociodemographic factors, and physical and mental health. The two skews showed single nucleotide polymorphisms-based heritabilities of 4-13%, but also substantial polygenicity in causal mixture model analysis, and no individually significant loci were found in genome-wide association studies for either skew. There was evidence for a significant genetic correlation between horizontal brain skew and autism, which requires future replication. These results provide the first large-scale description of population-average brain skews and their inter-individual variations, their replicable associations with handedness, and insights into biological and other factors which associate with human brain asymmetry.
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Encéfalo/fisiología , Lateralidad Funcional/genética , Genómica/métodos , Adulto , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Femenino , Lateralidad Funcional/fisiología , Genotipo , Sustancia Gris/diagnóstico por imagen , Estado de Salud , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Factores Sociodemográficos , Sustancia Blanca/diagnóstico por imagenRESUMEN
Considering genetic influence on brain structure and function, including motor control, we report a case of right-handed monozygotic twins with atypical organization of fine motor movement control that might imply genetic influence. Structural and functional organization of the twins' motor function was assessed using transcranial magnetic stimulation (TMS), fMRI with a motor-task paradigm, and diffusion tensor imaging (DTI) tractography. TMS revealed that both twins presented the same unexpected activation and inhibition of both motor cortices during volitional unilateral fine hand movement. The right ipsilateral corticospinal tract was weaker than the left contralateral one. The motor-task fMRI identified activation in the left primary motor cortex and bilateral secondary motor areas during right-hand (dominant) movement and activation in the bilateral primary motor cortex and secondary motor areas during left-hand movement. Based on DTI tractography, both twins showed a significantly lower streamline count (number of fibers) in the right corticospinal tract compared with a control group, which was not the case for the left corticospinal tract. Neither twin reported any difficulty in conducting fine motor movements during their activities of daily living. The combination of TMS and advanced neuroimaging techniques identified an atypical motor control organization that might be influenced by genetic factors. This combination emphasizes that activation of the unilateral uncrossed pyramidal tract represents an alternative scheme to a "failure" of building a standard pattern but may not necessarily lead to disability.
Asunto(s)
Lateralidad Funcional/genética , Neuroimagen/métodos , Neurofisiología/métodos , Adulto , Humanos , Masculino , Gemelos MonocigóticosRESUMEN
Non-shared environmental variance (NSEV) accounts for 76% of variance in genetic modelling of handedness. However, it is very misleading to suggest that NSEV, "highlights the importance of non-genetic factors for the ontogenesis of hemispheric asymmetries". NSEV is poorly named, is calculated only by subtraction, and provides no direct evidence for environmental effects in the sense of the external environment. Miller suggested that it would be better named as "residual effect". Mitchell has suggested that much or indeed most of NSEV is "developmental variance" and should be included under the heading of nature rather than nurture, and in handedness, "largely reflect[s] the outcome of randomness in brain development". Overall only a very small proportion of NSEV in handedness is likely to be related to external environmental factors in the usual sense of the term.