Genes with human-specific features are primarily involved with
brain, immune and metabolic evolution

Abstract Background Humans have adapted to widespread changes during the past 2 million years in both environmental and lifestyle factors. This is evident in overall body alterations such as average height and brain size. Although we can appreciate the uniqueness of our species in many aspects, molecular variations that drive such changes are far from being fully known and explained. Comparative genomics is able to determine variations in genomic sequence that may provide functional information to better understand species-specific adaptations. A large number of human-specific genomic variations have been reported but no currently available dataset comprises all of these, a problem which contributes to hinder progress in the field. Results Here we critically update high confidence human-specific genomic variants that mostly associate with protein-coding regions and find 856 related genes. Events that create such human-specificity are mainly gene duplications, the emergence of novel gene regions and sequence and structural alterations. Functional analysis of these human-specific genes identifies adaptations to brain, immune and metabolic systems to be highly involved. We further show that many of these genes may be functionally associated with neural activity and generating the expanded human cortex in dynamic spatial and temporal contexts. Conclusions This comprehensive study contributes to the current knowledge by considerably updating the number of human-specific genes following a critical bibliographic survey. Human-specific genes were functionally assessed for the first time to such extent, thus providing unique information. Our results are consistent with environmental changes, such as immune challenges and alterations in diet, as well as neural sophistication, as significant contributors to recent human evolution.

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Evolution of Human Brain Size-Associated NOTCH2NL Genes Proceeds toward Reduced Protein Levels

Molecular Biology and Evolution ◽

10.1093/molbev/msaa104 ◽

2020 ◽

Vol 37 (9) ◽

pp. 2531-2548

Author(s):

Gerrald A Lodewijk ◽

Diana P Fernandes ◽

Iraklis Vretzakis ◽

Jeanne E Savage ◽

Frank M J Jacobs

Keyword(s):

Human Brain ◽

Brain Size ◽

Modern Human ◽

Copy Number Variations ◽

Optimal Dosage ◽

Protein Coding ◽

Protein Levels ◽

Human Genomes ◽

Coding Variants ◽

Human Specific

Abstract Ever since the availability of genomes from Neanderthals, Denisovans, and ancient humans, the field of evolutionary genomics has been searching for protein-coding variants that may hold clues to how our species evolved over the last ∼600,000 years. In this study, we identify such variants in the human-specific NOTCH2NL gene family, which were recently identified as possible contributors to the evolutionary expansion of the human brain. We find evidence for the existence of unique protein-coding NOTCH2NL variants in Neanderthals and Denisovans which could affect their ability to activate Notch signaling. Furthermore, in the Neanderthal and Denisovan genomes, we find unusual NOTCH2NL configurations, not found in any of the modern human genomes analyzed. Finally, genetic analysis of archaic and modern humans reveals ongoing adaptive evolution of modern human NOTCH2NL genes, identifying three structural variants acting complementary to drive our genome to produce a lower dosage of NOTCH2NL protein. Because copy-number variations of the 1q21.1 locus, encompassing NOTCH2NL genes, are associated with severe neurological disorders, this seemingly contradicting drive toward low levels of NOTCH2NL protein indicates that the optimal dosage of NOTCH2NL may have not yet been settled in the human population.

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Effects of Maternal Obesity and Gestational Diabetes Mellitus on the Placenta: Current Knowledge and Targets for Therapeutic Interventions

Current Vascular Pharmacology ◽

10.2174/1570161118666200616144512 ◽

2020 ◽

Vol 19 (2) ◽

pp. 176-192

Author(s):

Samantha Bedell ◽

Janine Hutson ◽

Barbra de Vrijer ◽

Genevieve Eastabrook

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Maternal Obesity ◽

Environmental Changes ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Placental Development ◽

Exchange Site ◽

And Function

: Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development as well as metabolic and cardiovascular abnormalities in the offspring. This review aims to summarize current knowledge on the effects of obesity and GDM on placental development and function. Understanding these processes is key in developing therapeutic interventions with the goal of mitigating these effects and preventing future cardiovascular and metabolic pathology in subsequent generations.

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Pan-American Lancehead Pit-Vipers: Coagulotoxic Venom Effects and Antivenom Neutralisation of Bothrops asper and B. atrox Geographical Variants

Toxins ◽

10.3390/toxins13020078 ◽

2021 ◽

Vol 13 (2) ◽

pp. 78

Author(s):

Lachlan A. Bourke ◽

Christina N. Zdenek ◽

Edgar Neri-Castro ◽

Melisa Bénard-Valle ◽

Alejandro Alagón ◽

...

Keyword(s):

Evolutionary Biology ◽

Current Knowledge ◽

Clinical Manifestations ◽

In Vivo Studies ◽

Factor X ◽

Clotting Factors ◽

Bothrops Asper ◽

Species Specific

The toxin composition of snake venoms and, thus, their functional activity, can vary between and within species. Intraspecific venom variation across a species’ geographic range is a major concern for antivenom treatment of envenomations, particularly for countries like French Guiana that lack a locally produced antivenom. Bothrops asper and Bothrops atrox are the most medically significant species of snakes in Latin America, both producing a variety of clinical manifestations, including systemic bleeding. These pathophysiological actions are due to the activation by the venom of the blood clotting factors Factor X and prothrombin, thereby causing severe consumptive coagulopathy. Both species are extremely wide-ranging, and previous studies have shown their venoms to exhibit regional venom variation. In this study, we investigate the differential coagulotoxic effects on human plasma of six venoms (four B. asper and two B. atrox samples) from different geographic locations, spanning from Mexico to Peru. We assessed how the venom variation of these venom samples affects neutralisation by five regionally available antivenoms: Antivipmyn, Antivipmyn-Tri, PoliVal-ICP, Bothrofav, and Soro Antibotrópico (SAB). The results revealed both inter- and intraspecific variations in the clotting activity of the venoms. These variations in turn resulted in significant variation in antivenom efficacy against the coagulotoxic effects of these venoms. Due to variations in the venoms used in the antivenom production process, antivenoms differed in their species-specific or geographical neutralisation capacity. Some antivenoms (PoliVal-ICP, Bothrofav, and SAB) showed species-specific patterns of neutralisation, while another antivenom (Antivipmyn) showed geographic-specific patterns of neutralisation. This study adds to current knowledge of Bothrops venoms and also illustrates the importance of considering evolutionary biology when developing antivenoms. Therefore, these results have tangible, real-world implications by aiding evidence-based design of antivenoms for treatment of the envenomed patient. We stress that these in vitro studies must be backed by future in vivo studies and clinical trials before therapeutic guidelines are issued regarding specific antivenom use in a clinical setting.

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Seminal Plasma: Relevant for Fertility?

International Journal of Molecular Sciences ◽

10.3390/ijms22094368 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4368

Author(s):

Heriberto Rodriguez-Martinez ◽

Emilio A. Martinez ◽

Juan J. Calvete ◽

Fernando J. Peña Vega ◽

Jordi Roca

Keyword(s):

Seminal Plasma ◽

Current Knowledge ◽

Inorganic Ions ◽

Vitro Fertilization ◽

Dna And Rna ◽

Model Animal ◽

Sexual Glands ◽

Species Specific

Seminal plasma (SP), the non-cellular component of semen, is a heterogeneous composite fluid built by secretions of the testis, the epididymis and the accessory sexual glands. Its composition, despite species-specific anatomical peculiarities, consistently contains inorganic ions, specific hormones, proteins and peptides, including cytokines and enzymes, cholesterol, DNA and RNA—the latter often protected within epididymis- or prostate-derived extracellular vesicles. It is beyond question that the SP participates in diverse aspects of sperm function pre-fertilization events. The SP also interacts with the various compartments of the tubular genital tract, triggering changes in gene function that prepares for an eventual successful pregnancy; thus, it ultimately modulates fertility. Despite these concepts, it is imperative to remember that SP-free spermatozoa (epididymal or washed ejaculated) are still fertile, so this review shall focus on the differences between the in vivo roles of the SP following semen deposition in the female and those regarding additions of SP on spermatozoa handled for artificial reproduction, including cryopreservation, from artificial insemination to in vitro fertilization. This review attempts, including our own results on model animal species, to critically summarize the current knowledge of the reproductive roles played by SP components, particularly in our own species, which is increasingly affected by infertility. The ultimate goal is to reconcile the delicate balance between the SP molecular concentration and their concerted effects after temporal exposure in vivo. We aim to appraise the functions of the SP components, their relevance as diagnostic biomarkers and their value as eventual additives to refine reproductive strategies, including biotechnologies, in livestock models and humans.

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Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

Nature Communications ◽

10.1038/s41467-021-22262-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zhongbo Chen ◽

◽

David Zhang ◽

Regina H. Reynolds ◽

Emil K. Gustavsson ◽

...

Keyword(s):

Neurological Diseases ◽

Purifying Selection ◽

Whole Genome Sequencing Data ◽

Human Lineage ◽

Sequencing Data ◽

Protein Coding ◽

Potential Association ◽

High Depth ◽

Specific Sequences ◽

Human Specific

AbstractKnowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer’s disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease.

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Conserved long-range base pairings are associated with pre-mRNA processing of human genes

Nature Communications ◽

10.1038/s41467-021-22549-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Svetlana Kalmykova ◽

Marina Kalinina ◽

Stepan Denisov ◽

Alexey Mironov ◽

Dmitry Skvortsov ◽

...

Keyword(s):

Long Range ◽

Rna Folding ◽

Current Knowledge ◽

Rna Structures ◽

Base Pairs ◽

Protein Coding ◽

Proximity Ligation ◽

Transcriptional Suppression ◽

Human Genes ◽

Cleavage And Polyadenylation

AbstractThe ability of nucleic acids to form double-stranded structures is essential for all living systems on Earth. Current knowledge on functional RNA structures is focused on locally-occurring base pairs. However, crosslinking and proximity ligation experiments demonstrated that long-range RNA structures are highly abundant. Here, we present the most complete to-date catalog of conserved complementary regions (PCCRs) in human protein-coding genes. PCCRs tend to occur within introns, suppress intervening exons, and obstruct cryptic and inactive splice sites. Double-stranded structure of PCCRs is supported by decreased icSHAPE nucleotide accessibility, high abundance of RNA editing sites, and frequent occurrence of forked eCLIP peaks. Introns with PCCRs show a distinct splicing pattern in response to RNAPII slowdown suggesting that splicing is widely affected by co-transcriptional RNA folding. The enrichment of 3’-ends within PCCRs raises the intriguing hypothesis that coupling between RNA folding and splicing could mediate co-transcriptional suppression of premature pre-mRNA cleavage and polyadenylation.

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Link Between Short tandem Repeats and Translation Initiation Site Selection

10.1101/316950 ◽

2018 ◽

Author(s):

M Arabfard ◽

K Kavousi ◽

A Delbari ◽

M Ohadi

Keyword(s):

Amino Acids ◽

Translation Initiation ◽

Short Tandem Repeats ◽

Tandem Repeats ◽

Initiation Site ◽

Translation Initiation Site ◽

Vertebrate Species ◽

Protein Coding ◽

Human Specific ◽

Short Tandem

AbstractRecent work in yeast and humans suggest that evolutionary divergence in cis-regulatory sequences impact translation initiation sites (TISs). Cis-elements can also affect the efficacy and amount of protein synthesis. Despite their vast biological implication, the landscape and relevance of short tandem repeats (STRs)/microsatellites to the human protein-coding gene TISs remain largely unknown. Here we characterized the STR distribution at the 120 bp cDNA sequence upstream of all annotated human protein-coding gene TISs based on the Ensembl database. Furthermore, we performed a comparative genomics study of all annotated orthologous TIS-flanking sequences across 47 vertebrate species (755,956 transcripts), aimed at identifying human-specific STRs in this interval. We also hypothesized that STRs may be used as genetic codes for the initiation of translation. The initial five amino acid sequences (excluding the initial methionine) that were flanked by STRs in human were BLASTed against the initial orthologous five amino acids in other vertebrate species (2,025,817 pair-wise TIS comparisons) in order to compare the number of events in which human-specific and non-specific STRs occurred with homologous and non-homologous TISs (i.e. ≥50% and <50% similarity of the five amino acids). We characterized human-specific STRs and a bias of this compartment in comparison to the overall (human-specific and non-specific) distribution of STRs (Mann Whitney p=1.4 × 10−11). We also found significant enrichment of non-homologous TISs flanked by human-specific STRs (p<0.00001). In conclusion, our data indicate a link between STRs and TIS selection, which is supported by differential evolution of the human-specific STRs in the TIS upstream flanking sequence.AbbreviationscDNAComplementary DNACDSCoding DNA sequenceSTRShort Tandem RepeatTISTranslation Initiation SiteTSSTranscription Start Site

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Implication of the Identification of an Earlier Pseudorabies Virus (PRV) Strain HLJ-2013 to the Evolution of Chinese PRVs

Frontiers in Microbiology ◽

10.3389/fmicb.2020.612474 ◽

2020 ◽

Vol 11 ◽

Author(s):

Huimin Liu ◽

Zhibin Shi ◽

Chunguo Liu ◽

Pengfei Wang ◽

Ming Wang ◽

...

Keyword(s):

Phylogenetic Trees ◽

Pseudorabies Virus ◽

High Throughput Sequencing ◽

Genomic Sequence ◽

Full Genome Sequence ◽

Genome Sequences ◽

Protein Coding ◽

One Step ◽

Human Infections ◽

Full Length Genome

Pseudorabies viruses (PRVs) pose a great threat to the pig industry of many countries around the world. Human infections with PRV have also been reported occasionally in China. Therefore, understanding the epidemiology and evolution of PRVs is of great importance for disease control in the pig populations and humans as well. In this study, we isolated a PRV designated HLJ-2013 from PRV-positive samples that had been collected in Heilongjiang, China, in 2013. The full genome sequence of the virus was determined to be ∼143 kbp in length using high-throughput sequencing. The genomic sequence identities between this isolate and 21 other previous PRV isolates ranged from 92.4% (with Bartha) to 97.3% (with SC). Phylogenetic analysis based on the full-length genome sequences revealed that PRV HLJ-2013 clustered together with all the Chinese strains in one group belonging to Genotype II, but this virus occurred phylogenetically earlier than all the other Chinese PRV strains. Phylogenetic trees based on both protein-coding genes and non-coding regions revealed that HLJ-2013 probably obtained its genome sequences from three origins: a yet unknown parent virus, the European viruses, and the same ancestor of all Chinese PRVs. Recombination analysis showed that HLJ-2013-like virus possibly donated the main framework of the genome of the Chinese PRVs. HLJ-2013 exhibited cytopathic and growth characteristics similar to that of the Chinese PRV strains SC and HeN1, but its pathogenicity in mice was higher than that of SC and lower than that of HeN1. The identification of HLJ-2013 takes us one step closer to understanding the origin of PRVs in China and provides new knowledge about the evolution of PRVs worldwide.

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Emerging Roles of Long Non-Coding RNAs as Drivers of Brain Evolution

Cells ◽

10.3390/cells8111399 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1399 ◽

Cited By ~ 11

Author(s):

Geraldine Zimmer-Bensch

Keyword(s):

Human Brain ◽

Cognitive Abilities ◽

Brain Size ◽

Expression Patterns ◽

Brain Evolution ◽

Relative Volume ◽

Structural Reorganization ◽

Protein Coding ◽

Human Brain Evolution ◽

Transcriptional Regulatory

Mammalian genomes encode tens of thousands of long-noncoding RNAs (lncRNAs), which are capable of interactions with DNA, RNA and protein molecules, thereby enabling a variety of transcriptional and post-transcriptional regulatory activities. Strikingly, about 40% of lncRNAs are expressed specifically in the brain with precisely regulated temporal and spatial expression patterns. In stark contrast to the highly conserved repertoire of protein-coding genes, thousands of lncRNAs have newly appeared during primate nervous system evolution with hundreds of human-specific lncRNAs. Their evolvable nature and the myriad of potential functions make lncRNAs ideal candidates for drivers of human brain evolution. The human brain displays the largest relative volume of any animal species and the most remarkable cognitive abilities. In addition to brain size, structural reorganization and adaptive changes represent crucial hallmarks of human brain evolution. lncRNAs are increasingly reported to be involved in neurodevelopmental processes suggested to underlie human brain evolution, including proliferation, neurite outgrowth and synaptogenesis, as well as in neuroplasticity. Hence, evolutionary human brain adaptations are proposed to be essentially driven by lncRNAs, which will be discussed in this review.

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Evolving evidence on a link between the ZMYM3 exceptionally long GA-STR and human cognition

Scientific Reports ◽

10.1038/s41598-020-76461-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

H. Afshar ◽

S. Khamse ◽

F. Alizadeh ◽

A. Delbari ◽

R. Najafipour ◽

...

Keyword(s):

Late Onset ◽

Selective Advantage ◽

Human Cognition ◽

Control Group ◽

Protein Coding ◽

Allele Distribution ◽

Specific Formula ◽

Cognition Impairment ◽

Male Subjects ◽

Human Specific

Abstract The human X-linked zinc finger MYM-type protein 3 (ZMYM3) contains the longest GA-STR identified across protein-coding gene 5′ UTR sequences, at 32-repeats. This exceptionally long GA-STR is located at a complex string of GA-STRs with a human-specific formula across the complex as follows: (GA)8-(GA)4-(GA)6-(GA)32 (ZMYM3-207 ENST00000373998.5). ZMYM3 was previously reported among the top three genes involved in the progression of late-onset Alzheimer’s disease. Here we sequenced the ZMYM3 GA-STR complex in 750 human male subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 268) and matched controls (n = 482). We detected strict monomorphism of the GA-STR complex, except of the exceptionally long STR, which was architecturally skewed in respect of allele distribution between the NCD cases and controls [F (1, 50) = 12.283; p = 0.001]. Moreover, extreme alleles of this STR at 17, 20, 42, and 43 repeats were detected in seven NCD patients and not in the control group (Mid-P exact = 0.0003). A number of these alleles overlapped with alleles previously found in schizophrenia and bipolar disorder patients. In conclusion, we propose selective advantage for the exceptional length of the ZMYM3 GA-STR in human, and its link to a spectrum of diseases in which major cognition impairment is a predominant phenotype.

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