Biology subjects

Benitez-Burraco, A.

Publications and source records attributed to Benitez-Burraco, A..

15 recordsLinked to original sources

bioRxiv2022

The enrichment of self-domestication and neural crest function loci in the heritability of neurodevelopmental disorders is not independent of genomic regulatory functions

Self-domestication could play an important role in contributing to shape the biology of human brain and the predisposition to neurodevelopmental disorders. Leveraging genome-wide data from the Psychiatric Genomics Consortium, we tested the enrichment of self-domestication and neural crest function loci with respect to the heritability of autism spectrum disorder, schizophrenia (SCZ in East Asian and European ancestries, EAS and EUR, respectively), attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, and Tourettes syndrome (TS). Considering only self-domestication and neural-crest-function annotations in the linkage disequilibrium score regression (LDSC) model, our partitioned heritability analysis revealed statistically significant enrichments across all disorders investigated. The estimates of the heritability enrichments for self-domestication loci were similar across neurodevelopmental disorders, ranging from 0.902 (EAS SCZ, p=4.55x10-20) to 1.577 (TS, p=5.85x10-5). Conversely, a wider spectrum of heritability enrichment estimates was present for neural crest function with the highest enrichment observed for TS (enrichment=3.453, p=2.88x10-3) and the lowest for EAS SCZ (enrichment=1.971, p=3.8lx10-3). Although these estimates appear to be strong, the enrichments for self-domestication and neural crest function were null once we included additional annotations related to different genomic features. This indicates that the effect of self-domestication on the polygenic architecture of neurodevelopmental disorders is not independent of other functions of human genome.

genetics↗

bioRxiv2022

Fish as model systems to study epigenetic drivers in human self-domestication and neurodevelopmental cognitive disorders

Modern humans exhibit phenotypic traits that are shared across independent domestication events, suggesting the human self-domestication hypothesis. Epigenetic changes may facilitate early self-domestication in humans, since they can be the first layer of response to a novel environment. Here, we argue that fish provide model systems to study epigenetic drivers in human self-domestication. To do this, we compare genes that carry epigenetic changes in early domesticates of European sea bass with 1) anatomically modern humans and 2) neurodevelopmental cognitive disorders with abnormal self-domestication traits, i.e., schizophrenia, Williams syndrome and autism spectrum disorders. We found that genes with epigenetic changes in fish and in modern vs ancient humans were shared and were involved in processes like limb morphogenesis and phenotypes like abnormal snout morphology and hypopigmentation. Moreover, early domestication in fish and neurodevelopmental cognitive impairment in humans affected paralogue genes involved in processes such as neural crest differentiation and ectoderm differentiation. We conclude that parallel epigenetic changes may occur at the initial steps of domestication in absence of deliberate selection in phylogenetically distant vertebrates. These findings pave the way for future studies using fish as models to investigate epigenetic changes as drivers of human-self domestication and as triggers of cognitive disorders.

evolutionary biology↗

bioRxiv2020

Language impairment with a partial duplication of DOCK8

Copy-number variations of the distal region of the short arm of chromosome 9 are associated with learning disabilities and behavioral disturbances. Deletions of the 9p are more frequent than duplications. We report in detail on the cognitive and language features of a child with a duplication in the 9p24.3 region (arr[hg19] 9p24.3(266,045-459,076)x3). He exhibits marked expressive and receptive problems, which affect to both structural aspects of language (notably, inflectional morphology, complex syntax, and sentence semantics), and to functional aspects (pragmatics). These problems might result from a severe underlying deficit in working memory. Regarding the molecular causes of the observed symptoms, they might result from the altered expression of selected genes involved in procedural learning, particularly, some of components of the SLIT/ROBO/FOXP2 network, strongly related to the development and evolution of language. Dysregulation of specific components of this network can result in turn from an altered interaction between DOCK8, affected by the microduplication in 9p24.3 borne by our proband, and CDC42, acting as the hub component of the network encompassing language-related genes. Still, some genes found strongly upregulated in the subject and not related to these genes, particularly NRCAM, can contribute to the observed problems in the language domain, as well as to specific features of the proband, particularly, his impulsivity.

neuroscience↗

bioRxiv2020

Language impairment with a microduplication in 1q42.3q43

Deletions and duplications of the distal region of the long arm of chromosome 1 are associated with brain abnormalities and developmental delay. Because duplications are less frequent than deletions, no detailed account of the cognitive profile of the affected people is available, particularly, regarding their language (dis)abilities. In this paper we report on the cognitive and language features of a girl with one of the smallest interstitial duplications ever described in this region, affecting to 1q42.3q43 (arr[hg19] 1q42.3q43(235,963,632-236,972,276)x3). Standardized tests as well as the analysis of her language use in natural settings suggest that the probands speech is severely impaired, exhibiting dysarthric-like features, with speech problems also resulting from a phonological deficit boiling down to a verbal auditory memory deficit. Lexical and grammatical knowledge are also impaired, impacting negatively on both expressive and receptive abilities, seemingly as a consequence of the phonological deficit. Still, her pragmatic abilities seem to be significantly spared, granting her a good command on the principles governing conversational exchanges. In silico analyses (literature mining, network analysis) and in vitro analyses (microarray) point to several genes as potential candidates for the observed deficits in the language domain. These include one gene within the duplicated region (LYST), one predicted functional partner (CMIP), and three genes outside the 1q42.3q43 region, which are all highly expressed in the cerebellum: DDIT4 and SLC29A1, found strongly downregulated in the proband compared to their healthy parents, and CNTNAP3, found strongly upregulated.

neuroscience↗

bioRxiv2020

Abnormal features of human self-domestication in bipolar disorder

Bipolar disorder (BD) is a severe mental condition characterized by episodes of elevated mood and depression. Being a heritable condition, it features a complex genetic architecture, and it is not still clear how genes contribute to the onset and course of the disease. In this paper we adopted an evolutionary-genomic approach to this condition, focusing on changes occurring during human evolution as a source of our distinctive cognitive and behavioral phenotype. We show clinical evidence that the BD phenotype can be construed as an abnormal presentation of the human self-domestication phenotype. We further demonstrate that candidate genes for BD significantly overlap with candidates for mammal domestication, and that this common set of genes is enriched in functions that are important for the BD phenotype, especially neurotransmitter homeostasis. Finally, we show that candidates for domestication are differentially expressed in brain regions involved in BD pathology, particularly, the hippocampus and the prefrontal cortex. Overall, this link between domestication and BD should facilitate a better understanding of the BD etiopathology.

neuroscience↗

bioRxiv2020

Williams syndrome and autism: dissimilar socio-cognitive profiles with similar patterns of abnormal gene expression in the blood

Autism Spectrum Disorders (ASD) and Williams Syndrome (WS) exhibit quite opposite features in the social domain, but also share some common underlying behavioral and cognitive deficits. It is not clear, however, which genes account for the attested differences (and similarities) in the socio-cognitive domain. In this paper we adopted a comparative-molecular approach and looked for genes that might be differentially (or similarly) regulated in the blood of people with these two conditions. We found a significant overlap between differentially-expressed genes compared to neurotypical controls, with most of them exhibiting a similar trend in both conditions, but with genes being more dysregulated in WS than in ASD. These genes are involved in aspects of brain development and function (particularly, dendritogenesis) and are expressed in brain areas (particularly, the cerebellum, the thalamus and the striatum) of relevance for the ASD and the WS etiopathogenesis.

neuroscience↗

bioRxiv2019

Recent changes in candidate genes for domestication in humans in Europe: focusing on language

Human evolution resulted from changes in our biology, behavior, and culture. One source of these changes has been hypothesized to be our self-domestication (that is, the development in humans of features commonly found in domesticated strains of mammals, seemingly as a result of selection for reduced aggression). Signals of domestication, notably brain size reduction, have increased in recent times. In this paper we compare whole-genome data between Late Neolithic/Bronze Age individuals and modern Europeans and show that genes associated with mammal domestication and with neural crest development and function are significantly differently enriched in nonsynonymous single nucleotide polymorphisms between these two groups. We hypothesize how these changes might account for the increased features of self-domestication in modern humans and ultimately, for subtle recent changes in human cognition and behavior, including language.

evolutionary biology↗

bioRxiv2018

Robust candidates for language development and evolution are significantly dysregulated in the blood of people with Williams syndrome

Williams syndrome (WS) is a clinical condition entailing cognitive deficits and with an uneven language profile, which has been object of intense inquiry over the last decades. Although WS results from the hemideletion of around two dozens of genes in chromosome 7, no gene has been yet probed to account for, or contribute significantly to, the language problems exhibited by the affected people. In this paper we show that robust candidates for language disorder and for language evolution in the species, located outside the hemideleted region, are up- or downregulated in the blood of subjects with WS. Most of these genes play a role in the development and function of brain areas involved in language processing, which exhibit structural and functional anomalies in people with the condition. Overall, these genes emerge as robust candidates for language dysfunction in WS.

neuroscience↗

bioRxiv2018

The MER41 family of HERVs is uniquely involved in the immune-mediated regulation of cognition/behavior-related genes: pathophysiological implications for autism spectrum disorders

Social behavior and neuronal connectivity in rodents have been shown to be shaped by the prototypical T lymphocyte-derived pro-inflammatory cytokine Interferon-gamma (IFN{gamma}). It has also been demonstrated that STAT1 (Signal Transducer And Activator Of Transcription 1), a transcription factor (TF) crucially involved in the IFN{gamma} pathway, binds consensus sequences that, in humans, are located with a high frequency in the LTRs (Long Terminal Repeats) of the MER41 family of primate-specific HERVs (Human Endogenous Retrovirus). However, the putative role of an IFN{gamma}/STAT1/MER41 pathway in human cognition and/or behavior is still poorly documented. Here, we present evidence that the promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 HERVs. This observation is specific to MER41 among more than 130 HERVs examined. Moreover, we have not found such a significant enrichment in the promoter regions of genes that associate with autism spectrum disorder (ASD) or schizophrenia. Interestingly, ID-associated genes exhibit promoter-localized MER41 LTRs that harbor TF binding sites (TFBSs) for not only STAT1 but also other immune TFs such as, in particular, NFKB1 (Nuclear Factor Kappa B Subunit 1) and STAT3 (Signal Transducer And Activator Of Transcription 3). Moreover, IL-6 (Interleukin 6) rather than IFN{gamma}, is identified as the main candidate cytokine regulating such an immune/MER41/cognition pathway. Of note, functionally-relevant differences between humans and chimpanzees are observed regarding the 3 main components of this pathway: i) the protein sequences of immunes TFs binding MER41 LTRs, ii) the insertion sites of MER41 LTRs in the promoter regions of ID-associated genes and iii) the protein sequences of the targeted ID-associated genes. Finally, a survey of the human proteome has allowed us to map a protein-protein network which links the identified immune/MER41/cognition pathway to FOXP2 (Forkhead Box P2), a key TF involved in the emergence of human speech. Together, these results suggest that the stepped self-domestication of MER41 in the genomes of primates could have been a driver of cognitive evolution. Our data further indicate that non-inherited forms of ID might result from alterations of the immune/MER41/cognition pathway induced notably by the untimely or quantitatively inappropriate exposure of human neurons to IL-6.

neuroscience↗

bioRxiv2017

Paleo-Oscillomics: Reconstructing Language-Relevant Computational Capacities in Neanderthals from the Molecular Basis of Neural Oscillations

Language seemingly evolved from changes in brain anatomy and wiring. We argue that language evolution can be better understood if particular changes in phasal and cross-frequency coupling properties of neural oscillations, resulting in core features of language, are considered. Because we cannot track the oscillatory activity of the brain from extinct hominins, we used our current understanding of the language oscillogenome (that is, the set of genes responsible for basic aspects of the oscillatory activity relevant for language) to infer some properties of the Neanderthal oscillome. We have found that several candidates for the language oscillogenome show differences in their methylation patterns between Neanderthals and humans. We argue that differences in their expression levels could be informative of differences in cognitive functions important for language.

neuroscience↗

bioRxiv2017

Human-specific changes in two functional enhancers of FOXP2

Two functional enhancers of FOXP2, a gene important for language development and evolution, exhibit several human-specific changes compared to extinct hominins that are located within the binding site for different transcription factors. Specifically, Neanderthals and Denisovans bear the ancestral allele in one position within the binding site for SMARCC1, involved in brain development and vitamin D metabolism. This change might have resulted in a different pattern of FOXP2 expression in our species compared to extinct hominins.

evolutionary biology↗

bioRxiv2017

Language and cognitive impairment associated to a novel p.Cys63Arg change in the MED13L gene

Mutations of the MED13L gene, which encodes a subunit of a transcriptional regulatory complex, result in a complex phenotype entailing physical and cognitive anomalies. Deep language impairment has been reported, mostly in patients with CNV. Case presentation. We report on a child who presents with a non-synonymous change p.Cys63Arg in MED13L (Chr12:116675396A>G, GRCh37) and who exhibits profound language impairment in the expressive domain, cognitive delay, behavioral disturbances, and some autistic features. Conclusions. Because of the brain areas in which MED13L is expressed and because of the functional links between MED13L and the products of some candidate genes for language disorders, the probands linguistic phenotype may result from changes in a functional network important for language development.

neuroscience↗

bioRxiv2017

The language oscillogenome

Language has been argued to arise, both ontogenetically and phylogenetically, from specific patterns of brain wiring. We argue that it can further be shown that core features of language processing emerge from particular phasal and cross-frequency coupling properties of neural oscillations; what has been referred to as the language oscillome. It is expected that basic aspects of the language oscillome result from genetic guidance, what we will here call the language oscillogenome, for which we will put forward a list of candidate genes. We have considered genes for altered brain rhythmicity in conditions involving language deficits (autism spectrum disorders, schizophrenia, specific language impairment and dyslexia) for which we have confident genome-oscillome-phenome connections. These selected genes map on to aspects of brain function, particularly on to neurotransmitter function. Our aim is to propose a set of biologically robust genome-to-language linking hypotheses that, given testing, would grant causal and explanatory power to brain rhythms with respect to language processing.

neuroscience↗

bioRxiv2017

An oscillopathic approach to developmental dyslexia: from genes to speech processing

Developmental dyslexia is a heterogeneous condition entailing problems with reading and spelling. Several genes have been linked or associated to the disease, many of which contribute to the development and function of brain areas that are important for auditory and phonological processing. Nonetheless, a clear link between genes, the brain, and the symptoms of dyslexia is still pending. The goal of this paper is contributing to bridge this gap. With this aim, we have focused on how the dyslexic brain fails to process speech sounds and reading cues. We have adopted an oscillatory perspective, according to which dyslexia results from a deficient integration of different brain rhythms during reading/spellings tasks. Moreover, we show that some candidates for this condition are related to brain rhythms. This approach should help gain a better understanding of the aetiology and the clinical presentation of developmental dyslexia, but also achieve an earlier and more accurate diagnosis of the disease.

neuroscience↗

bioRxiv2016

Variable penetrance of the 15q11.2 BP1-BP2 microduplication in a family with cognitive and language impairment

The 15q11.2 BP1-BP2 region is found duplicated or deleted in people with cognitive, language, and behavioral impairment. Case presentation. We report on a family (the father and three male twin siblings) who presents with a duplication of the 15q11.2 BP1-BP2 region and a variable phenotype: whereas the father and the fraternal twin are normal carriers, the monozygotic twins exhibit severe language and cognitive delay and behavioral disturbances. The genes located within the duplicated region are involved in brain development and function, and some of them are related to language processing. Conclusions. The probands phenotype may result from changes in the expression level of some of these genes important for cognitive development.

neuroscience↗