Human Genome Evolution Research Articles

Sources of gene expression variation in a globally diverse human cohort.

Genetic variation that influences gene expression and splicing is a key source of phenotypic diversity1-5. Although invaluable, studies investigating these links in humans have been strongly biased towards participants of European ancestries, which constrains generalizability and hinders evolutionary research. Here to address these limitations, we developed MAGE, an open-access RNA sequencing dataset of lymphoblastoid cell lines from 731 individuals from the 1000 Genomes Project6, spread across 5 continental groups and 26 populations. Most variation in gene expression (92%) and splicing (95%) was distributed within versus between populations, which mirrored the variation in DNA sequence. We mapped associations between genetic variants and expression and splicing of nearby genes (cis-expression quantitative trait loci (eQTLs) and cis-splicing QTLs (sQTLs), respectively). We identified more than 15,000 putatively causal eQTLs and more than 16,000 putatively causal sQTLs that are enriched for relevant epigenomic signatures. These include 1,310 eQTLs and 1,657 sQTLs that are largely private to underrepresented populations. Our data further indicate that the magnitude and direction of causal eQTL effects are highly consistent across populations. Moreover, the apparent 'population-specific' effects observed in previous studies were largely driven by low resolution or additional independent eQTLs of the same genes that were not detected. Together, our study expands our understanding of human gene expression diversity and provides an inclusive resource for studying the evolution and function of human genomes.

Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms

Alternative splicing events are a major causal mechanism for complex traits, but they have been understudied due to the limitation of short-read sequencing. Here, we generate a full-length isoform annotation of human immune cells from an individual by long-read sequencing for 29 cell subsets. This contains a number of unannotated transcripts and isoforms such as a read-through transcript of TOMM40-APOE in the Alzheimer’s disease locus. We profile characteristics of isoforms and show that repetitive elements significantly explain the diversity of unannotated isoforms, providing insight into the human genome evolution. In addition, some of the isoforms are expressed in a cell-type specific manner, whose alternative 3’-UTRs usage contributes to their specificity. Further, we identify disease-associated isoforms by isoform switch analysis and by integration of several quantitative trait loci analyses with genome-wide association study data. Our findings will promote the elucidation of the mechanism of complex diseases via alternative splicing.

LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons

The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits. Here, we report that the hominid-specific gene LRRC37B encodes a receptor expressed in human cortical pyramidal neurons (CPNs) and selectively localized to the axon initial segment (AIS), the subcellular compartment triggering action potentials. Ectopic expression of LRRC37B in mouse CPNs invivo leads to reduced intrinsic excitability, a distinctive feature of some classes of human CPNs. Molecularly, LRRC37B binds to the secreted ligand FGF13A and to the voltage-gated sodium channel (Nav) β-subunit SCN1B. LRRC37B concentrates inhibitory effects of FGF13A on Nav channel function, thereby reducing excitability, specifically at the AIS level. Electrophysiological recordings in adult human cortical slices reveal lower neuronal excitability in human CPNs expressing LRRC37B. LRRC37B thus acts as a species-specific modifier of human neuron excitability, linking human genome and cell evolution, with important implications for human brain function and diseases.

Human Endogenous Retrovirus-K (HML-2)-Related Genetic Variation: Human Genome Diversity and Disease.

Human endogenous retroviruses (HERVs) comprise a significant portion of the human genome, making up roughly 8%, a notable comparison to the 2-3% represented by coding sequences. Numerous studies have underscored the critical role and importance of HERVs, highlighting their diverse and extensive influence on the evolution of the human genome and establishing their complex correlation with various diseases. Among HERVs, the HERV-K (HML-2) subfamily has recently attracted significant attention, integrating into the human genome after the divergence between humans and chimpanzees. Its insertion in the human genome has received considerable attention due to its structural and functional characteristics and the time of insertion. Originating from ancient exogenous retroviruses, these elements succeeded in infecting germ cells, enabling vertical transmission and existing as proviruses within the genome. Remarkably, these sequences have retained the capacity to form complete viral sequences, exhibiting activity in transcription and translation. The HERV-K (HML-2) subfamily is the subject of active debate about its potential positive or negative effects on human genome evolution and various pathologies. This review summarizes the variation, regulation, and diseases in human genome evolution arising from the influence of HERV-K (HML-2).

PhaseDancer: a novel targeted assembler of segmental duplications unravels the complexity of the human chromosome 2 fusion going from 48 to 46 chromosomes in hominin evolution

Resolving complex genomic regions rich in segmental duplications (SDs) is challenging due to the high error rate of long-read sequencing. Here, we describe a targeted approach with a novel genome assembler PhaseDancer that extends SD-rich regions of interest iteratively. We validate its robustness and efficiency using a golden-standard set of human BAC clones and in silico-generated SDs with predefined evolutionary scenarios. PhaseDancer enables extension of the incomplete complex SD-rich subtelomeric regions of Great Ape chromosomes orthologous to the human chromosome 2 (HSA2) fusion site, informing a model of HSA2 formation and unravelling the evolution of human and Great Ape genomes.

SNP-based Computational Analysis Reveals Recombination-associated Genome Evolution in Humans

Background: Meiotic recombination is an important source of genetic variation, but how recombination shapes the genome is not clearly understood yet. Objective: Here, we investigate the roles of recombination on human genome evolution from two aspects: How does recombination shape single nucleotide polymorphism (SNP)-related genomic variation features? Whether recombination drives genome evolution through a neighbor-dependent mutational bias? Methods: We analyzed the relationship of recombination rate with mutational bias and selection effect at SNP sites derived from the 1000 Genomes Project. Results: Our results show that SNP density, Ts/Tv, nucleotide diversity, and Tajima's D were positively correlated with the recombination rate, while Ka/Ks were negatively correlated with the recombination rate. Moreover, compared with non-coding regions, gene exonic regions have lower nucleotide diversity but higher Tajima's D, suggesting that coding regions are subject to stronger negative selection but have fewer rare alleles. Gene set enrichment analysis of the protein-coding genes with extreme Ka/Ks ratio implies that under the effect of high recombination rates, the genes involved in the cell cycle, RNA processing, and oocyte meiosis are subject to strong negative selection. Our data also support S (G or C) > W (A or T) mutational bias and W>S fixation bias in high recombination regions. In addition, the neighbor-dependent mutational bias was found to be stronger at high recombination regions. Conclusion: Our data suggest that genetic variation patterns, particularly the neighbor-dependent mutational bias at SNP sites in the human genome, are mediated by recombination.

HiSV: A control-free method for structural variation detection from Hi-C data.

Structural variations (SVs) play an essential role in the evolution of human genomes and are associated with cancer genetics and rare disease. High-throughput chromosome capture (Hi-C) technology probed all genome-wide crosslinked chromatin to study the spatial architecture of chromosomes. Hi-C read pairs can span megabases, making the technology useful for detecting large-scale SVs. So far, the identification of SVs from Hi-C data is still in the early stages with only a few methods available. Especially, no algorithm has been developed that can detect SVs without control samples. Therefore, we developed HiSV (Hi-C for Structural Variation), a control-free method for identifying large-scale SVs from a Hi-C sample. Inspired by the single image saliency detection model, HiSV constructed a saliency map of interaction frequencies and extracted saliency segments as large-scale SVs. By evaluating both simulated and real data, HiSV not only detected all variant types, but also achieved a higher level of accuracy and sensitivity than existing methods. Moreover, our results on cancer cell lines showed that HiSV effectively detected eight complex SV events and identified two novel SVs of key factors associated with cancer development. Finally, we found that integrating the result of HiSV helped the WGS method to identify a total number of 94 novel SVs in two cancer cell lines.

Global Distribution and Natural Recombination of Hepatitis D Virus: Implication of Kyrgyzstan Emerging HDVs in the Clinical Outcomes.

Discrepancies in human hepatitis delta virus (HDV) genotypes impact the virus’ biological behavior, clinical manifestation, and treatment response. Herein, this report aims to explore the role of recombination in the worldwide genotypic distribution and genetic diversity of HDV. Three-hundred-forty-eight human HDV full-length genomic sequences of ~1678 nt in length, isolated in twenty-eight countries worldwide between 1986 and 2018, were analysed. Similarity analysis and recombination mapping were performed, and forty-eight recombination events were identified, twenty-nine of which were isolated from Kyrgyzstan and determined to be involved in the diversity and extension of HDV sub-genotypes. HDV recombination occurred only between the genetically close genotypes (genotype 5 and genotype 2) or mainly within genotype 1, suggesting the complex replicative molecular mechanisms of HDV-RNA. The global distribution and classification of HDV genotypes have been updated, indicating that HDV recombination is one of the driving forces behind the biodiversity and the evolution of human HDV genomes. The outcome analysis suggests that the expansion of HDV sub-genotypes and the complex recombination networks might be related to the genomic character of Kyrgyzstan circulating strains and extensive mobility within countries and across borders. These findings will be of great importance in formulating more effective public health HDV surveillance strategies and guiding future molecular and epidemiological research to achieve better clinical outcomes.

Comprehensive In Silico Analysis of Retrotransposon Insertions within the Survival Motor Neuron Genes Involved in Spinal Muscular Atrophy.

Simple SummaryTransposable elements are DNA sequences that can move throughout the genome. They play essential roles in gene regulation and function. Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality worldwide. Since transposable elements have been linked to other genetic diseases, we examined the genomes from SMA patients as well as healthy genomes for the presence of transposable elements. We identified distinct transposable elements that may impact gene expression by affecting promoter activity or transcriptional termination of the SMN genes. These elements within the SMA genes may play key roles in understanding this early-onset neurodegenerative disease as well as how transposable elements can impact gene expression. Understanding the roles of transposable elements in SMA may provide key insights into other neurodegenerative diseases.Transposable elements (TEs) are interspersed repetitive and mobile DNA sequences within the genome. Better tools for evaluating TE-derived sequences have provided insights into the contribution of TEs to human development and disease. Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease that is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene but retention of its nearly perfect orthologue SMN2. Both genes are highly enriched in TEs. To establish a link between TEs and SMA, we conducted a comprehensive, in silico analysis of TE insertions within the SMN1/2 loci of SMA, carrier and healthy genomes. We found an Alu insertion in the promoter region and one L1 element in the 3′UTR that may play an important role in alternative promoter as well as in alternative transcriptional termination. Additionally, several intronic Alu repeats may influence alternative splicing via RNA circularization and causes the presence of new alternative exons. These Alu repeats present throughout the genes are also prone to recombination events that could lead to SMN1 exons deletions and, ultimately, SMA. TE characterization of the SMA genomic region could provide for a better understanding of the implications of TEs on human disease and genomic evolution.

De novo deletions and duplications at recombination hotspots in mouse germlines

Numerous DNA double-strand breaks (DSBs) arise during meiosis to initiate homologous recombination. These DSBs are usually repaired faithfully, but here, we uncover a distinct type of mutational event in which deletions form via joining of ends from two closely spaced DSBs (double cuts) within a single hotspot or at adjacent hotspots on the same or different chromatids. Deletions occur in normal meiosis but are much more frequent when DSB formation is dysregulated in the absence of the ATM kinase. Events between chromosome homologs point to multi-chromatid damage and aborted gap repair. Some deletions contain DNA from other hotspots, indicating that double cutting at distant sites creates substrates for insertional mutagenesis. End joining at double cuts can also yield tandem duplications or extrachromosomal circles. Our findings highlight the importance of DSB regulation and reveal a previously hidden potential for meiotic mutagenesis that is likely to affect human health and genome evolution.

Reconstruction of human genome evolution in yeast: an educational primer for use with "systematic humanization of the yeast cytoskeleton discerns functionally replaceable from divergent human genes".

The evolution of eukaryotic organisms starting with the last eukaryotic common ancestor was accompanied by lineage-specific expansion of gene families. A paper by Garge et al. provides an excellent opportunity to have students explore how expansion of gene families via gene duplication results in protein specialization, in this case in the context of eukaryotic cytoskeletal organization . The authors tested hypotheses about conserved protein function by systematic "humanization" of the yeast cytoskeletal components while employing a wide variety of methodological approaches. We outline several exercises to promote students' ability to explore the genomic databases, perform bioinformatic analyses, design experiments for functional analysis of human genes in yeast and critically interpret results to address both specific and general questions.

Tautopathy - An Effective Treatment for Drug Induced Diseases

Tautopathy is a term, used to denote the application of a drug prepared in homoeopathic potency for the same condition or syndrome, which is caused by the crude version of the identical drug. There have been many evidences among research studies, in support of Tautopathy, proving it to be efficacious in removing toxicological effects of the drug. With the advancement in biological and scientific experiments, there has been a substantial increment in the exposure of various chemicals and radiations to our body, which led to one of the major causes of chronic health diseases. To combat these, a system of medicine is required. Tautopathy is one such system that provides treatment by the similimum for toxicological effects of the drugs. The side effects of various drugs was recognized even during the Hahnemann’s time, for which Nux vomica was advised to counter such effects. But due to the evolution of human genomes and subsequent discoveries of modern drugs, these previously advised homoeopathic antidotes are less effective. The allergies due to antibiotics should be treated by the law of similimum using the same drugs in potentised form that produced those allergies. Furthermore, drugs like cortisone and corticosterone only suppress the manifestations and also make the patients resistant to them. Hence a deep study on the subject poses a good scope for the management of iatrogenic diseases. Cases treated with homoeopathy and related researches make a better understanding about the efficacy of Tautopathy. Moreover, they help in gaining the knowledge regarding how to approach a patient, who was treated previously by modern drugs and now has become either allergic or resistant to it. In this article, various such references are being discussed along with the clinical researches supporting them.

Nucleosome positioning stability is a modulator of germline mutation rate variation across the human genome

Nucleosome organization has been suggested to affect local mutation rates in the genome. However, the lack of de novo mutation and high-resolution nucleosome data has limited the investigation of this hypothesis. Additionally, analyses using indirect mutation rate measurements have yielded contradictory and potentially confounding results. Here, we combine data on >300,000 human de novo mutations with high-resolution nucleosome maps and find substantially elevated mutation rates around translationally stable (‘strong’) nucleosomes. We show that the mutational mechanisms affected by strong nucleosomes are low-fidelity replication, insufficient mismatch repair and increased double-strand breaks. Strong nucleosomes preferentially locate within young SINE/LINE transposons, suggesting that when subject to increased mutation rates, transposons are then more rapidly inactivated. Depletion of strong nucleosomes in older transposons suggests frequent positioning changes during evolution. The findings have important implications for human genetics and genome evolution.

Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans

A detailed understanding of the genome-wide variability of single-nucleotide germline mutation rates is essential to studying human genome evolution. Here, we use ~36 million singleton variants from 3560 whole-genome sequences to infer fine-scale patterns of mutation rate heterogeneity. Mutability is jointly affected by adjacent nucleotide context and diverse genomic features of the surrounding region, including histone modifications, replication timing, and recombination rate, sometimes suggesting specific mutagenic mechanisms. Remarkably, GC content, DNase hypersensitivity, CpG islands, and H3K36 trimethylation are associated with both increased and decreased mutation rates depending on nucleotide context. We validate these estimated effects in an independent dataset of ~46,000 de novo mutations, and confirm our estimates are more accurate than previously published results based on ancestrally older variants without considering genomic features. Our results thus provide the most refined portrait to date of the factors contributing to genome-wide variability of the human germline mutation rate.

Mobile elements contribute to the uniqueness of human genome with 15,000 human-specific insertions and 14Mbp sequence increase.

Mobile elements (MEs) collectively contribute to at least 50% of the human genome. Due to their past incremental accumulation and ongoing DNA transposition, MEs serve as a significant source for both inter- and intra-species genetic and phenotypic diversity during primate and human evolution. By making use of the most recent genome sequences for human and many other closely related primates and robust multi-way comparative genomic approach, we identified a total of 14,870 human-specific MEs (HS-MEs) with more than 8,000 being newly identified. Collectively, these HS-MEs contribute to a total of 14.2 Mbp net genome sequence increase. Several new observations were made based on these HS-MEs, including the finding of Y chromosome as a strikingly hot target for HS-MEs and a strong mutual preference for SINE-R/VNTR/Alu (SVAs). Furthermore, ∼8,000 of these HS-MEs were found to locate in the vicinity of ∼4,900 genes, and collectively they contribute to ∼84 kb sequences in the human reference transcriptome in association with over 300 genes, including protein-coding sequences for 40 genes. In conclusion, our results demonstrate that MEs made a significant contribution to the evolution of human genome by participating in gene function in a human-specific fashion.

Abstract 2993: A switch in epigenetic silencing mechanisms of endogenous retroviruses during human genome evolution

Abstract Approximately 9% of the human genome is derived from Endogenous Retroviruses (ERVs), which are a type of transposable element. ERVs started to become integrated into the ancestral human genome about 100 million years ago. Recent studies have reported that silencing mechanisms of long terminal repeats regions (LTRs), which are the putative promoters of ERVs, depend on DNA methylation, heterochromatin conformation (H3K9me3) and the PRC2 complex (H3K27me3). However, extensive maps of LTR distribution and the associated epigenetic marks have not yet been provided in human cancer cells. Here we report a switch in epigenetic silencing mechanisms of the approximately 450,000 LTR elements present in the non-genic regions of human DNA. Total RNA-seq in human colon cancer HCT116 cells following DNA methylation inhibitor treatment or knockdown of individual H3K9me2/3 histone methyltransferases (G9a, SETDB1, SETDB2, SUV39H1 and SUV39H2), H3K27me3 (EZH2) or a scaffold protein TRIM28 revealed that about 1,000 of evolutionary young LTRs were predominantly silenced by DNA methylation, whereas about 800 of intermediate age LTRs were silenced by histone methylation. They therefore have undergone an “epigenetic switch” in silencing mechanism during host genome evolution. Eventually, evolutionary old LTRs become inactive by accumulation of loss-of-function mutations. Consistent with these results, CpG sites in evolutionary young LTRs were methylated at higher levels than in intermediate age LTRs, whereas H3K9me2 and H3K9me3 marks were enriched on intermediate age LTRs. Interestingly, knockdowns of EZH2 showed limited upregulation of LTRs by itself, but multiple LTRs were upregulated by combination treatment with DNA methylation inhibitor. This is probably due to a process, in which removal of DNA methylation leads to the subsequent recruitment of EZH2 resulting in suppression by the polycomb repressive complex PRC2. Our earlier studies showed that LTR expressions lead to activation of viral defense pathways and apoptosis, however the species of LTRs was not characterized. We found that the activation of viral defense pathway was correlated with the upregulation of evolutionary young, but not intermediate age LTRs. Dual inhibition of DNA methylation and histone modifications by knockdown of G9a, SUV39H1 and EZH2 showed further upregulation of evolutionary young LTRs. Therefore, combination treatment targeting DNA methylation and the histone methyltransferases (G9a, SUV39H1 and EZH2) inhibitor may be useful in epigenetic therapy for cancer patients. Citation Format: Hitoshi Ohtani, Minmin Liu, Wanding Zhou, Gangning Liang, Peter A. Jones. A switch in epigenetic silencing mechanisms of endogenous retroviruses during human genome evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2993.

Transposable elements, placental development, and oocyte activation: Cellular stress and AMPK links jumping genes with the creation of human life

Transposable elements (TEs), also known as “jumping genes”, are DNA sequences first described by Nobel laureate Barbara McClintock that comprise nearly half of the human genome and are able to transpose or move from one genomic location to another. As McClintock also noted that a genome “shock” or stress may induce TE activation and transposition, accumulating evidence suggests that cellular stress (e.g. mediated by increases in intracellular reactive oxygen species [ROS] and calcium [Ca2+], etc.) induces TE mobilization in several model organisms and L1s (a member of the retrotransposon class of TEs) are active and capable of retrotransposition in human oocytes, human sperm, and in human neural progenitor cells. Cellular stress also plays a critical role in human placental development, with cytotrophoblast (CTB) differentiation leading to the formation of the syncytiotrophoblast (STB), a cellular layer that facilitates nutrient and gas exchange between the mother and the fetus. Syncytin-1, a protein that promotes fusion of CTB cells and is necessary for STB formation, and its receptor is found in human sperm and human oocytes, respectively, and increases in ROS and Ca2+ promote trophoblast differentiation and syncytin-1 expression. Cellular stress is also essential in promoting human oocyte maturation and activation which, similar to TE mobilization, can be induced by compounds that increase intracellular Ca2+ and ROS levels. AMPK is a master metabolic regulator activated by increases in ROS, Ca2+, and/or an AMP(ADP)/ATP ratio increase, etc. as well as compounds that induce L1 mobilization in human cells. AMPK knockdown inhibits trophoblast differentiation and AMPK-activating compounds that promote L1 mobility also enhance trophoblast differentiation. Cellular stressors that induce TE mobilization (e.g. heat shock) also promote oocyte maturation in an AMPK-dependent manner and the antibiotic ionomycin activates AMPK, promotes TE activation, and induces human oocyte activation, producing normal, healthy children. Metformin promotes AMPK-dependent telomerase activation (critical for telomere maintenance) and induces activation of the endonuclease RAG1 (promotes DNA cleavage and transposition) via AMPK. Both RAG1 and telomerase are derived from TEs. It is our hypothesis that cellular stress and AMPK links TE activation and transposition with placental development and oocyte activation, facilitating both human genome evolution and the creation of all human life. We also propose the novel observation that various cellular stress-inducing compounds (e.g. metformin, resveratrol, etc.) may facilitate beneficial TE activation and transposition and enhance fertilization and embryological development through a common mechanism of AMPK activation.

Profiling of Human Molecular Pathways Affected by Retrotransposons at the Level of Regulation by Transcription Factor Proteins.

Endogenous retroviruses and retrotransposons also termed retroelements (REs) are mobile genetic elements that were active until recently in human genome evolution. REs regulate gene expression by actively reshaping chromatin structure or by directly providing transcription factor binding sites (TFBSs). We aimed to identify molecular processes most deeply impacted by the REs in human cells at the level of TFBS regulation. By using ENCODE data, we identified ~2 million TFBS overlapping with putatively regulation-competent human REs located in 5-kb gene promoter neighborhood (~17% of all TFBS in promoter neighborhoods; ~9% of all RE-linked TFBS). Most of REs hosting TFBS were highly diverged repeats, and for the evolutionary young (0–8% diverged) elements we identified only ~7% of all RE-linked TFBS. The gene-specific distributions of RE-linked TFBS generally correlated with the distributions for all TFBS. However, several groups of molecular processes were highly enriched in the RE-linked TFBS regulation. They were strongly connected with the immunity and response to pathogens, with the negative regulation of gene transcription, ubiquitination, and protein degradation, extracellular matrix organization, regulation of STAT signaling, fatty acids metabolism, regulation of GTPase activity, protein targeting to Golgi, regulation of cell division and differentiation, development and functioning of perception organs and reproductive system. By contrast, the processes most weakly affected by the REs were linked with the conservative aspects of embryo development. We also identified differences in the regulation features by the younger and older fractions of the REs. The regulation by the older fraction of the REs was linked mainly with the immunity, cell adhesion, cAMP, IGF1R, Notch, Wnt, and integrin signaling, neuronal development, chondroitin sulfate and heparin metabolism, and endocytosis. The younger REs regulate other aspects of immunity, cell cycle progression and apoptosis, PDGF, TGF beta, EGFR, and p38 signaling, transcriptional repression, structure of nuclear lumen, catabolism of phospholipids, and heterocyclic molecules, insulin and AMPK signaling, retrograde Golgi-ER transport, and estrogen signaling. The immunity-linked pathways were highly represented in both categories, but their functional roles were different and did not overlap. Our results point to the most quickly evolving molecular pathways in the recent and ancient evolution of human genome.

Sukkula retrotransposon movements in the human genome

ABSTRACTRetrotransposons, a subclass of mobile genetic elements, have been discovered in many organisms. In this study, we identified a plant-specific retrotransposon (Sukkula) in the human genome (24 different DNA samples) by using retrotransposon-based molecular marker technique: inter-retrotransposon amplified polymorphism. There were five different groups related to the ages of the subjects. The polymorphism ratios were 8%–100% among all samples, 10%–91% among females (12 subjects) and 13%–100% among males (12 subjects). Moreover, we also observed 8%–91% polymorphism ratios when comparing males to females. To the best of our knowledge, this is one of the first reports on plant-specific retrotransposons in the human genome. The obtained findings are expected to contribute to broadening the knowledge about plant retrotransposons in the human genome and their role in human genome evolution.

Human NDE1 splicing and mammalian brain development

Exploring genetic and molecular differences between humans and other close species may be the key to explain the uniqueness of our brain and the selective pressures under which it evolves. Recent discoveries unveiled the involvement of Nuclear distribution factor E-homolog 1 (NDE1) in human cerebral cortical neurogenesis and suggested a role in brain evolution; however the evolutionary changes involved have not been investigated. NDE1 has a different gene structure in human and mouse resulting in the production of diverse splicing isoforms. In particular, mouse uses the terminal exon 8 T, while Human uses terminal exon 9, which is absent in rodents. Through chimeric minigenes splicing assay we investigated the unique elements regulating NDE1 terminal exon choice. We found that selection of the terminal exon is regulated in a cell dependent manner and relies on gain/loss of splicing regulatory sequences across the exons. Our results show how evolutionary changes in cis as well as trans acting signals have played a fundamental role in determining NDE1 species specific splicing isoforms supporting the notion that alternative splicing plays a central role in human genome evolution, and possibly human cognitive predominance.