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The clusterin ( CLU ) rs11136000 CC genotype is a probable risk factor for Alzheimer's disease (AD). CLU , also known as the apolipoprotein J gene, shares certain properties with the apolipoprotein E ( APOE ) gene with a well-established relationship with AD. This study aimed to determine whether the electrophysiological patterns of brain activation during the letter fluency task (LFT) depend on CLU genotypes in adults without dementia. Previous studies have shown that LFT performance involves activation of the frontal cortex. We examined EEG alpha1 and alpha2 band desynchronization in the frontal regions during the LFT in 94 nondemented individuals stratified by CLU (rs11136000) genotype. Starting at 30 years of age, CLU CC carriers exhibited more pronounced task-related alpha2 desynchronization than CLU CT&TT carriers in the absence of any differences in LFT performance. In CLU CC carriers, alpha2 desynchronization was significantly correlated with age. Increased task-related activation in individuals at genetic risk for AD may reflect greater "effort" to perform the task and/or neuronal hyperexcitability. The results show that the CLU genotype is associated with neuronal hyperactivation in the frontal cortex during cognitive tasks performances in nondemented individuals, suggesting systematic vulnerability of LFT related cognitive networks in people carrying unfavorable CLU alleles.

Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in slow excitatory postsynaptic conductance, synapse formation, synaptic plasticity, and motor control. The GRM1 gene is expressed mainly in the brain, with the highest expression in the cerebellum. Mutations in the GRM1 gene have previously been known to cause autosomal recessive and autosomal dominant spinocerebellar ataxias. In this study, whole-exome sequencing of a patient from a family of Azerbaijani origin with a diagnosis of congenital cerebellar ataxia was performed, and a new homozygous missense mutation in the GRM1 gene was identified. The mutation leads to the homozygous amino acid substitution of p.Thr824Arg in an evolutionarily highly conserved region encoding the transmembrane domain 7, which is critical for ligand binding and modulating of receptor activity. This is the first report in which a mutation has been identified in the last transmembrane domain of the mGluR1, causing a congenital autosomal recessive form of cerebellar ataxia with no obvious intellectual disability. Additionally, we summarized all known presumable pathogenic genetic variants in the GRM1 gene to date. We demonstrated that multiple rare variants in the GRM1 underlie a broad diversity of clinical neurological and behavioral phenotypes depending on the nature and protein topology of the mutation.

We propose an approach for the identification of mutant genes for rare diseases in single cases of unknown etiology. All genes with rare biologically significant variants sorted from individual exome data are tested further for profiling of their spatial-temporal and cell/tissue specific expression compared to that of their paralogs. We developed a simple bioinformatics tool ("Essential Paralogue by Expression" (EPbE)) for such analysis. Here, we present rare clinical forms of early ataxia with cerebellar hypoplasia. Using whole-exome sequencing and the EPbE tool, we identified two novel mutant genes previously not associated with congenital human diseases. In Family I, the unique missense mutation (p.Lys258Glu) was found in the LRCH2 gene inherited in an X-linked manner. p.Lys258Glu occurs in the evolutionarily invariant site of the leucine-rich repeat domain of LRCH2. In Family II and Family III, the identical genetic variant was found in the CSMD1 gene inherited as an autosomal-recessive trait. The variant leads to amino acid substitution p.Gly2979Ser in a highly conserved region of the complement-interacting domain of CSMD1. The LRCH2 gene for Family I patients (in which congenital cerebellar hypoplasia was associated with demyelinating polyneuropathy) is expressed in Schwann and precursor Schwann cells and predominantly over its paralogous genes in the developing cerebellar cortex. The CSMD1 gene is predominantly expressed over its paralogous genes in the cerebellum, specifically in the period of late childhood. Thus, the comparative spatial-temporal expression of the selected genes corresponds to the neurological manifestations of the disease., (© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.)

Paleogenomics is one of the urgent and promising areas of interdisciplinary research in the today's world science. New genomic methods of ancient DNA (aDNA) analysis, such as next generation sequencing (NGS) technologies, make it possible not only to obtain detailed genetic information about historical and prehistoric human populations, but also to study individual microbial and viral pathogens and microbiomes from different ancient and historical objects. Studies of aDNA of pathogens by reconstructing their genomes have so far yielded complete sequences of the ancient pathogens that played significant role in the history of the world: Yersinia pestis (plague), Variola virus (smallpox), Vibrio cholerae (cholera), HBV (hepatitis B virus), as well as the equally important endemic human infectious agents: Mycobacterium tuberculosis (tuberculosis), Mycobacterium leprae (leprosy), and Treponema pallidum (syphilis). Genomic data from these pathogens complemented the information previously obtained by paleopathologists and allowed not only to identify pathogens from the past pandemics, but also to recognize the pathogen lineages that are now extinct, to refine chronology of the pathogen appearance in human populations, and to reconstruct evolutionary history of the pathogens that are still relevant to public health today. In this review, we describe state-of-the-art genomic research of the origins and evolution of many ancient pathogens and viruses and examine mechanisms of the emergence and spread of the ancient infections in the mankind history.

Bipedalism, speech, and intellect are the most prominent traits that emerged in the evolution of Homo sapiens . Here, we describe a novel genetic cause of an "involution" phenotype in four patients, who are characterized by quadrupedal locomotion, intellectual impairment, the absence of speech, small stature, and hirsutism, observed in a consanguineous Brazilian family. Using whole-genome sequencing analysis and homozygous genetic mapping, we identified genes bearing homozygous genetic variants and found a homozygous 36.2 kb deletion in the gene of glutamate receptor delta 2 ( GRID2 ) in the patients, resulting in the lack of a coding region from the fifth to the seventh exons. The GRID2 gene is highly expressed in the cerebellum cortex from prenatal development to adulthood, specifically in Purkinje neurons. Deletion in this gene leads to the loss of the alpha chain in the extracellular amino-terminal protein domain (ATD), essential in protein folding and transport from the endoplasmic reticulum (ER) to the cell surface. Then, we studied the evolutionary trajectories of the GRID2 gene. There was no sign of strong selection of the highly conservative GRID2 gene in ancient hominids (Neanderthals and Denisovans) or modern humans; however, according to in silico tests using the Mfold tool, the GRID 2 gene possibly gained human-specific mutations that increased the stability of GRID2 mRNA.

LINE-1 (L1) is a class of autonomous mobile genetic elements that form somatic mosaicisms in various tissues of the organism. The activity of L1 retrotransposons is strictly controlled by many factors in somatic and germ cells at all stages of ontogenesis. Alteration of L1 activity was noted in a number of diseases: in neuropsychiatric and autoimmune diseases, as well as in various forms of cancer. Altered activity of L1 retrotransposons for some pathologies is associated with epigenetic changes and defects in the genes involved in their repression. This review discusses the molecular genetic mechanisms of the retrotransposition and regulation of the activity of L1 elements. The contribution of various factors controlling the expression and distribution of L1 elements in the genome occurs at all stages of the retrotransposition. The regulation of L1 elements at the transcriptional, post-transcriptional and integration into the genome stages is described in detail. Finally, this review also focuses on the evolutionary aspects of L1 accumulation and their interplay with the host regulation system.

LINE1 retrotransposons are members of a class of mobile genetic elements capable of retrotransposition in the genome via a process of reverse transcription. LINE1 repeats, integrating into different chromosomal loci, affect the activity of genes and cause different genomic mutations. Somatic variability of the human genome is linked to the activity of some subfamilies of LINE1, in particular, a high level of LINE1 retrotranspositions has been observed in brain tissues. However, the contribution of LINE1 to genomic variability during normal aging and in age-related neurodegenerative diseases is poorly understood. We conducted quantitative real-time PCR analysis of active subfamilies of LINE1 repeats (aL1) using genomic DNA extracted from brain specimens of Alzheimer's disease (AD) patients and individuals without neuropsychiatric pathologies, as well as DNA extracted from blood specimens of individuals of different ages (healthy and AD subjects). Inter-individual quantitative variations of active families of aL1 repeats in the genome were observed. No significant age-dependent differences were identified. Likewise, no difference of aL1 copy number in brain and blood were indicated between AD patients and the aged-matched control group without dementia. These data imply that aging and the AD-associated neurodegenerative process are not the major factors contributing to the retrotransposition processes of active LINE1 repeats.

Genome-wide association studies have identified novel risk variants for Alzheimer's disease (AD). Among these, a gene carrying one of the highest risks for AD is PICALM. The PICALM rs3851179 A allele is thought to have a protective effect, whereas the G allele appears to confer risk for AD. The influence of the PICALM genotype on brain function in nondemented subjects remains largely unknown. We examined the possible effect of the PICALM rs3851179 genotype on quantitative electroencephalography recording at rest in 137 nondemented volunteers (age range: 20-79 years) subdivided into cohorts of those younger than and those older than 50 years of age. The homozygous presence of the AD risk variant PICALM GG was associated with an increase in beta relative power, with the effect being more pronounced in the older cohort. Beta power elevation in resting-state electroencephalography has previously been linked to cortical disinhibition and hyperexcitability. The increase in beta relative power in the carriers of the AD risk PICALM GG genotype suggests changes in the cortical excitatory-inhibitory balance, which are heightened during normal aging., (Copyright © 2016 Elsevier Inc. All rights reserved.)

X-linked congenital cerebellar ataxia is a heterogeneous nonprogressive neurodevelopmental disorder with onset in early childhood. We searched for a genetic cause of this condition, previously reported in a Buryat pedigree of Mongolian ancestry from southeastern Russia. Using whole-genome sequencing on Illumina HiSeq 2000 platform, we found a missense mutation in the ABCB7 (ABC-binding cassette transporter B7) gene, encoding a mitochondrial transporter, involved in heme synthesis and previously associated with sideroblastic anemia and ataxia. The mutation resulting in a substitution of a highly conserved glycine to serine in position 682 is apparently a major causative factor of the cerebellar hypoplasia/atrophy found in affected individuals of a Buryat family who had no evidence of sideroblastic anemia. Moreover, in these affected men we also found the genetic defects in two other genes closely linked to ABCB7 on chromosome X: a deletion of a genomic region harboring the second exon of copper-transporter gene (ATP7A) and a complete deletion of PGAM4 (phosphoglycerate mutase family member 4) retrogene located in the intronic region of the ATP7A gene. Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers. The role of the PGAM4 gene has been previously implicated in human reproduction, but our data indicate that its complete loss does not disrupt male fertility. Our finding links cerebellar pathology to the genetic defect in ABCB7 and ATP7A structural variant inherited as X-linked trait, and further reveals the genetic heterogeneity of X-linked cerebellar disorders.

A study of the intensity of oxygen consumption by mice lymphocytes at different stages of cultivation with PHA showed a pronounced increase of the respiratory activity beginning from the 14th hour. Maximum values of oxygen consumption by stimulated cells were observed at the 16th and 30th hours of cultivation (before the beginning of blastogenesis and before the maximum uptake of H3-thymidine, respectively.