Imbalanced genomic imprinting in brain development: an evolutionary basis for the aetiology of autism

We describe a new hypothesis for the development of autism, that it is driven by imbalances in brain development involving enhanced effects of paternally expressed imprinted genes, deficits of effects from maternally expressed genes, or both. This hypothesis is supported by: (1) the strong genomic-imprinting component to the genetic and developmental mechanisms of autism, Angelman syndrome, Rett syndrome and Turner syndrome; (2) the core behavioural features of autism, such as self-focused behaviour, altered social interactions and language, and enhanced spatial and mechanistic cognition and abilities, and (3) the degree to which relevant brain functions and structures are altered in autism and related disorders. The imprinted brain theory of autism has important implications for understanding the genetic, epigenetic, neurological and cognitive bases of autism, as ultimately due to imbalances in the outcomes of intragenomic conflict between effects of maternally vs. paternally expressed genes.     

Genome-wide quantitative trait locus association scan of general cognitive ability using pooled DNA and 500K single nucleotide polymorphism microarrays

General cognitive ability ( g ), which refers to what cognitive abilities have in common, is an important target for molecular genetic research because multivariate quantitative genetic analyses have shown that the same set of genes affects diverse cognitive abilities as well as learning disabilities. In this first autosomal genome-wide association scan of g , we used a two-stage quantitative trait locus (QTL) design with pooled DNA to screen more than 500 000 single nucleotide polymorphisms (SNPs) on microarrays, selecting from a sample of 7000 7-year-old children. In stage 1, we screened for allele frequency differences between groups pooled for low and high g . In stage 2, 47 SNPs nominated in stage 1 were tested by individually genotyping an independent sample of 3195 individuals, representative of the entire distribution of g scores in the full 7000 7-year-old children. Six SNPs yielded significant associations across the normal distribution of g , although only one SNP remained significant after a false discovery rate of 0.05 was imposed. However, none of these SNPs accounted for more than 0.4% of the variance of g , despite 95% power to detect associations of that size. It is likely that QTL effect sizes, even for highly heritable traits such as cognitive abilities and disabilities, are much smaller than previously assumed. Nonetheless, an aggregated 'SNP set' of the six SNPs correlated 0.11 ( P  < 0.00000003) with g . This shows that future SNP sets that will incorporate many more SNPs could be useful for predicting genetic risk and for investigating functional systems of effects from genes to brain to behavior.     

Human behavioural genetics of cognitive abilities and disabilities

Although neither the genome nor the environment can be manipulated in research on human behaviour, some of the new tools of molecular genetics can be brought to bear on human behavioural disorders (e.g. cognitive disabilities) and quantitative traits (e.g. cognitive abilities). The inability to manipulate the human genome experimentally has had the positive effect of focusing attention on naturally occuring genetic variation responsible for behavioural differences among individuals in all their complex multifactorial splendour. Genes in such complex multiple-gene systems are called quantitative trait loci (QTLs), which merge the two worlds of genetic research, quantitative genetics and molecular genetics. Although most genetic research on complex human behaviour has focused on severe mental disorders, cognitive abilities and disabilities may be even more immediately relevant to neuroscience. For example, verbal ability and spatial ability are two of the most heritable cognitive abilities, and reading disability is the first behavioural disability for which replicated QTL linkage has been found. The purpose of this essay is to provide an overview of the genetics of cognitive abilities and disabilities as an example of the impending merger of quantitative genetics and molecular genetics in QTL analysis of complex traits.     

Is the Capacity for Vocal Learning in Vertebrates Rooted in Fish Schooling Behavior?

The capacity to learn and reproduce vocal sounds has evolved in phylogenetically distant tetrapod lineages. Vocal learners in all these lineages express similar neural circuitry and genetic factors when perceiving, processing, and reproducing vocalization, suggesting that brain pathways for vocal learning evolved within strong constraints from a common ancestor, potentially fish. We hypothesize that the auditory-motor circuits and genes involved in entrainment have their origins in fish schooling behavior and respiratory-motor coupling. In this acoustic advantages hypothesis, aural costs and benefits played a key role in shaping a wide variety of traits, which could readily be exapted for entrainment and vocal learning, including social grouping, group movement, and respiratory-motor coupling. Specifically, incidental sounds of locomotion and respiration (ISLR) may have reinforced synchronization by communicating important spatial and temporal information between school-members and extending windows of silence to improve situational awareness. This process would be mutually reinforcing. Neurons in the telencephalon, which were initially involved in linking ISLR with forelimbs, could have switched functions to serve vocal machinery (e.g. mouth, beak, tongue, larynx, syrinx). While previous vocal learning hypotheses invoke transmission of neurons from visual tasks (gestures) to the auditory channel, this hypothesis involves the auditory channel from the onset. Acoustic benefits of locomotor-respiratory coordination in fish may have selected for genetic factors and brain circuitry capable of synchronizing respiratory and limb movements, predisposing tetrapod lines to synchronized movement, vocalization, and vocal learning. We discuss how the capacity to entrain is manifest in fish, amphibians, birds, and mammals, and propose predictions to test our acoustic advantages hypothesis.     

Behavioral and anatomical consequences of early versus late symbol training in macaques

Distinct brain regions, reproducible from one person to the next, are specialized for processing different kinds of human expertise, such as face recognition?and reading. Here, we explore the relationship between age of learning, learning ability, and specialized brain structures. Specifically, we ask whether the existence of reproducible cortical domains necessarily means that certain abilities are innate, or innately easily learned, or whether reproducible domains can be formed, or refined, by interactions between genetic programs and common early experience. Functional MRI showed that intensive early, but not late, experience caused the formation of category-selective regions in macaque temporal lobe for stimuli never naturally encountered by monkeys. And behaviorally, early training produced more fluent processing of these stimuli than the same training in adults. One explanation for these results is that in higher cortical areas, as in early sensory areas, experience drives functional clustering and functional clustering determines how that information is processed.     

Adaptive evolution of four microcephaly genes and the evolution of brain size in anthropoid primates

The anatomical basis and adaptive function of the expansion in primate brain size have long been studied; however, we are only beginning to understand the genetic basis of these evolutionary changes. Genes linked to human primary microcephaly have received much attention as they have accelerated evolutionary rates along lineages leading to humans. However, these studies focus narrowly on apes, and the link between microcephaly gene evolution and brain evolution is disputed. We analyzed the molecular evolution of four genes associated with microcephaly (ASPM, CDK5RAP2, CENPJ, MCPH1) across 21 species representing all major clades of anthropoid primates. Contrary to prevailing assumptions, positive selection was not limited to or intensified along the lineage leading to humans. In fact we show that all four loci were subject to positive selection across the anthropoid primate phylogeny. We developed clearly defined hypotheses to explicitly test if selection on these loci was associated with the evolution of brain size. We found positive relationships between both CDK5RAP2 and ASPM and neonatal brain mass and somewhat weaker relationships between these genes and adult brain size. In contrast, there is no evidence linking CENPJ and MCPH1 to brain size evolution. The stronger association of ASPM and CDK5RAP2 evolution with neonatal brain size than with adult brain size is consistent with these loci having a direct effect on prenatal neuronal proliferation. These results suggest that primate brain size may have at least a partially conserved genetic basis. Our results contradict a previous study that linked adaptive evolution of ASPM to changes in relative cortex size; however, our analysis indicates that this conclusion is not robust. Our finding that the coding regions of two widely expressed loci has experienced pervasive positive selection in relation to a complex, quantitative developmental phenotype provides a notable counterexample to the commonly asserted hypothesis that cis-regulatory regions play a dominant role in phenotypic evolution.     

Genome‐wide screening for DNA variants associated with reading and language traits

Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome‐wide association scan (GWAS) meta‐analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading‐ and language‐related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10^–7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on‐going international efforts to identify genes contributing to reading and language skills.     

Numerical Capacities as Domain-Specific Predictors beyond Early Mathematics Learning: A Longitudinal Study

The first aim of the present study was to investigate whether numerical effects (Numerical Distance Effect, Counting Effect and Subitizing Effect) are domain-specific predictors of mathematics development at the end of elementary school by exploring whether they explain additional variance of later mathematics fluency after controlling for the effects of general cognitive skills, focused on nonnumerical aspects. The second aim was to address the same issues but applied to achievement in mathematics curriculum that requires solutions to fluency in calculation. These analyses assess whether the relationship found for fluency are generalized to mathematics content beyond fluency in calculation. As a third aim, the domain specificity of the numerical effects was examined by analyzing whether they contribute to the development of reading skills, such as decoding fluency and reading comprehension, after controlling for general cognitive skills and phonological processing. Basic numerical capacities were evaluated in children of 3^rd and 4^th grades (n=49). Mathematics and reading achievements were assessed in these children one year later. Results showed that the size of the Subitizing Effect was a significant domain-specific predictor of fluency in calculation and also in curricular mathematics achievement, but not in reading skills, assessed at the end of elementary school. Furthermore, the size of the Counting Effect also predicted fluency in calculation, although this association only approached significance. These findings contrast with proposals that the core numerical competencies measured by enumeration will bear little relationship to mathematics achievement. We conclude that basic numerical capacities constitute domain-specific predictors and that they are not exclusively “start-up” tools for the acquisition of Mathematics; but they continue modulating this learning at the end of elementary school.     

注意缺陷多动障碍共患阅读障碍：认知-脑-基因的多维度研究进展

注意缺陷多动障碍（Attention-Deficit/Hyperactivity Disorder, ADHD）和发展性阅读障碍（Developmental Dyslexia, DD）是两种常见的神经发育性障碍,二者共患的比率高达25%～48%。本文拟从认知-脑-基因等多个维度对ADHD共患DD的研究进展进行综述。ADHD和DD共患的共同认知损害可能是加工速度缺陷,其作为内表型能够很好的帮助解释遗传因素如何通过影响认知功能进而导致出现ADHD共患DD的临床表型。而国内对ADHD共患DD的研究较少,已有的多项研究仅关注ADHD伴学习障碍,但缺乏标准的DD临床诊断标准。本文指出了统一诊断标准、结合多学科研究以及未来个体化训练的必要性。     

Cognitive abilities and language comprehension in preschool children with perinatal brain lesion

Perinatal brain lesion is a risk factor for development, making parents of such children particularly worried about consequences it may have on the child's cognitive and language development. Although literature findings on the outcome of perinatal brain lesion are inconsistent, most of the studies have found a positive general outcome, but also subtle deficits that affect the child's academic success. Since language comprehension and cognitive abilities influence learning abilities at school, we wanted to know how six-year olds who were selected based on pathological ultrasonographical findings (ischemic or hemorrhagic brain lesion) would perform on subtests of Wechsler battery (WISC) and language comprehension measures (Reynell Developmental Language Scale and Peabody Picture Vocabulary Test), compared with controls. The second issue we investigated was whether in children who suffered a perinatal brain lesion cognitive abilities predicted the level of language comprehension in the same way as in children without perinatal brain lesion. The relation between cognitive and linguistic abilities is still a controversial one, and a different relation would mean that these two groups of children have different structure of abilities probably due to perinatal brain lesion. Forty children who suffered a perinatal brain lesion and forty age-matched children without perinatal risk factors were examined. Our results showed that the groups differed more in linguistic than in cognitive variables. Also, the two groups showed different relation patterns between cognitive abilities and language comprehension. Cognitive abilities were statistically significantly associated with language comprehension in children who suffered a perinatal brain lesion, while this association was not statistically significant within the control group. Since a number of participants with perinatal brain lesion had language difficulties, it is presumed that they rely on cognitive abilities in order to overcome and compensate for language shortcomings.     

Generalist genes and cognitive neuroscience

Multivariate genetic research suggests that a single set of genes affects most cognitive abilities and disabilities. This finding already has far-reaching implications for cognitive neuroscience, and will become even more revealing when this - presumably large - set of generalist genes is identified. Similar to other complex disorders and dimensions, molecular genetic research on cognitive abilities and disabilities is adopting genome-wide association strategies. These strategies involve very large samples to detect DNA associations of small effect size using microarrays that simultaneously assess hundreds of thousands of DNA markers. When this set of generalist genes is identified, it can be used to provide solid footholds in the climb towards a systems-level understanding of how genetically driven brain processes work together to affect diverse cognitive abilities and disabilities.     

Nonrandom association of genetic markers in a sample of South African blacks

According to classical genetic theory, allelic genes at one locus are expected to segregate and be manifested independently of allelic genes at another locus. At the population level any significant deviation from this general hypothesis resulting from specific biologic and genetic effects can be recognized in the form of nonrandom associations between genetic markers. The present data, consisting of 24 genetic polymorphisms determined from a sample of 998 unselected and unrelated South African blacks, offers an opportunity to test whether or not any such nonrandom associations exist between the genetic markers. After appropriate statistical calculations on the population data, we found that 13 pairs of genetic polymorphisms demonstrate a nonrandom association (statistically significant). Because the results cannot be explained in terms of known biologic mechanisms, we conclude that the associations observed could be due to random statistical effects (repeated application of the chi-square test) and/or to real (as yet unknown) biologic phenomena in the population studied. This tentative conclusion can serve as a guideline for more specific investigations.     

The interaction between plant competition and disease

It is well documented that pathogens can affect the survival, reproduction, and growth of individual plants. Drawing together insights from diverse studies in ecology and agriculture, we evaluate the evidence for pathogens affecting competitive interactions between plants of both the same and different species. Our objective is to explore the potential ecological and evolutionary consequences of such interactions. First, we address how disease interacts with intraspecific competition and present a simple graphical model suggesting that diverse outcomes should be expected. We conclude that the presence of pathogens may have either large or minimal effects on population dynamics depending on many factors including the density-dependent compensatory ability of healthy plants and spatial patterns of infection. Second, we consider how disease can alter competitive abilities of genotypes, and thus may affect the genetic composition of populations. These genetic processes feed back on population dynamics given trade-offs between disease resistance and other fitness components. Third, we examine how the effect of disease on interspecific plant interactions may have potentially far-reaching effects on community composition. A host-specific pathogen, for example, may alter a competitive hierarchy that exists between host and non-host species. Generalist pathogens can also induce indirect competitive interactions between host species. We conclude by highlighting lacunae in our current understanding and suggest that future studies should (1) examine a broader taxonomic range of pathogens since work to date has largely focused on fungal pathogens; (2) increase the use of field competition studies; (3) follow interactions for multiple generations; (4) characterize density-dependent processes; and (5) quantify pathogen, as well as plant, population and community dynamics.     

Sex-Specific Effects of Diets High in Unsaturated Fatty Acids on Spatial Learning and Memory in Guinea Pigs

Unsaturated fatty acids (UFAs), including omega-3, omega-6 polyunsaturated and omega-9 monounsaturated fatty acids, are essential components and modulators of neuromembranes and may affect various aspects of physiology and cognition. UFAs are suggested to positively affect spatial learning and memory and also to diminish the negative consequences of physiological stress on cognitive abilities. Due to pronounced sex differences in neurophysiological functions, we hypothesize that these UFA-related effects might differ between male and female individuals. We therefore determined the effects of dietary UFAs on cognitive performances in a radial-Y-maze in male and female guinea pigs in relation to saliva cortisol concentrations, a marker for physiological stress. Animals were assigned to four treatment groups and maintained on diets enriched in either chia seeds (omega-3), walnuts (omega-6), or peanuts (omega-9), or a control diet. Female learning abilities throughout a three-day learning phase were positively affected by omega-3 and omega-9, as determined by a decreasing latency to pass the test and the number of conducted errors, while males generally showed distinct learning abilities, irrespective of the diet. A sex difference in learning performances was found in the control group, with males outperforming females, which was not detected in the UFA-supplemented groups. This was paralleled by significantly increased saliva cortisol concentrations in males throughout the cognition test compared to females. Three days after this learning phase, UFA-supplemented males and all females showed unchanged performances, while control males showed an increased latency and therefore an impaired performance. These results were corroborated by pronounced differences in the plasma UFA-status, corresponding to the different dietary treatments. Our findings indicate sex-specific effects of dietary UFAs, apparently enhancing spatial learning abilities only in females and protecting males from long-term memory impairment, while male learning abilities seem to be more strongly affected by an acute physiological stress response to the maze task.     

Imaging genetic influences in human brain function

The association between genes and brain function using functional brain imaging techniques is an emerging and promising area of research that will help to better characterize the influence of genes on cognition and behavior as well as the link between genetic susceptibility and neuropsychiatric disorders. Neurophysiological imaging provides information regarding the effect of genes on brain function at the level of information processing, and neurochemical imaging provides information on the intrinsic mechanisms on how these genes affect the brain response. In this review, we highlight recent studies that have begun to explore the influence of genetic mutations on brain function with these techniques. The results, even from these few studies, illustrate the potential of these techniques to provide a more sensitive assay than behavioral measures used alone. The results also show that neuroimaging techniques can elucidate the influence of genes on brain function in relatively small sample populations, sometimes even in the absence of significant differences in behavioral measures.     

Evaluation of visual motion perception ability in mice with knockout of the dyslexia candidate susceptibility gene Dcdc2

Developmental dyslexia is a heritable disability characterized by difficulties in learning to read and write. The neurobiological and genetic mechanisms underlying dyslexia remain poorly understood; however, several dyslexia candidate risk genes have been identified. One of these candidate risk genes—doublecortin domain containing 2 (DCDC2)—has been shown to play a role in neuronal migration and cilia function. At a behavioral level, variants of DCDC2 have been associated with impairments in phonological processing, working memory and reading speed. Additionally, a specific mutation in DCDC2 has been strongly linked to deficits in motion perception—a skill subserving reading abilities. To further explore the relationship between DCDC2 and dyslexia, a genetic knockout (KO) of the rodent homolog of DCDC2 (Dcdc2) was created. Initial studies showed that Dcdc2 KOs display deficits in auditory processing and working memory. The current study was designed to evaluate the association between DCDC2 and motion perception, as these skills have not yet been assessed in the Dcdc2 KO mouse model. We developed a novel motion perception task, utilizing touchscreen technology and operant conditioning. Dcdc2 KOs displayed deficits on the Pairwise Discrimination task specifically as motion was added to visual stimuli. Following behavioral assessment, brains were histologically prepared for neuroanatomical analysis of the lateral geniculate nucleus (LGN). The cumulative distribution showed that Dcdc2 KOs exhibited more small neurons and fewer larger neurons in the LGN. Results compliment findings that DCDC2 genetic alteration results in anomalies in visual motion pathways in a subpopulation of dyslexic patients.     

Alternative strategies in fungal race-specific parasitism

Summary Based on the gene-for-gene relation in race-specific resistance versus virulence, racial complexity of a pathogen population can be revealed by using host lines each with a single gene for resistance as detector. Such inventories of cereal rusts have shown: i. Genes for virulence may have pleiotropic effects acting on general fitness and their relative prevalence. ii. Genes for virulence are, as most other genes, dependent on genetic background for their general fitness. iii. Specific and general gene erosion in a pathogen population submitted to the assortative function of a race-specific host selection pressure is proportional to the degree of existing recombination and thus ultimately upon mode of reproduction (sexual or asexual). iv. Genetic storage capacity is dependent on ploidy constitution. v. Host alternation for safe annual survival favours a genetic system able to store temporarily unnecessary genes for virulence. — Due to shifting circumstances, pathogens like rusts will even inside the same forma specialis show different strategies. The trend may lead to a process of stabilizing selection and dependence on immediate and provisional flexibility just as typical of true haploids. It may lead to a pattern of preparedness: i.e. accumulation of unnecessary genes for virulence. In the latter case, the modern concept of gene diversification in breeding for disease resistance is less effective. In the former case, gene accumulation can also work.     

Chronic Allopurinol Treatment during the Last Trimester of Pregnancy in Sows: Effects on Low and Normal Birth Weight Offspring

Low-birth-weight (LBW) children are born with several risk factors for disease, morbidity and neonatal mortality, even if carried to term. Placental insufficiency leading to hypoxemia and reduced nutritional supply is the main cause for LBW. Brain damage and poor neurological outcome can be the consequence. LBW after being carried to term gives better chances for survival, but these children are still at risk for poor health and the development of cognitive impairments. Preventive therapies are not yet available. We studied the risk/efficacy of chronic prenatal treatment with the anti-oxidative drug allopurinol, as putative preventive treatment in piglets. LBW piglets served as a natural model for LBW. A cognitive holeboard test was applied to study the learning and memory abilities of these allopurinol treated piglets after weaning. Preliminary analysis of the plasma concentrations in sows and their piglets suggested that a daily dose of 15 mg.kg⁻¹ resulted in effective plasma concentration of allopurinol in piglets. No adverse effects of chronic allopurinol treatment were found on farrowing, birth weight, open field behavior, learning abilities, relative brain, hippocampus and spleen weights. LBW piglets showed increased anxiety levels in an open field test, but cognitive performance was not affected by allopurinol treatment. LBW animals treated with allopurinol showed the largest postnatal compensatory body weight gain. In contrast to a previous study, no differences in learning abilities were found between LBW and normal-birth-weight piglets. This discrepancy might be attributable to experimental differences. Our results indicate that chronic prenatal allopurinol treatment during the third trimester of pregnancy is safe, as no adverse side effects were observed. Compensatory weight gain of treated piglets is a positive indication for the chronic prenatal use of allopurinol in these animals. Further studies are needed to assess the possible preventive effects of allopurinol on brain functions in LBW piglets.