The Derived Allele of ASPM Is Associated with Lexical Tone Perception

The ASPM and MCPH1 genes have been implicated in the adaptive evolution of the human brain [Mekel-Bobrov N. et al., 2005. Ongoing adaptive evolution of ASPM, a brain size determinant in homo sapiens. Science 309; Evans P.D. et al., 2005. Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans. Science 309]. Curiously, experimental attempts have failed to connect the implicated SNPs in these genes with higher-level brain functions. These results stand in contrast with a population-level study linking the population frequency of their alleles with the tendency to use lexical tones in a language [Dediu D., Ladd D.R., 2007. Linguistic tone is related to the population frequency of the adaptive haplogroups of two brain size genes, ASPM and microcephalin. Proc. Natl. Acad. Sci. U.S.A. 104]. In the present study, we found a significant correlation between the load of the derived alleles of ASPM and tone perception in a group of European Americans who did not speak a tone language. Moreover, preliminary results showed a significant correlation between ASPM load and hemodynamic responses to lexical tones in the auditory cortex, and such correlation remained after phonemic awareness, auditory working memory, and non-verbal IQ were controlled. As in previous studies, no significant correlation between ASPM and cognitive measures were found. MCPH1 did not correlate with any measures. These results suggest that the association between the recently derived allele of ASPM is likely to be specific and is tied to higher level brain functions in the temporal cortex related to human communication

Evidence of Contemporary Modern Human Evolution Contained Within the Human Genome

The question of whether or not modern humans are still evolving is being asked more than ever with the vast amount of technology, culture and medicine which have the ability to buffer environmental stressors that would otherwise drive evolutionary adaptations in humans. The purpose of this paper was to determine, in spite of these "advances," if modern humans are still evolving by searching for proof within the human genome. The three prime examples of current evolution discussed are: certain populations' resistance to malaria, lactase persistence and resistance to HIV, each of which are adaptations regulated by mutant alleles. Each adaptation was broken down by the different mutations responsible for that adaptation. In order to determine if these mutations are, in fact, evidence of modern evolution, they were each subjected to a strict list of criteria necessary to be deemed adaptive and evolutionary. In all cases except one, the mutations passed the criteria and are considered proof that modern humans are still evolving. It is concluded that even though modern humans have the ability to buffer environmental stressors that would typically cause evolutionary changes, not all of these can be buffered and as a result, the human genome is evolving to adapt to these stressors

Whole Brain Size and General Mental Ability: A Review

We review the literature on the relation between whole brain size and general mental ability (GMA) both within and between species. Among humans, in 28 samples using brain imaging techniques, the mean brain size/GMA correlation is 0.40 (N = 1,389; p < 10−10); in 59 samples using external head size measures it is 0.20 (N = 63,405; p < 10−10). In 6 samples using the method of correlated vectors to distill g, the general factor of mental ability, the mean r is 0.63. We also describe the brain size/GMA correlations with age, socioeconomic position, sex, and ancestral population groups, which also provide information about brain–behavior relationships. Finally, we examine brain size and mental ability from an evolutionary and behavior genetic perspective

A Transcription Factor Map as Revealed by a Genome-Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis

Background: Several lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls. Methodology/Principal Findings: We have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V$KROX_Q6, p-value ,3.31E-6; V$CREBP1_Q2, p-value ,9.93E-6, V$YY1_02, p-value ,1.65E-5). Conclusions/Significance: Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation

Role of microcephalin at mitosis

A large brain is one of the most distinguishing features of humans compared to other members of the animal kingdom. During mammalian evolution there has been a disproportionate enlargement of the brain relative to body size and this expansion has been particularly prominent during the past 3 million years of human lineage. This must be the consequence of adaptive genetic alterations during mammalian evolution, but the genes and molecular processes altered are essentially unknown. One approach for identifying candidate genes for brain size regulation is through characterisation of Mendelian disorders of brain development. In particular, primary microcephaly has received considerable interest as a model disease for studying brain size regulators because patients present with a profoundly reduced brain size but have no other malformations. Genetic studies have identified mutations in seven genes that can cause primary microcephaly. All the primary microcephaly proteins localise to the centrosome at some stage during the cell cycle and have roles in a diverse range of functions including centrosome maturation, centriole formation and microtubule organisation at the spindle pole. The precise mechanism leading to primary microcephaly is not known but a prevalent hypothesis is that centrosome dysfunction disrupts mitosis of neural progenitor cells. Despite there being strong evidence in support of this hypothesis for most primary microcephaly genes, MCPH1 (the first primary microcephaly gene to be identified) always appeared to be functionally distinct from other primary microcephaly proteins. Most work on MCPH1 has focussed on its role in the DNA damage response and cell cycle timing rather than on its mitotic role. As a result, the aim of this thesis is to perform a detailed analysis of MCPH1 function during mitosis. In this thesis, three isoforms of MCPH1 were characterised and their localisation, expression and stability examined. It was established that MCPH1 is highly regulated during mitosis. MCPH1 transcript and protein levels vary significantly throughout the cell cycle and MCPH1 protein is targeted for degradation late in mitosis. In addition, MCPH1 is hyperphosphorylated during mitosis (in prometaphase-arrested cells) suggesting that phosphorylation could potentially regulate MCPH1 mitotic function. Twelve mitotic phosphorylation sites were identified by phosphopeptide mapping, many of which were CDK1 and PLK1 consensus sites. Both PLK1 and CDK1 also contribute to MCPH1 phosphorylation in vivo. Although MCPH1 non-phosphorylatable mutants localise normally during mitosis, binding to interaction partners may be affected which may have functional consequences. During mitosis MCPH1 localises to the centrosomes and kinetochores. Consistent with this localisation, RNAi-mediated knockdown of MCPH1 leads to metaphase arrest with multipolar spindles, major defects in chromosome alignment and loss of chromatid cohesion. In addition, MCPH1 deficient mouse embryonic fibroblast cells also demonstrate similar chromosome alignment defects, strengthening this finding in an independent system. Live-imaging of MCPH1 depleted cells demonstrate that a normal bipolar spindle and metaphase plate are initially formed, but subsequently chromosomes and chromatids drop off the metaphase plate and eventually the spindle collapses. This suggests that the primary function of MCPH1 is to allow timely progression through metaphase, possibly by mediating kinetochore-microtubule attachments to satisfy the spindle activated checkpoint. Therefore my work describes several roles for MCPH1 in mitosis (centrosome stability, chromosome alignment and metaphase progression) suggesting that its role in mitosis could result in primary microcephaly in a number of different ways

Bases genéticas de la esquizofrenia: aspectos emocionales, cognitivos y neuroanatómicos.

La esquizofrenia es un desorden mental severo, con una incidencia del 1% y una elevada heredabilidad (alrededor del 80%). Por ello, hay un enorme interés en conocer los factores genéticos implicados en la vulnerabilidad a padecer esquizofrenia. Sin embargo, esta enfermedad presenta una herencia poligénica y además un importante número de factores ambientales parecen influir en su aparición. Asimismo, la heterogeneidad clínica también es elevada y esto dificulta el tener un fenotipo bien definido para el estudio genético. Por ello, el estudio de fenotipos más recortados y mejor definidos puede ser de gran utilidad. En el presente trabajo, se han seleccionado nueve genes de interés. Nuestra hipótesis principal es que variaciones en estos genes modulan la vulnerabilidad a padecer esquizofrenia o alguno de sus rasgos característicos, particularmente las alucinaciones auditivas, el deterioro cognitivo y la disfunción emocional. Como objetivo, nos planteamos el estudio de polimorfismos genéticos en varias muestras caso-control y familiares de España, Alemania y Estados Unidos. Se realizaron análisis de asociación caso-control, basados en familias y estudios de asociación con diferentes escalas clínicas. Asimismo, se estudió el impacto de ciertos polimorfismos sobre fenotipos de neuroimagen estructural y funcional. Los resultados más interesantes fueron los siguientes: por una parte, diferentes genes del sistema serotoninérgico (principalmente los genes SLC6A4 y HTR2A) parecían influir en el estado emocional del paciente, así como en la respuesta emocional del paciente a las alucinaciones auditivas. Además, el gen ASPM se asoció con el riesgo de psicosis y con diferentes parámetros cognitivos y de neuroimagen. Otros genes como NOS1, STMN1, PDE4D y PLEKHB1 parecían influir sobre el riesgo de psicosis, así como sobre las puntuaciones obtenidas en diferentes escalas psicopatológicas, si bien en estos casos la significación fue menor. Todos estos resultados permiten proponer un modelo de vulnerabilidad, según el cual ciertos genes tendrían un mayor efecto sobre la vulnerabilidad a sufrir esquizofrenia, mientras que otros genes influirían sobre la severidad de ciertos síntomas. Además, nuestros resultados apoyan la existencia de una vulnerabilidad genética a respuestas emocionales aberrantes, que podría estar modulada por la variación en ciertos genes, tales como el transportador de serotonina.Schizophrenia is a severe psychotic mental disorder, with a prevalence of around 1% in general population. It is well known that this disease presents a high heritability (around 80%). For this reason, there is a great interest in discovering the genetic factors affecting the risk for schizophrenia. However, due to the polygenic inheritance of this disorder, it is particularly hard to discover schizophrenia-related genes. Moreover, it has been hypothesized that an important number of environmental factors of different nature may affect the vulnerability to schizophrenia. Furthermore, schizophrenia is a clinically heterogeneous disorder and it can be particularly difficult to have a well-defined phenotype for genetic studies. For all these reasons, we consider that it is important to study the neurobiology of schizophrenia as a global entity, but also to complement these studies with other approaches, for example through the use of other alternative phenotypes, such as cognitive impairment, electrophysiological responses or auditory hallucinations, for example. In the present study, different candidate genes were selected. Our main hypothesis is that variations in these nine genes modulate the vulnerability to schizophrenia and some of their most characteristic and important features, particularly auditory hallucinations, cognitive impairment and, finally, the emotional dysfunction associated to schizophrenia. To test this hypothesis, we focused the study on the analysis of genetic polymorphisms (mainly single nucleotide polymorphisms) in three case-control samples from Spain, Germany and United States and a family sample from the United States. All samples were of Caucasian origin. Different analysis were performed, namely case-control association analysis, family-based association analysis (in some cases) and association analysis with clinical measures that corresponded to different psychopathological scales (BPRS, KGV, PANSS and PSYRATS for auditory hallucinations and delusions). Moreover, we also assessed the impact of certain genetic polymorphisms on functional and structural neuroimaging phenotypes, which evaluated both cognitive and emotional aspects. The most interesting results were the following: first, several polymorphisms from serotonergic system genes (mainly SLC6A4 and HTR2A genes, but also TPH2 gene to a lesser extent) appeared to modulate the patient's emotional state, including the emotional response to auditory hallucinations, assessed with clinical scales and neuroimaging techniques. Moreover, the positive selection gene ASPM, involved in neurodevelopmental processes, was associated with the risk for psychosis and with different cognitive and neuroimaging measures in both the Spanish and the American sample. Other genes such as NOS1, STMN1, PDE4D and PLEKHB1 also appeared to influence the risk for psychosis and the scores in some psychopathological scales, although in these cases significance was weaker.All these findings allow us to propose a vulnerability model. According to this model, some genes would have a major effect on the vulnerability to schizophrenia, while other genes would have an effect on the severity to certain symptoms. Regarding the vulnerability to auditory hallucinations, our results also support the existence of a genetic vulnerability to aberrant emotional responses, which could be modulated by the variation in different genes, such as the serotonin transporter gene, among others